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  • 51.
    Isine Bolstad, Anne
    et al.
    University of Bergen.
    Le Hellard, Stephanie
    University of Bergen.
    Kristjansdottir, Gudlaug
    Uppsala University.
    Vasaitis, Lilian
    Uppsala University.
    Kvarnstrom, Marika
    Karolinska Institute.
    Sjöwall, Christoffer
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland.
    Joar Auglaend Johnsen, Svein
    Stavanger University Hospital.
    Eriksson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Njurmedicinska kliniken US.
    Omdal, Roald
    Stavanger University Hospital.
    Brun, Johan G
    University of Bergen.
    Wahren-Herlenius, Marie
    Karolinska Institute.
    Theander, Elke
    Lund University.
    Syvanen, Ann-Christine
    Uppsala University.
    Ronnblom, Lars
    Uppsala University.
    Nordmark, Gunnel
    Uppsala University.
    Jonsson, Roland
    University of Bergen.
    Association between genetic variants in the tumour necrosis factor/lymphotoxin alpha/lymphotoxin beta locus and primary Sjogrens syndrome in Scandinavian samples2012Ingår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 71, nr 6, s. 981-988Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objectives Lymphotoxin beta (LTB) has been found to be upregulated in salivary glands of patients with primary Sjogrens syndrome (pSS). An animal model of pSS also showed ablation of the lymphoid organisation and a marked improvement in salivary gland function on blocking the LTB receptor pathway. This study aimed to investigate whether single-nucleotide polymorphisms (SNP) in the lymphotoxin alpha (LTA)/LTB/tumour necrosis factor (TNF) gene clusters are associated with pSS. less thanbrgreater than less thanbrgreater thanMethods 527 pSS patients and 532 controls participated in the study, all of Caucasian origin from Sweden and Norway. 14 SNP markers were genotyped and after quality control filtering, 12 SNP were analysed for their association with pSS using single marker and haplotype tests, and corrected by permutation testing. less thanbrgreater than less thanbrgreater thanResults Nine markers showed significant association with pSS at the p=0.05 level. Markers rs1800629 and rs909253 showed the strongest genotype association (p=1.64E-11 and p=4.42E-08, respectively, after correcting for sex and country of origin). When the analysis was conditioned for the effect of rs1800629, only the association with rs909253 remained nominally significant (p=0.027). In haplotype analyses the strongest effect was observed for the haplotype rs909253G_rs1800629A (p=9.14E-17). The associations were mainly due to anti-Ro/SSA and anti-La/SSB antibody-positive pSS. less thanbrgreater than less thanbrgreater thanConclusions A strong association was found between several SNP in the LTA/LTB/TNF alpha locus and pSS, some of which led to amino acid changes. These data suggest a role for this locus in the development of pSS. Further studies are needed to examine if the genetic effect described here is independent of the known genetic association between HLA and pSS.

  • 52.
    Kanmert, Daniel
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Molekylär fysik. Linköpings universitet, Tekniska fakulteten.
    Enocsson, Helena
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Tekniska fakulteten.
    Wetterö, Jonas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet.
    Kastbom, Alf
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Medicincentrum, Länskliniken för Reumatologi i Östergötland.
    Skogh, Thomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Medicincentrum, Länskliniken för Reumatologi i Östergötland.
    Enander, Karin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Molekylär fysik. Linköpings universitet, Tekniska fakulteten.
    Designed Surface with Tunable IgG Density as an in Vitro Model for Immune Complex Mediated Stimulation of Leukocytes2010Ingår i: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 26, nr 5, s. 3493-3497Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We present the design of an in vitro for immune-complex-mediated stimulation of leukocytes and its functional characteristics with respect to monocyte adhesion. The model was based on orientation-controlled immobilization of a humanized IgG1 monoclonal antibody (rituximab) via its interaction with a biotinylated peptide epitope derived from the CD20 marker. The peptide was linked to neutravidin covalently attached to it mixed self-assembled monolayer of carboxyl- and methoxy-terminated oligo(ethylene glycol) alkane thiolates on gold. The surface adhesion propensity of human monocytes (cell line U917) was highly dependent on the lateral IgG density and indicated that there exists a distance between IgG-Fc on the surface where interactions with Fc gamma receptors are optimal. This well-defined platform allows for a careful control of the size and orientation of artificial IgG immune complexes, it is easily made compatible with, for example, cellular imaging, and it will become useful for in vitro studies on the importance of Fc gamma receptor interactions in chronic immune-mediated diseases.

  • 53.
    Kanmert, Daniel
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi. Linköpings universitet, Tekniska högskolan.
    Kastbom, Alf
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland.
    Almroth, Gunnel
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet.
    Skogh, Thomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland.
    Enander, Karin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Sensorvetenskap och Molekylfysik. Linköpings universitet, Tekniska högskolan.
    Wetterö, Jonas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet.
    IgG Rheumatoid Factor Against the Four Human Fc-gamma Subclasses in Early Rheumatoid Arthritis (the Swedish TIRA Project)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Rheumatoid factor (RF), i.e. a family of autoantibodies against the Fc part of IgG, is an important seromarker of rheumatoid arthritis (RA). Traditional particle agglutination without disclosing the antibody isotype remains the predominating diagnostic method in clinical routine. Although IgG-RF attracts pathogenic interest, its detection remains technically challenging. The present study aimed at developing a set of tests identifying IgG-RFs directed against the four IgG subclasses. IgG-RF against either subclass of human IgG-Fc were analyzed with four novel enzyme-linked immunosorbent assays (ELISAs) utilizing four recombinant human Fc-gamma fragments (hIgG1-4) as sources of antigen. Sera from 40 patients with recent-onset RA (20 seropositive and 20 seronegative by IgM-RF and IgA-RF-isotype specific ELISA) were analyzed. Sera from 20 healthy blood donors served as reference. Among the IgM-/IgA-RF positive RA-sera, IgG-RF was found directed against hIgG1, hIgG4, and most notably, with strikingly high reactivity against hIgG2, but not hIgG3. Significant correlations were seen between IgG-RF against hIgG2-Fc and IgA-RF (r = 0.513) and IgM-RF (r = 0.736) levels. Further prospective studies are warranted to elucidate any correlation to disease course and outcome.

  • 54.
    Kanmert, Daniel
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Molekylär fysik. Linköpings universitet, Tekniska fakulteten.
    Kastbom, Alf
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland.
    Almroth, Gunnel
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet.
    Skogh, Thomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland.
    Enander, Karin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Molekylär fysik. Linköpings universitet, Tekniska fakulteten.
    Wetterö, Jonas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet.
    IgG Rheumatoid Factors Against the Four Human Fc-gamma Subclasses in Early Rheumatoid Arthritis (The Swedish TIRA Project)2012Ingår i: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 75, nr 1, s. 115-119Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Rheumatoid factor (RF), i.e. a family of autoantibodies against the Fc part of IgG, is an important seromarker of rheumatoid arthritis (RA). Traditional particle agglutination without disclosing the antibody isotype remains the predominating diagnostic method in clinical routine. Although IgG-RF attracts pathogenic interest, its detection remains technically challenging. The present study aimed at developing a set of tests identifying IgG-RFs directed against the four IgG subclasses. IgG-RF against either subclass of human IgG-Fc were analysed with four novel enzyme-linked immunosorbent assays (ELISAs) utilizing four recombinant human Fc-gamma fragments (hIgG14) as sources of antigen. Sera from 40 patients with recent onset RA (20 seropositive and 20 seronegative by IgM-RF and IgA-RF-isotype-specific ELISA) were analysed. Sera from 20 healthy blood donors served as reference. Among the IgM-/IgA-RF-positive RA-sera, IgG-RF was found directed against hIgG1 and hIgG2, but not against hIgG3 or hIgG4. Significant correlations were seen between IgG-RF against hIgG2-Fc and IgM-RF (r = 0.666) levels. Further prospective studies are warranted to elucidate any correlation to disease course and outcome.

  • 55.
    Kastbom, Alf
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Medicincentrum, Länskliniken för Reumatologi i Östergötland.
    Autoantibodies and genetic variation in rheumatoid arthritis: aspects on susceptibility and disease course2007Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and subsequent destruction of synovial joints. Although its causes remain largely unknown, a substantial genetic contribution is known to exist. During the last decades the benefits of early aggressive treatment have become evident, and more potent therapeutic options have become available. These advances have increased the demands for rapid accurate diagnosis and prognostic markers of disease course and therapy response.

    The ‘rheumatoid factor’ (RF) has long been used as a diagnostic and prognostic marker of RA. In this thesis, the utility of measuring antibodies to cyclic citrullinated peptides (CCP) was investigated. In a population-based arthritis incidence study, 69 very early arthritis patients (symptom duration < 3 months) were identified. The anti-CCP test, performed at baseline and related to diagnosis at the 2-year follow-up, had a diagnostic specificity for RA of 96% and a sensitivity of 44%, both of which were superior to RF. In a prospective cohort of 242 incident cases of RA (symptom duration < 1 year), 64% of the patients tested positive for anti-CCP at baseline (equal to RF). Despite receiving more active anti-rheumatic therapy, the anti-CCP-positive patients had a more aggressive disease course during 3 years as compared to those testing negative.

    The 158VV genotype of Fcγ Receptor type IIIA (FcγRIIIA), which binds IgG with higher affinity than 158FF, was associated with an increased susceptibility to RA in men, but not in women. Previous studies report conflicting results, and none stratified according to gender. The 158V/F polymorphism of FcγRIIIA was not found to influence outcome of anti-tumour necrosis factor therapy in 282 RA patients, contradicting hints from previous studies. Genetic variation in proteins of the inflammasome, an interleukin-1 (IL-1) regulating intracellular protein complex, is associated with rare autoinflammatory conditions and possibly with Crohn’s disease. In this first study on genetic variation of the inflammasome in RA, we describe a compound polymorphism of the genes CIAS1 and TUCAN that associates both with susceptibility to RA and to the severity of the disease. Hypothetically, these genes may identify a subgroup of RA patients that would benefit from anti-IL-1 therapy.

    This thesis work emphasizes the benefits of testing for anti-CCP in the diagnosis and outcome prediction in early arthritis. FcγRIIIA genotype is likely to affect RA susceptibility and further work should apply a gender perspective. Inflammasome genetics may influence the risk of developing RA. Additional studies are warranted to settle whether it also identifies a subgroup of RA patients benefiting from IL-1 targeted therapy.

  • 56.
    Kastbom, Alf
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet.
    Ahmadi, Ahmad
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Skogh, Thomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet.
    The 158V polymorphism of Fc gamma receptor type IIIA in early rheumatoid arthritis: increased susceptibility and severity in male patients (the Swedish TIRA project)2005Ingår i: Rheumatology, ISSN 1462-0324, Vol. 44, nr 10, s. 1294-1298Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objectives. To evaluate the influence of Fc receptor IIIA (FcRIIIA) 158V/F polymorphism on susceptibility and disease severity in early rheumatoid arthritis (RA).

    Methods. In 181 Swedish patients (128 women, 53 men) with RA of recent onset, disease and disability variables such as erythrocyte sedimentation rate, 28-joint disease activity score (DAS28) and health assessment questionnaire (HAQ) scores were monitored regularly during 3 yr. Three hundred and sixty-two controls were recruited from the same geographical area as the patients. FcRIIIA genotyping was performed using denaturing high-performance liquid chromatography.

    Results. In all RA patients, FcRIIIA-158VV was significantly over-represented compared with controls [odds ratio (OR) 1.9, 95% confidence interval (CI) 1.01–3.5, P<0.05]. After stratifying for sex, the difference remained in the male population (OR 3.2, 95%CI 1.03–11, P<0.05) but disappeared among women (OR 1.4, 95%CI 0.7–3.1, P=0.4). In addition, 158VV patients were more likely to exhibit early joint erosions (OR 6.1, 95%CI 1.4–28, P<0.01). At baseline, patients with different FcRIIIA genotypes did not differ with respect to measures of disease activity or functional ability. Thereafter, in male patients with at least one V allele the mean DAS28 and HAQ scores were higher compared with 158FF. In contrast, female patients with at least one 158V allele displayed lower mean DAS28 and HAQ scores compared with those with 158FF.

    Conclusions. In a male population, the FcRIIIA-158VV genotype is associated with an increased risk of developing RA, and the 158V allele with more severe disease in early RA.

  • 57.
    Kastbom, Alf
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Medicincentrum, Länskliniken för Reumatologi i Östergötland.
    Bratt, Johan
    Karolinska University Hospital Huddinge and Karolinska Institutet, Stockholm, Sweden.
    Ernestam, Sofia
    Karolinska University Hospital Huddinge and Karolinska Institutet, Stockholm, Sweden.
    Lampa, Jon
    Karolinska University Hospital Solna and Karolinska Institutet, Stockholm, Sweden.
    Padyukov, Leonid
    Karolinska University Hospital Solna and Karolinska Institutet, Stockholm, Sweden.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Skogh, Thomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Medicincentrum, Länskliniken för Reumatologi i Östergötland.
    Fcγ receptor type IIIA genotype and response to tumor necrosis factor alpha-blocking agents in patients with rheumatoid arthritis2007Ingår i: Arthritis and Rheumatism, ISSN 0004-3591, Vol. 56, nr 2, s. 448-452Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: To determine whether a functional single-nucleotide polymorphism in the gene encoding Fc receptor type IIIA (FcRIIIA) correlates with the response to treatment with tumor necrosis factor inhibitors in rheumatoid arthritis (RA).

    Methods: The study population comprised 282 Swedish patients with RA in whom the therapeutic efficacy of conventional disease-modifying antirheumatic drugs had been insufficient. Infliximab or etanercept treatment was initiated, and patients were evaluated after 3 months, using the American College of Rheumatology 20% improvement criteria (ACR20), the ACR50, and the ACR70 or the European League Against Rheumatism (EULAR) criteria. The chi-square test was used to compare response rates across FcRIIIA genotypes.

    Results: No differences in genotype distribution were observed among nonresponders compared with ACR20 responders (P = 0.80), ACR50 responders (P = 0.56), or ACR70 responders (P = 0.91). Similar results were observed when analyzing infliximab and etanercept separately or when using the EULAR response criteria.

    Conclusion: Unlike the findings of a previous study, the results of the current study suggest that the 158V/F polymorphism of FcRIIIA is very unlikely to influence the clinical efficacy of infliximab or etanercept in patients with RA.

  • 58.
    Kastbom, Alf
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland.
    Cöster, Lars
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland.
    Ärlestig, Lisbeth
    Umeå University, Sweden .
    Chatzidionysiou, Aikaterini
    Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden .
    van Vollenhoven, Ronald F.
    Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden .
    Padyukov, Leonid
    Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden .
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Sweden .
    Saevarsdottir, Saedis
    Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden .
    Influence of FCGR3A genotype on the therapeutic response to rituximab in rheumatoid arthritis: an observational cohort study2012Ingår i: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 2, nr 5Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objectives To determine whether a polymorphism in the Fcγ receptor type IIIA (FCGR3A-F158V), influencing immunoglobulin G binding affinity, relates to the therapeutic efficacy of rituximab in rheumatoid arthritis (RA) patients.

    Design Observational cohort study.

    Setting Three university hospital rheumatology units in Sweden.

    Participants Patients with established RA (n=177; 145 females and 32 males) who started rituximab (Mabthera) as part of routine care.

    Primary outcome measures Response to rituximab therapy in relation to FCGR3A genotype, including stratification for sex.

    Results The frequency of responders differed significantly across FCGR3A genotypes (p=0.017 in a 3×2 contingency table). Heterozygous patients showed the highest response rate at 83%, as compared with patients carrying 158FF (68%) or 158VV (56%) (p=0.028 and 0.016, respectively). Among 158VV patients, response rates differed between male and female patients (p=0.036), but not among 158FF or 158VF patients (p=0.72 and 0.46, respectively).

    Conclusions Therapeutic efficacy of rituximab in RA patients is influenced by FCGR3A genotype, with the highest response rates found among heterozygous patients. This may suggest that different rituximab mechanisms of action in RA are optimally balanced in FCGR3A-158VF patients. Similar to the previously described associations with RA susceptibility and disease course, the impact of 158VV on rituximab response may be influenced by sex.

  • 59.
    Kastbom, Alf
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Medicincentrum, Länskliniken för Reumatologi i Östergötland.
    Johansson, Martin
    Umeå University.
    Verma, Deepti
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Rantapaa-Dahlqvist, Solbritt
    Umeå University.
    CARD8 p.C10X polymorphism is associated with inflammatory activity in early rheumatoid arthritis2010Ingår i: ANNALS OF THE RHEUMATIC DISEASES, ISSN 0003-4967, Vol. 69, nr 4, s. 723-726Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objectives CARD8 and NLRP3 are constituents of the inflammasome which regulates interleukin 1 beta production. The influence of polymorphisms in CARD8 and NLRP3 on rheumatoid arthritis (RA) susceptibility and severity were evaluated. Methods CARD8 p.C10X and NLRP3 p.Q705K genotypes were assessed in andgt;500 controls and patients with early RA from northern Sweden. The patients were monitored regularly over a 2-year period. The 28-joint disease activity score (DAS28) and its separate components were compared across genotypes. Results Patients with one or more variant alleles in CARD8 (CARD8-X) had increased DAS28, tender joint count and erythrocyte sedimentation rate during the 2-year follow-up period despite receiving disease-modifying antirheumatic drugs to a greater extent. CARD8-X was significantly over-represented among patients who received anti-tumour necrosis factor therapy during the first 2 years. CARD8 and NLRP3 genotypes did not influence radiological joint damage and were not associated with an increased susceptibility. Conclusions Carriage of CARD8-X is associated with a worse disease course in early RA.

  • 60.
    Kastbom, Alf
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland.
    Klingberg, E
    University of Gothenburg, Sweden .
    Verma, Deepti
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet.
    Carlsten, H
    University of Gothenburg, Sweden .
    Forsblad-dElia, H
    University of Gothenburg, Sweden .
    Wesamaa, J
    Örebro University Hospital, Sweden .
    Cedergren, Jan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland.
    Eriksson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland.
    Söderkvist, P
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Genetic variants in CARD8 but not in NLRP3 are associated with ankylosing spondylitis2013Ingår i: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 42, nr 6, s. 465-468Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objectives: The NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome is important for interleukin-1beta (IL-1 beta) processing as part of an innate immune response. Caspase recruitment domain family, member 8 (CARD8) is an inhibitor of nuclear factor kappa B (NF-kappa B) and possibly also a part of the NLRP3 inflammasome. The objective of this study was to evaluate one single nucleotide polymorphism (SNP) in CARD8 and three SNPs in NLRP3 in ankylosing spondylitis (AS) susceptibility and disease phenotype. less thanbrgreater than less thanbrgreater thanMethod: We recruited 492 AS patients from Southern Sweden fulfilling the modified New York criteria for AS, and assessed phenotypic characteristics from medical records and questionnaires. Patients with psoriasis or clinically overt inflammatory bowel disease (IBD) were excluded, as were patients without human leucocyte antigen B27 (HLA-B27). Three NLRP3 SNPs (rs35829419, rs4353135, and rs10733113) and one SNP in CARD8 (rs2043211) were genotyped by commercially available TaqMan assays, and the results compared at genotype and allele levels to those of 793 population-based controls. In a subgroup of the patients (n = 169), faecal calprotectin was assessed as a marker of subclinical intestinal inflammation. less thanbrgreater than less thanbrgreater thanResults: The minor allele (A) of CARD8-C10X (rs2043211) was associated with a decreased risk of AS in a dominant model [odds ratio (OR) 0.74, 95% confidence interval (CI) 0.54-0.94, p = 0.012] and at the allelic level (OR 0.81, 95% CI 0.68-0.97, p = 0.02), but was not associated with levels of faecal calprotectin. There was no association regarding NLRP3 SNPs and AS susceptibility, and none of the investigated SNPs were associated with iritis, anti-tumour necrosis factor (anti-TNF) therapy, or peripheral joint involvement. less thanbrgreater than less thanbrgreater thanConclusion: In a Swedish population, the minor allele of CARD8-C10X is associated with a decreased risk of AS, but not with levels of faecal calprotectin or disease phenotype.

  • 61.
    Kastbom, Alf
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Medicincentrum, Länskliniken för Reumatologi i Östergötland.
    Strandberg, Gunnar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Medicincentrum, Länskliniken för Reumatologi i Östergötland.
    Lindroos, Annette
    Skogh, Thomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Medicincentrum, Länskliniken för Reumatologi i Östergötland.
    Anti-CCP antibody test predicts the disease course during 3 years in early rheumatoid arthritis (the Swedish TIRA project)2004Ingår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, Vol. 63, nr 9, s. 1085-1089Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objectives: To evaluate the diagnostic sensitivity of antibodies to cyclic citrullinated peptide (CCP) in recent onset rheumatoid arthritis (RA) at diagnosis and 3 years later, and to evaluate anti-CCP antibody as a predictor of the disease course during 3 years.

    Methods: 242 patients with recent onset (≤ 1 year) RA were followed up regularly during 3 years after inclusion in the Swedish multicentre study "TIRA" 1996-98. Anti-CCP antibodies were analysed by an enzyme immunoassay (EIA). Rheumatoid factors (RFs) were analysed by latex agglutination and two isotype-specific (IgM and IgA) EIAs. Disease activity was assessed by plasma CRP, ESR, 28 joint disease activity score, and the physician's global assessment of disease activity. Functional ability was evaluated by the Health Assessment Questionnaire.

    Results: Overall, the diagnostic sensitivity of anti-CCP antibodies was 64% and the proportion of positive tests increased with the number of fulfilled classification criteria according to the American College of Rheumatology. The anti-CCP antibody results correlated with RF, but were better than RF as predictor of a more aggressive disease course. After 3 years 5/97 patients had changed anti-CCP status: 2 from negative to positive and 3 from positive to negative. The mean level of anti-CCP antibodies declined by 131 U/ml during the 3 year follow up (95% Cl 34 to 228 U/ml).

    Conclusion: The anti-CCP antibody assay has a similar diagnostic sensitivity to that of RF in early RA, but is better as a predictor of the disease course over 3 years. Although the mean serum level declines, anti-CCP antibody positivity remains essentially unaltered 3 years after diagnosis and start of antirheumatic treatment.

  • 62.
    Kastbom, Alf
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet.
    Verma, Deepti
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Eriksson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet.
    Skogh, Thomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet.
    Wingren, Gun
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Yrkes- och miljömedicin. Linköpings universitet, Hälsouniversitetet.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Genetic variation in proteins of the cryopyrin inflammasome influences susceptibility and severity of rheumatoid arthritis (the Swedish TIRA project)2008Ingår i: Rheumatology, ISSN 1462-0324, Vol. 47, nr 4, s. 415-417Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objectives: The genetic background to RA is incompletely understood.As new cytokine-targeted therapies emerge, early predictorsof disease severity are becoming increasingly important. Theinflammasomes are essential regulators of cytokine production.We investigated whether two polymorphisms in the genes encodingcryopyrin (CIAS1) and TUCAN (CARD8) influence susceptibilityand disease course in RA.

    Methods: Genotype frequencies were assessed in 174 Swedish patientswith early RA and 360 population-based controls without rheumaticdisease. Genotypes were categorized according to the presence(+) or absence (–) of two wild-type alleles and comparedbetween patients and controls. In the RA patients, antibodiestowards cyclic citrullinated peptides (anti-CCP) and the ‘sharedepitope’ (SE) were assessed, and medication and measuresof disease activity were monitored regularly during 3 yrs.

    Results: The combination of CIAS1/TUCAN/–, ascompared with CIAS1/TUCAN +/+, was significantly more commonamong patients than in controls [odds ratio (OR) 2.2, 95% CI1.03–4.6]. This association was strengthened when patientswere divided into anti-CCP+ [OR 2.8 (1.1–6.7)] or presenceof 1 SE copy [OR 2.8 (1.3–6.2)]. At most time-points duringthe 3-yr follow-up, patients with CIAS1/TUCAN/–showed significantly higher disease activity. Furthermore, CIAS1/TUCAN/– patients proved to be much more likely to receiveTNF-blocking therapy [relative risk 20 (2.6–149)].

    Conclusions: Compound polymorphisms in CIAS1 and TUCAN associatewith RA susceptibility and severity. The cryopyrin inflammasomeneeds further attention regarding a possible aetiopathogeneticconnection with RA.

  • 63.
    Kwiecinski, J
    et al.
    Sahlgrenska Academy.
    Josefsson, E
    Sahlgrenska Academy.
    Mitchell, J
    Trinity College, Dublin.
    Higgins, J
    Trinity College, Dublin.
    Magnusson, Mattias
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet.
    Foster, T
    Trinity College, Dublin.
    Jin, T
    Sahlgrenska Academy.
    Bokarewa, M
    Sahlgrenska Academy.
    Activation of Plasminogen by Staphylokinase Reduces the Severity of Staphylococcus aureusSystemic Systemic Infection2010Ingår i: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 202, nr 7, s. 1041-1049Artikel i tidskrift (Refereegranskat)
    Abstract [en]

     

    Background. Theoretical and experimental data support the geographic differentiation strategy as a valuable tool for detecting loci under selection. In the context of Plasmodium falciparum malaria, few populations have been studied, with limited genomic coverage.

    Methods. Wild-type S. aureus strain LS-1, which lacks the ability to produce SAK, was modified by an insertion of the sak gene into its chromosome. The sak gene was integrated in 2 forms—(1) linked to its own promoter and (2) fused to the promoter of the protein A gene—which resulted in the overexpression of SAK. SAK is highly specific for human plg and exhibits almost no activity toward murine plg. To investigate the role played by SAK in a murine infection model, human plg transgenic mice and their wild-type counterparts were inoculated intravenously with congenic S. aureus strains differing in SAK production.

    Results. Human plg transgenic mice inoculated with SAK-expressing strains displayed significantly reduced mortality, less weight loss, and lower bacterial loads in kidneys than did the wild-type mice. No difference in the severity of sepsis was observed between transgenic and wild-type mice infected with a SAK-deficient strain.

    Conclusions. The results suggest that expression of SAK followed by activation of plg alleviates the course of S. aureus sepsis. 

     

     

     

     

     

     

     

     

     

      

     

     

     

     

     

     

     

     

     

     

     

     

     

    Background.

     

    Staphylokinase (SAK) is produced by the majority of Staphylococcus aureus strains. It is an extracellular protein that activates the conversion of human plasminogen (plg) to plasmin. The role played by SAK in staphylococcal infection is unclear.Methods. Wild-type S. aureus strain LS-1, which lacks the ability to produce SAK, was modified by an insertion of the sak gene into its chromosome. The sak gene was integrated in 2 forms—(1) linked to its own promoter and (2) fused to the promoter of the protein A gene—which resulted in the overexpression of SAK. SAK is highly specific for human plg and exhibits almost no activity toward murine plg. To investigate the role played by SAK in a murine infection model, human plg transgenic mice and their wild-type counterparts were inoculated intravenously with congenic S. aureus strains differing in SAK production.Results. Human plg transgenic mice inoculated with SAK-expressing strains displayed significantly reduced mortality, less weight loss, and lower bacterial loads in kidneys than did the wild-type mice. No difference in the severity of sepsis was observed between transgenic and wild-type mice infected with a SAK-deficient strain.Conclusions. The results suggest that expression of SAK followed by activation of plg alleviates the course of S. aureus

    sepsis.

  • 64.
    Lessard, Christopher J.
    et al.
    Oklahoma Medical Research Fdn, OK USA .
    Li, He
    Oklahoma Medical Research Fdn, OK USA .
    Adrianto, Indra
    Oklahoma Medical Research Fdn, OK USA .
    Ice, John A.
    Oklahoma Medical Research Fdn, OK USA .
    Rasmussen, Astrid
    Oklahoma Medical Research Fdn, OK USA .
    Grundahl, Kiely M.
    Oklahoma Medical Research Fdn, OK USA .
    Kelly, Jennifer A.
    Oklahoma Medical Research Fdn, OK USA .
    Dozmorov, Mikhail G.
    Oklahoma Medical Research Fdn, OK USA .
    Miceli-Richard, Corinne
    University of Paris 11, France .
    Bowman, Simon
    University Hospital Birmingham, England .
    Lester, Sue
    Queen Elizabeth Hospital, Australia .
    Eriksson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland.
    Eloranta, Maija-Leena
    Uppsala University, Sweden .
    Brun, Johan G.
    University of Bergen, Norway .
    Goransson, Lasse G.
    Stavanger University Hospital, Norway .
    Harboe, Erna
    Stavanger University Hospital, Norway .
    Guthridge, Joel M.
    Oklahoma Medical Research Fdn, OK USA .
    Kaufman, Kenneth M.
    Cincinnati Childrens Hospital Medical Centre, OH USA .
    Kvarnstrom, Marika
    Karolinska Institute, Sweden .
    Jazebi, Helmi
    Karolinska Institute, Sweden .
    Cunninghame Graham, Deborah S.
    Kings Coll London, England .
    Grandits, Martha E.
    United Medical Specialties, MN USA .
    Nazmul-Hossain, Abu N M.
    University of Colorado, CO USA .
    Patel, Ketan
    University of Minnesota, MN USA .
    Adler, Adam J.
    Oklahoma Medical Research Fdn, OK USA .
    Maier-Moore, Jacen S.
    Oklahoma Medical Research Fdn, OK USA .
    Darise Farris, A
    Oklahoma Medical Research Fdn, OK USA .
    Brennan, Michael T.
    Carolinas Medical Centre, NC USA .
    Lessard, James A.
    Valley Bone and Joint Clin, ND USA .
    Chodosh, James
    Harvard University, MA USA .
    Gopalakrishnan, Rajaram
    University of Minnesota, MN USA .
    Hefner, Kimberly S.
    Hefner Eye Care and Opt Centre, OK USA .
    Houston, Glen D.
    University of Oklahoma, OK USA .
    Huang, Andrew J W.
    Washington University, MO USA .
    Hughes, Pamela J.
    University of Oklahoma, OK USA .
    Lewis, David M.
    University of Oklahoma, OK USA .
    Radfar, Lida
    University of Oklahoma, OK USA .
    Rohrer, Michael D.
    University of Minnesota, MN USA .
    Stone, Donald U.
    University of Oklahoma, OK USA .
    Wren, Jonathan D.
    Oklahoma Medical Research Fdn, OK USA .
    Vyse, Timothy J.
    Kings Coll London, England .
    Gaffney, Patrick M.
    Oklahoma Medical Research Fdn, OK USA .
    James, Judith A.
    Oklahoma Medical Research Fdn, OK USA .
    Omdal, Roald
    Stavanger University Hospital, Norway .
    Wahren-Herlenius, Marie
    Karolinska Institute, Sweden .
    Illei, Gabor G.
    National Institute Dent and Craniofacial Research, MD USA .
    Witte, Torsten
    Hannover Medical Sch, Germany .
    Jonsson, Roland
    Haukeland Hospital, Norway .
    Rischmueller, Maureen
    Queen Elizabeth Hospital, Australia .
    Ronnblom, Lars
    Uppsala University, Sweden .
    Nordmark, Gunnel
    Uppsala University, Sweden .
    Ng, Wan-Fai
    Newcastle University, England .
    Mariette, Xavier
    University of Paris 11, France .
    Anaya, Juan-Manuel
    University of Rosario, Colombia .
    Rhodus, Nelson L.
    University of Minnesota, MN USA .
    Segal, Barbara M.
    University of Minnesota, MN USA .
    Hal Scofield, R
    Oklahoma Medical Research Fdn, OK USA .
    Montgomery, Courtney G.
    Oklahoma Medical Research Fdn, OK USA .
    Harley, John B.
    Cincinnati Childrens Hospital Medical Centre, OH USA .
    Sivils, Kathy L.
    Oklahoma Medical Research Fdn, OK USA .
    Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjogren's syndrome2013Ingår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 45, nr 11, s. 1284-+Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Sjogrens syndrome is a common autoimmune disease (affecting similar to 0.7% of European Americans) that typically presents as keratoconjunctivitis sicca and xerostomia. Here we report results of a large-scale association study of Sjogrens syndrome. In addition to strong association within the human leukocyte antigen (HLA) region at 6p21 (P-meta = 7.65 x 10(-114)), we establish associations with IRF5-TNPO3 (P-meta = 2.73 x 10(-19)), STAT4 (Pmeta = 6.80 x 10-15), IL12A (P-meta = 1.17 x 10(-10)), FAM167ABLK (P-meta = 4.97 x 10(-10)), DDX6-CXCR5 (P-meta = 1.10 x 10(-8)) and TNIP1 (P-meta = 3.30 x 10(-8)). We also observed suggestive associations (P-meta andlt; 5 x 10(-5)) with variants in 29 other regions, including TNFAIP3, PTTG1, PRDM1, DGKQ, FCGR2A, IRAK1BP1, ITSN2 and PHIP, among others. These results highlight the importance of genes that are involved in both innate and adaptive immunity in Sjogrens syndrome.

  • 65.
    Martinsson, Klara
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Skogh, Thomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Medicincentrum, Länskliniken för Reumatologi i Östergötland.
    Mousavi, Seyed Ali
    Rikshospital University Hospital, Oslo.
    Berg, Trond
    University of Oslo.
    Jönsson, Jan-Ingvar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi. Linköpings universitet, Hälsouniversitetet.
    Hultman, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Molekylär och immunologisk patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Deficiency of Activating Fc gamma-Receptors Reduces Hepatic Clearance and Deposition of IC and Increases CIC Levels in Mercury-Induced Autoimmunity2010Ingår i: PLOS ONE, ISSN 1932-6203, Vol. 5, nr 10Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Inorganic mercury (Hg) induces a T-cell dependent, systemic autoimmune condition (HgIA) where activating Fc gamma-receptors (Fc gamma Rs) are important for the induction. In this study we examined the influence of activating Fc gamma Rs on circulating levels and organ localization of immune complexes (IC) in HgIA. Methods and Principal Findings: Mercury treated BALB/c wt mice showed a significant but modest increase of circulating IC (CIC) from day 12 until day 18 and day 35 for IgG2a- and IgG1- CIC, respectively. Mercury-treated mice lacking the transmembrane gamma-chain of activating Fc gamma Rs (FcR gamma(-/-)) had significantly higher CIC levels of both IgG1-CIC and IgG2a-CIC than wt mice during the treatment course. The hepatic uptake of preformed CIC was significantly more efficient in wt mice compared to Fc gamma R-/- mice, but also development of extrahepatic tissue IC deposits was delayed in FcR gamma(-/-) mice. After 35 days of Hg treatment the proportion of immune deposits, as well as the amounts was significantly reduced in vessel FcR gamma(-/-) mice compared to wt mice. Conclusions: We conclude that mice lacking functional activating Fc gamma Rs respond to Hg with increased levels and altered quality of CIC compared with wt mice. Lack of functional activating Fc gamma Rs delayed the elimination of CIC, but also significantly reduced extrahepatic tissue localization of CIC.

  • 66.
    Mathsson, L.
    et al.
    Uppsala University.
    Åhlin, E.
    Uppsala University.
    Sjöwall, Christoffer
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Medicincentrum, Länskliniken för Reumatologi i Östergötland.
    Skogh, Thomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Medicincentrum, Länskliniken för Reumatologi i Östergötland.
    Rönnelid, J.
    Uppsala University.
    Cytokine induction by circulating immune complexes and signs of in-vivo complement activation in systemic lupus erythematosus are associated with the occurrence of anti-Sjögren's syndrome A antibodies2007Ingår i: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 147, nr 3, s. 513-520Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Circulating immune complexes (IC) and levels of IC-induced cytokines have been correlated with complement activation and autoantibody profiles in systemic lupus erythematosus (SLE). SLE sera were analysed concerning levels of immune complexes (IC), classical complement function and different antinuclear and anti-C-reactive protein (CRP) autoantibodies. Blood mononuclear cells from healthy donors were stimulated with isolated IC and production of interleukin (IL)-10, IL-6 and IL-12p40 was measured. Functional experiments revealed that increased levels of IC-induced cytokines were associated with both increased classical complement activation and the occurrence of anti-Sjögren's syndrome A (SSA) and anti-SSB but not other autoantibodies. Biochemical measurement of circulating IC showed that the degree of complement activation and the occurrence of anti-SSA were synergistically associated with levels of circulating IC in SLE sera, as complement activation was a prerequisite for the enhancing effect of anti-SSA. Anti-CRP was associated with complement activation, but not with other autoantibodies. Our results indicate that anti-SSA and possibly anti-SSB antibodies influence IC formation and subsequent IC-induced cytokine induction, and that they thereby participate in the inflammatory process in active SLE.

  • 67.
    Milovanovic, Micha
    et al.
    Linköpings universitet, Institutionen för samhälls- och välfärdsstudier, Hälsa, Aktivitet, Vård (HAV). Linköpings universitet, Hälsouniversitetet.
    Nillsson, Ethel
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Närsjukvården i östra Östergötland.
    Järemo, Petter
    Linköpings universitet, Institutionen för medicin och hälsa, Kardiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Närsjukvården i östra Östergötland, Medicinkliniken ViN.
    Relationships between platelets and inflammatory markers in rheumatoid arthritis2004Ingår i: Clinica Chimica Acta, ISSN 0009-8981, E-ISSN 1873-3492, Vol. 343, nr 1-2, s. 237-240Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aim of the study: To investigate platelets and different inflammatory markers in conjunction with a substantial inflammatory reaction. We used individuals with active rheumatoid arthritis (RA) as an experimental cohort. Methods: We selected 16 patients with active RA having at least one affected joint. On day 1, platelet and neutrophil counts together with C-reactive protein (CRP) were determined. We further analysed platelet volume (MPV) and plasma levels of thrombopoietin (TPO), P-selectin, myeloperoxidase and interleukin 6 (IL-6). After 2 years when all patients failed to show any swollen joints all analyses were repeated. Results and conclusions: As expected platelet count, CRP and IL-6 were elevated in active RA. The measures correlated with each other thus reflecting the same characteristic of the inflammatory response. The neutrophil count, MPV and myeloperoxidase also mirror disease activity. They failed to correlate with other activity markers thus providing unique information. MPV and myeloperoxidase on day 1 correlated with recovery values. Therefore, they could be suitable to use when following the inflammatory reaction over a long period of time.

  • 68. Nimeri, G
    et al.
    Majeed, Meytham
    Linköpings universitet, Filosofiska fakulteten. Linköpings universitet, Institutionen för hälsa och miljö.
    Elwing, H
    Öhman, Lena
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Infektionsmedicin. Östergötlands Läns Landsting, Medicincentrum, Infektionskliniken i Östergötland.
    Wetterö, Jonas
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi.
    Bengtsson, Torbjörn
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi.
    Oxygen radical production in neutrophils interacting with platelets and surface-immobilized plasma proteins: role of tyrosine phosphorylation2003Ingår i: Journal of Biomedical Materials Research, ISSN 0021-9304, E-ISSN 1097-4636, Vol. 67A, nr 2, s. 439-447Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The interaction between neutrophil granulocytes and platelets is considered to play an important role in the inflammatory process induced by an implanted foreign material. However, the cellular mechanisms involved remain incompletely understood. We used a luminol-dependent chemiluminescence (CL) technique to analyze the generation of reactive oxygen species (ROS) in human neutrophils interacting with different plasma protein-coated surfaces in the presence or absence of unstimulated or stimulated platelets. The role of tyrosine phosphorylation in the regulation of NADPH oxidase activity was evaluated with quantitative fluorescence microscopy and the specific tyrosine kinase inhibitor genistein. We found that the ROS-production is 2 to 3 times higher in neutrophils on immunoglobulin G (IgG)coated surfaces than in cells interacting with albumin- or fibrinogen-coated surfaces. Incubation with superoxide dismutase and catalase revealed that about 45% of the ROS was released extracellularly on IgG surfaces whereas corresponding values were 90% and 85% in neutrophils interacting with albumin and fibrinogen, respectively. The presence of platelets markedly increased the extracellular generation of ROS, mainly in neutrophils. interacting with IgG- or fibrinogen-coated surfaces whereas the intracellular production was only modestly affected. Quantitative fluorescence microscopy of neutrophils stained with FITC-conjugated anti-phosphotyrosine antibodies showed a correlation between tyrosine phosphorylation, cell spreading, and ROS production. Platelets markedly amplified the anti-phosphotyrosine staining on both fibrinogen- and IgG-coated surfaces whereas the low level of tyrosine phosphorylation in neutrophils on albumin-coated surfaces was not further elevated by platelets. Furthermore, the tyrosine kinase inhibitor genistein inhibited both extra- and intracellular ROS production in neutrophils regardless of the presence of platelets. We demonstrate that plasma protein coating and the presence of platelets are crucial for the inflammatory response of adhering neutrophils and that the oxidative response correlates with the extent of tyrosine phosphorylation of proteins in focal contacts. (C) 2003 Wiley Periodicals, Inc.

  • 69.
    Nordmark, G
    et al.
    Uppsala University.
    Kristjansdottir, G
    Uppsala University.
    Theander, E
    Malmö University Hospital.
    Appel, S
    University of Bergen, Norway.
    Eriksson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Njurmedicinska kliniken US.
    Vasaitis, L
    Uppsala University.
    Kvarnström, M
    Karolinska Institutet, Stockholm.
    Delaleu, N
    University of Bergen, Norway.
    Lundmark, P
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet.
    Lundmark, A
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland.
    Brun, J G
    Haukeland Hospital, Bergen, Norway.
    Jonsson, M V
    University of Bergen, Norway.
    Harboe, E
    Stavanger University Hospital, Norway.
    Gøransson, L G
    Stavanger University Hospital, Norway.
    Johnsen, S J
    Stavanger University Hospital, Norway.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Eloranta, M-L
    Uppsala University.
    Alm, G
    Swedish University of Agricultural Sciences, Uppsala.
    Baecklund, E
    Uppsala University.
    Wahren-Herlenius, M
    Karolinska Institutet, Stockholm.
    Omdal, R
    Stavanger University Hospital, Norway.
    Rönnblom, L
    Uppsala University.
    Jonsson, R
    University of Bergen, Norway.
    Syvänen, A-C
    Uppsala University.
    Association of EBF1, FAM167A(C8orf13)-BLK andTNFSF4 gene variants with primary Sjo¨gren’s syndrome2011Ingår i: Genes and Immunity, ISSN 1466-4879, E-ISSN 1476-5470, Vol. 12, nr 2, s. 100-109Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We performed a candidate gene association study in 540 patients with primary Sjögren's Syndrome (SS) from Sweden (n=344) and Norway (n=196) and 532 controls (n=319 Swedish, n=213 Norwegian). A total of 1139 single-nucleotide polymorphisms (SNPs) in 84 genes were analyzed. In the meta-analysis of the Swedish and Norwegian cohorts, we found high signals for association between primary SS and SNPs in three gene loci, not previously associated with primary SS. These are the early B-cell factor 1 (EBF1) gene, P=9.9 × 10(-5), OR 1.68, the family with sequence similarity 167 member A-B-lymphoid tyrosine kinase (FAM167A-BLK) locus, P=4.7 × 10(-4), OR 1.37 and the tumor necrosis factor superfamily (TNFSF4=Ox40L) gene, P=7.4 × 10(-4), OR 1.34. We also confirmed the association between primary SS and the IRF5/TNPO3 locus and the STAT4 gene. We found no association between the SNPs in these five genes and the presence of anti-SSA/anti-SSB antibodies. EBF1, BLK and TNFSF4 are all involved in B-cell differentiation and activation, and we conclude that polymorphisms in several susceptibility genes in the immune system contribute to the pathogenesis of primary SS

  • 70.
    Nordmark, G
    et al.
    Uppsala University.
    Kristjansdottir, G
    Uppsala University.
    Theander, E
    Malmö University Hospital.
    Eriksson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Medicincentrum, Länskliniken för Reumatologi i Östergötland.
    Brun, J G
    Haukeland Hospital.
    Wang, C
    Uppsala University.
    Padyukov, L
    Karolinska University Hospital.
    Truedsson, L
    Lund University.
    Alm, G
    Swedish University of Agriculture Science.
    Eloranta, M-L
    Uppsala University.
    Jonsson, R
    Haukeland Hospital.
    Ronnblom, L
    Uppsala University.
    Syvanen, A-C
    Uppsala University.
    Additive effects of the major risk alleles of IRF5 and STAT4 in primary Sjogrens syndrome2009Ingår i: GENES AND IMMUNITY, ISSN 1466-4879, Vol. 10, nr 1, s. 68-76Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Primary Sjogrens syndrome (SS) shares many features with systemic lupus erythematosus (SLE). Here we investigated the association of the three major polymorphisms in IRF5 and STAT4 found to be associated with SLE, in patients from Sweden and Norway with primary SS. These polymorphisms are a 5-bp CGGGG indel in the promoter of IRF5, the single nucleotide polymorphism (SNP) rs10488631 downstream of IRF5 and the STAT4 SNP rs7582694, which tags the major risk haplotype of STAT4. We observed strong signals for association between all three polymorphisms and primary SS, with odds ratios (ORs) > 1.4 and P-values < 0.01. We also found a strong additive effect of the three risk alleles of IRF5 and STAT4 with an overall significance between the number of risk alleles and primary SS of P = 2.5 x 10(-9). The OR for primary SS increased in an additive manner, with an average increase in OR of 1.78. For carriers of two risk alleles, the OR for primary SS is 1.43, whereas carriers of five risk alleles have an OR of 6.78. IRF5 and STAT4 are components of the type I IFN system, and our findings emphasize the importance of this system in the etiopathogenesis of primary SS.

  • 71.
    Nordmark, Gunnel
    et al.
    University Uppsala Hospital.
    Kristjansdotti, Gudlaug
    Uppsala University.
    Theander, Elke
    Lund University.
    Appel, Silke
    University of Bergen.
    Eriksson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Medicincentrum, Länskliniken för Reumatologi i Östergötland.
    Vasaitis, Lilian
    University Uppsala Hospital.
    Wahren-Herlenius, Marie
    Karolinska Institute.
    Omdal, Roald
    University of Bergen.
    Ronnblom, Lars
    University Uppsala Hospital.
    Jonsson, Roland
    Uppsala University.
    GENE VARIANTS IN FAM167A-BLK AND TNFSF4 ARE ASSOCIATED WITH PRIMARY SJOGRENS SYNDROME in SCANDINAVIAN JOURNAL OF RHEUMATOLOGY, vol 39, issue , pp 32-322010Ingår i: SCANDINAVIAN JOURNAL OF RHEUMATOLOGY, Informa Healthcare , 2010, Vol. 39, s. 32-32Konferensbidrag (Refereegranskat)
    Abstract [en]

    n/a

  • 72.
    Nordmark, Gunnel
    et al.
    Uppsala University, Sweden .
    Wang, Chuan
    Uppsala University, Sweden .
    Vasaitis, Lilian
    Uppsala University, Sweden .
    Eriksson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland.
    Theander, Elke
    Lund University, Sweden .
    Kvarnström, Marika
    Karolinska Institutet, Stockholm, Sweden.
    Forsblad-d'Elia, Helena
    University of Gothenburg, Sweden .
    Jazebi, Helmi
    Karolinska Institutet, Stockholm, Sweden.
    Sjöwall, Christoffer
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland.
    Reksten, Tove Ragna
    University of Bergen, Norway .
    Brun, Johan G.
    Haukeland University Hospital, Bergen, Norway.
    Jonsson, Malin V.
    University of Bergen, Norway .
    Johnsen, Svein J.
    Stavanger University Hospital, Norway .
    Wahren-Herlenius, Marie
    Karolinska Institutet, Stockholm, Sweden.
    Omdal, Roald
    Stavanger University Hospital, Norway .
    Jonsson, Roland
    University of Bergen, Norway.
    Bowman, Simon
    University Hospital Birmingham, UK.
    Ng, Wan-Fai
    Newcastle University, UK.
    Eloranta, Maija-Leena
    Uppsala University, Sweden .
    Syvänen, Ann-Christine
    Uppsala University, Sweden .
    Association of Genes in the NF-κB Pathway with Antibody-Positive Primary Sjögren's Syndrome2013Ingår i: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 78, nr 5, s. 447-454Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Primary Sjogrens syndrome (SS) is a systemic autoimmune inflammatory disease characterized by focal lymphocytic infiltrates in the lachrymal and salivary glands and autoantibodies against the SSA/Ro and SSB/La antigens. Experimental studies have shown an activation of NF-B in primary SS. NF-B activation results in inflammation and autoimmunity and is regulated by inhibitory and activating proteins. Genetic studies have shown an association between multiple autoimmune diseases and TNFAIP3 (A20) and TNIP1 (ABIN1), both repressors of NF-B and of IKBKE (IKK epsilon), which is an NF-B activator. The aim of this study was to analyse single nucleotide polymorphisms (SNPs) in the IKBKE, NFKB1, TNIP1 and TNFAIP3 genes for association with primary SS. A total of 12 SNPs were genotyped in 1105 patients from Scandinavia (Sweden and Norway, n=684) and the UK (n=421) and 4460 controls (Scandinavia, n=1662, UK, n=2798). When patients were stratified for the presence of anti-SSA and/or anti-SSB antibodies (n=868), case-control meta-analysis found an association between antibody-positive primary SS and two SNPs in TNIP1 (P=3.4x10(-5), OR=1.33, 95%CI: 1.16-1.52 for rs3792783 and P=1.3x10(-3), OR=1.21, 95%CI: 1.08-1.36 for rs7708392). A TNIP1 risk haplotype was associated with antibody-positive primary SS (P=5.7x10(-3), OR=1.47, 95%CI: 1.12-1.92). There were no significant associations with IKBKE, NFKB1 or TNFAIP3 in the meta-analysis of the Scandinavian and UK cohorts. We conclude that polymorphisms in TNIP1 are associated with antibody-positive primary SS.

  • 73.
    Pettersson, Sofia
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet.
    Wetterö, Jonas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet.
    Kratz, Gunnar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Hand och plastikkirurgi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Hand- och plastikkirurgiska kliniken US.
    The Role of Platelet Rich Plasma and Dynamic Centrifugation on Extracellular Matrix Formation of Human Articular Chondrocytes on Macroporous Gelatin Microcarriers in Pellet CultureManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Platelet rich plasma (PRP) has been investigated for its beneficial use in cartilage tissue engineering previously. Here, we address the effect of using PRP as encapsulating agent for gelatin-supported chondrocyte pellet culture in vitro. Furthermore, the concept of using dynamic centrifugation to stimulate extracellular matrix (ECM) formation of the chondrocytes is explored. Human articular chondrocytes were expanded on macroporous gelatin microcarriers in a spinner flask system. The cell-seeded microcarriers were allowed to form pellets with or without re-calcified citrated PRP, and subjected to dynamic centrifugation (f = 0.0125 Hz) for a total of 16 min every other day using a standard tabletop centrifuge. Three acceleration curves with differing top speeds (corresponding to 500 g, 1500 g and 3000 g respectively) were used for the experimental groups and unstimulated controls were set for comparison. Pellets were kept in culture for up to 12 weeks, paraffin embedded and sectioned for histological and immunohistochemical analysis. Results showed increasing numbers of cells and ECM with time, as well as a gradual degradation of the gelatin microcarriers, indicating ongoing cell proliferation and metabolism throughout the culture period. Cell densities and ECM formation were more pronounced in the PRP-containing groups after four weeks, although this difference diminished with time. At the last time point several cartilage markers were found in the produced ECM, however including the fibrocartilaginous marker collagen type I. Dynamic centrifugation did not visibly increase the ECM accumulation over the 12-week duration of this experiment, although non-conclusive indications of collagen fiber organization were seen in the two groups with the highest acceleration limits at the last time point.

  • 74.
    Pettersson, Sofia
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Hand och plastikkirurgi. Linköpings universitet, Hälsouniversitetet.
    Wetterö, Jonas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet.
    Tengvall, Pentti
    Institute of Clinical Sciences, Department of Biomaterials, The Sahlgrenska Academy at University of Gothenburg, Gothenburg.
    Kratz, Gunnar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Hand och plastikkirurgi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Hand- och plastikkirurgiska kliniken US.
    Cell expansion of human articular chondrocytes on macroporous gelatine scaffolds: — impact of micro carrier selection on cell proliferation2011Ingår i: Biomedical Materials, ISSN 1748-6041, E-ISSN 1748-605X, Vol. 6, nr 6, s. 065001-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    This study investigates human chondrocyte expansion on four macroporous gelatine microcarriers (CultiSpher) differing with respect to two manufacturing processes—the amount of emulsifier used during initial preparation and the gelatine cross-linking medium. Monolayer-expanded articular chondrocytes from three donors were seeded onto the microcarriers and cultured in spinner flask systems for a total of 15 days. Samples were extracted every other day to monitor cell viability and establish cell counts, which were analysed using analysis of variance and piecewise linear regression. Chondrocyte densities increased according to a linear pattern for all microcarriers, indicating an ongoing, though limited, cell proliferation. A strong chondrocyte donor effect was seen during the initial expansion phase. The final cell yield differed significantly between the microcarriers and our results indicate that manufacturing differences affected chondrocyte densities at this point. Remaining cells stained positive for chondrogenic markers SOX-9 and S-100 but extracellular matrix formation was modest to undetectable. In conclusion, the four gelatine microcarriers supported chondrocyte adhesion and proliferation over a two week period. The best yield was observed for microcarriers produced with low emulsifier content and cross-linked in water and acetone. These results add to the identification of optimal biomaterial parameters for specific cellular processes and populations.

  • 75.
    Pettersson, Sofia
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet.
    Wetterö, Jonas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet.
    Tengvall, Pentti
    University of Gothenburg.
    Kratz, Gunnar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Hand och plastikkirurgi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Hand- och plastikkirurgiska kliniken US.
    Human articular chondrocytes on macroporous gelatin microcarriers form structurally stable constructs with blood-derived biological glues in vitro2009Ingår i: JOURNAL OF TISSUE ENGINEERING AND REGENERATIVE MEDICINE, ISSN 1932-6254, Vol. 35, nr 6, s. 450-460Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Biodegradable macroporous gelatin microcarriers fixed with blood-derived biodegradable glue are proposed as a delivery system for human autologous chondrocytes. Cell-seeded microcarriers were embedded in four biological glues - recalcified citrated whole blood, recalcified citrated plasma with or without platelets, and a commercially available fibrin glue - and cultured in an in vitro model under static conditions for 16 weeks. No differences could be verified between the commercial fibrin glue and the blood-derived alternatives. Five further experiments were conducted with recalcified citrated platelet-rich plasma alone as microcarrier sealant, using two different in vitro culture models and chondrocytes from three additional donors. The microcarriers supported chondrocyte adhesion and expansion as well as extracellular matrix (ECM) synthesis. Matrix formation occurred predominantly at sample surfaces under the static conditions. The presence of microcarriers proved essential for the glues to support the structural takeover of ECM proteins produced by the embedded chondrocytes, as exclusion of the microcarriers resulted in unstable structures that dissolved before matrix formation could occur. Immunohistochemical analysis revealed the presence of SOX-9- and S-100-positive chondrocytes as well as the production of aggrecan and collagen type I, but not of the cartilage-specific collagen type II. These results imply that blood-derived glues are indeed potentially applicable for encapsulation of chondrocyte-seeded microcarriers. However, the static in vitro models used in this study proved incapable of supporting cartilage formation throughout the engineered constructs.

  • 76.
    Rusakiewicz, Sylvie
    et al.
    Institut Gustave Roussy (IGR), Villejuif, France .
    Nocturne, Gaetane
    Université Paris-Sud, Le Kremlin Bicêtre, France.
    Lazure, Thierry
    Hôpitaux Universitaires Paris-Sud, Le Kremlin Bicêtre, France. .
    Semeraro, Michaela
    Institut Gustave Roussy (IGR), Villejuif, France .
    Flament, Caroline
    Institut Gustave Roussy (IGR), Villejuif, France .
    Caillat-Zucman, Sophie
    Hôpital St-Vincent de Paul, Paris, France.
    Sene, Damien
    Hôpital St-Vincent de Paul, Paris, France.
    Delahaye, Nicolas
    Institut Gustave Roussy (IGR), Villejuif, France .
    Vivier, Eric
    Centre d'Immunologie Marseille Luminy, INSERM, U1104, France.
    Chaba, Kariman
    Institut Gustave Roussy (IGR), Villejuif, France .
    Poirier-Colame, Vichnou
    Institut Gustave Roussy (IGR), Villejuif, France .
    Nordmark, Gunnel
    Uppsala University, Sweden .
    Eloranta, Maija-Leena
    Uppsala University, Sweden .
    Eriksson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland.
    Theander, Elke
    Skåne University Hospital, Lund University, Malmö, Sweden.
    Forsblad-dElia, Helena
    Sahlgrenska Academy at University of Gothenburg, Sweden.
    Omdal, Roald
    Stavanger University Hospital, Norway .
    Wahren-Herlenius, Marie
    Karolinska Institutet, Stockholm, Sweden.
    Jonsson, Roland
    University of Bergen, Norway .
    Rönnblom, Lars
    Uppsala University, Sweden .
    Nititham, Joanne
    University of California, San Francisco, USA .
    Taylor, Kimberly E.
    University of California, San Francisco, USA .
    Lessard, Christopher J.
    University of Oklahoma Health Sciences Center, Oklahoma City, USA .
    Moser Sivils, Kathy L.
    University of Oklahoma Health Sciences Center, Oklahoma City, USA .
    Gottenberg, Jacques-Eric
    Strasbourg University Hospital, France .
    Criswell, Lindsey A.
    University of California, San Francisco, USA .
    Miceli-Richard, Corinne
    Institut Gustave Roussy (IGR), Villejuif, France .
    Zitvogel, Laurence
    Institut Gustave Roussy (IGR), Villejuif, France .
    Mariette, Xavier
    Université Paris-Sud, Le Kremlin Bicêtre, France.
    NCR3/NKp30 Contributes to Pathogenesis in Primary Sjögren’s Syndrome2013Ingår i: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 5, nr 195Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Primary Sjögrens syndrome (pSS) is a chronic autoimmune disease characterized by a lymphocytic exocrinopathy. However, patients often have evidence of systemic autoimmunity, and they are at markedly increased risk for the development of non-Hodgkins lymphoma. Similar to other autoimmune disorders, a strong interferon (IFN) signature is present among subsets of pSS patients, although the precise etiology remains uncertain. NCR3/NKp30 is a natural killer (NK)-specific activating receptor regulating the cross talk between NK and dendritic cells and type II IFN secretion. We performed a case-control study of genetic polymorphisms of the NCR3/NKp30 gene and found that rs11575837 (Gandgt;A) residing in the promoter was associated with reduced gene transcription and function as well as protection to pSS. We also demonstrated that circulating levels of NCR3/NKp30 were significantly increased among pSS patients compared with controls and correlated with higher NCR3/NKp30 but not CD16-dependent IFN-gamma secretion by NK cells. Excess accumulation of NK cells in minor salivary glands correlated with the severity of the exocrinopathy. B7H6, the ligand of NKp30, was expressed by salivary epithelial cells. These findings suggest that NK cells may promote an NKp30-dependent inflammatory state in salivary glands and that blockade of the B7H6/NKp30 axis could be clinically relevant in pSS.

  • 77.
    Sahdo, Berolla
    et al.
    Örebro University, Sweden.
    Fransén, Karin
    Örebro University, Sweden.
    Asfaw Idosa, Berhane
    Örebro University, Sweden.
    Eriksson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland.
    Söderquist, Bo
    Örebro University Hospital, Sweden.
    Kelly, Anne
    Örebro University Hospital and Örebro University, Sweden.
    Särndahl, Eva
    Örebro University, Sweden.
    Cytokine Profile in a Cohort of Healthy Blood Donors Carrying Polymorphisms in Genes Encoding the NLRP3 Inflammasome2013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 10Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The NLRP3 inflammasome has been recognized as one of the key components of the innate immunity by sensing a diversity of insults. Inflammasome activation results in the maturation of the pro-inflammatory cytokines interleukin (IL)-1 beta and IL-18. Increased production of IL-1 beta is found in patients with gain-of-function polymorphisms in genes encoding the NLRP3 inflammasome. Since approximately 5% of the Swedish population are heterozygote carriers of these combined gene variants, their impact on inflammasome status and a relationship on disease development is therefore highly relevant to study. The present study investigates levels of inflammasome-produced cytokines as a measure of inflammasome activation in healthy individuals carrying Q705K polymorphism in the NLRP3 gene combined with C10X in the CARD8 gene. Materials and Methods: Genotyping of 1006 healthy blood donors was performed for the polymorphisms Q705K in the NLRP3 and C10X in the CARD8 genes. IL-1 beta, IL-18, IL-33, as well as a number of other pro-inflammatory cytokines, were analyzed by Luminex or ELISA in plasma from individuals carrying the polymorphisms and in age and gender matched non-carrier controls. Results & Discussion: The prevalence of the polymorphisms was in line with previous studies. Plasma levels of IL-1 beta and IL-33 were elevated among carriers of combined Q705K+C10X polymorphisms compared to controls, whereas no difference was found for IL-18 and the other cytokines measured. Moreover, carriers of C10X or Q705K per se had similar plasma levels of IL-1 beta as non-carriers. These data suggest that the combined polymorphisms create inflammasomes with increased basal activation state, which might provide a more favourable innate immune response. In spite of this, it could also represent the mechanisms by which the inflammatory loop is triggered into a long-term inflammatory phenotype.

  • 78.
    Salomonsson, S.
    et al.
    Karolinska Institutet, Stockholm.
    Dzikaite, V.
    Karolinska Institutet, Stockholm.
    Zeffer, E.
    Karolinska Institutet, Stockholm.
    Eliasson, H.
    Karolinska Institutet, Stockholm.
    Ambrosi, A.
    Karolinska Institutet, Stockholm.
    Bergman, G.
    Karolinska Institutet, Stockholm.
    Fernlund, E.
    Skåne University Hospital, Malmö.
    Theander, E.
    Skåne University Hospital, Malmö.
    Öhman, A.
    Uppsala University.
    Rydberg, A.
    Umeå University.
    Skogh, Thomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland.
    Wållberg-Jonsson, S.
    Umeå University.
    Elfving, Å.
    Karolinska Institutet, Stockholm.
    Fored, M.
    Karolinska Institutet, Stockholm.
    Ekbom, A.
    Karolinska Institutet, Stockholm.
    Lundström, U.
    The Queen Silvia Children′s Hospital, Sahlgrenska University Hospital, Göteborg.
    Mellander, M.
    The Queen Silvia Children′s Hospital, Sahlgrenska University Hospital, Göteborg, Sweden.
    Winqvist, O.
    Karolinska Institutet, Stockholm.
    Sonesson, S.-E.
    Karolinska Institutet, Stockholm.
    Gadler, F.
    Karolinska Institutet, Stockholm.
    Jonzon, A.
    Uppsala University.
    Wahren-Herlenius, M.
    Karolinska Institutet, Stockholm.
    A Population-based Investigation of the Autoantibody Profile in Mothers of Children with Atrioventricular Block2011Ingår i: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 74, nr 5, s. 511-517Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The objective of the study was to investigate the antigen specificity and occurrence of individual autoantibodies in mothers of children diagnosed with atrioventricular (AV) block in a nation-wide setting. Patients with AV block detected before 15 years of age were identified using national quality registries as well as a network of pediatric and adult cardiologists and rheumatologists at the six university hospitals in Sweden. Patients with gross heart malformations, surgically or infectiously induced blocks were excluded. Blood samples were obtained from the mothers and maternal autoantibody profile, including the occurrence of antibodies against Ro52, Ro60, La, SmB, SmD, RNP-70k, RNP-A, RNP-C, CENP-C, Scl-70, Jo-1, ribosomal RNP and histones was investigated in 193 mothers of children with AV block by immunoblotting and ELISA. Autoantibody reactivity was detected in 48% (93/193) of the mothers of children with AV block. In autoantibody-positive mothers, the vast majority, 95% (88/93), had antibodies against Ro52, while 63% (59/93) had autoantibodies to Ro60 and 58% (54/93) had autoantibodies to La. In addition, 13% (12/93) of the autoantibody-positive mothers had antibodies to other investigated antigens besides Ro52, Ro60 and La, and of these anti-histone antibodies were most commonly represented, detected in 8% (7/93) of the mothers. In conclusion, this Swedish population-based study confirms that maternal autoantibodies may associate with heart block in the child. Further, our data demonstrate a dominant role of Ro52 antibodies in association with AV block.

  • 79.
    Shleev, Sergey
    et al.
    Malmö University.
    Wetterö, Jonas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet.
    Magnusson , Karl-Eric
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
    Ruzgas, Tautgirdas
    Malmö University.
    Simultaneous use of electrochemistry and chemiluminescence to detect reactive oxygen species produced by human neutrophils2008Ingår i: Cell Biology International, ISSN 1065-6995, E-ISSN 1095-8355, Vol. 32, nr 12, s. 1486-1496Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A novel approach for the simultaneous optical and electrochemical detection of biologically produced reactive oxygen species has been developed and applied. The set-up consists of a luminol-dependent chemiluminescence assay combined with two amperometric biosensors sensitive to superoxide anion radicals (O-2(center dot-))and hydrogen peroxide (H2O2), respectively. The method permits direct, real-time in vitro determination of both extra-and intracellular O-2(center dot-) and H2O2 produced by human neutrophil granulocytes. The rate of O-2(center dot-) production by stimulated neutrophils was calculated to about 10(-17) mol s(-1) per single cell. With inhibited NADPH oxidase, a distinct extracellular release of H2O2 instead of O-2(center dot-) was obtained from stimulated neutrophils with the rate of about 3 . 10(-18) mol s(-1) per single cell. When the H2O2 release was discontinued, fast H2O2 utilisation was observed. Direct interaction with and possibly attachment of neutrophils to redox protein-modified gold electrodes, resulted in a spontaneous respiratory burst in the population of cells closely associated to the electrode surface. Hence, further stimulation of human neutrophils with a potent receptor agonist (fMLF) did not significantly increase the O-2(center dot-) sensitive amperometric response. By contrast, the H2O2 sensitive biosensor, based on an HRP-modified graphite electrode, was able to reflect the bulk concentration of H2O2, produced by stimulated neutrophils and would be very useful in modestly equipped biomedical research laboratories. In summary, the system would also be appropriate for assessment of several other metabolites in different cell types, and tissues of varying complexity, with only minor electrode modifications.

  • 80.
    Simard, Julia F
    et al.
    Karolinska Institute.
    Arkema, Elizabeth V
    Lund University.
    Saxne, Tore
    Lund University.
    Baecklund, Eva
    Uppsala University.
    Cöster, Lars
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Medicincentrum, Länskliniken för Reumatologi i Östergötland.
    Dackhammar, Christina
    Sahlgrens University Hospital.
    Jacobsson, Lennart
    Lund University.
    Feltelius, Nils
    Medical Product Agency, Uppsala.
    Lindblad, Staffan
    Karolinska Institute.
    Rantapaa-Dahlqvist, Solbritt
    Umea University, Department Med, Rheumatol Unit, University Hospital, Umea, Sweden .
    Klareskog, Lars
    Karolinska Institute, Karolinska University Hospital, Department Med, Rheumatol Unit, S-17176 Stockholm, Sweden .
    van Vollenhoven, Ronald F
    Karolinska Institute.
    Neovius, Martin
    Karolinska Institute.
    Ten years with biologics: to whom do data on effectiveness and safety apply?2011Ingår i: RHEUMATOLOGY, ISSN 1462-0324, Vol. 50, nr 1, s. 204-213Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Methods. We identified all adult patients with RA (n = 9612), PsA (n = 1417) and other SpA (n = 1652) initiating a first biologic therapy between 1 January 1999 and 31 December 2008, registered in the Swedish Biologics Register (ARTIS), including information on demographics, disease characteristics and 1-year risk of first-line treatment discontinuation. Results. Over calendar time, measures of disease activity at start declined substantially for all indications, and diminished between first-, second- and third-line therapy starts. One-year risks of first-line therapy discontinuation increased. Switchers to anti-TNF and non-TNF biologics had different comorbidities. Despite andlt; 50% drug retention at 5 years, most patients remained exposed to some biologic. Conclusions. The trends in baseline characteristics and drug retention underscores that any effects of biologics, including comparison between different biologics, must be interpreted in light of the characteristics of the population treated. The observed differences further call for continued vigilance to properly evaluate the safety profiles of biologic treatments as they are currently used. Exposure to multiple biologics presents a challenge for attribution of long-term effects.

  • 81.
    Sjöwall, Christoffer
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Närsjukvården i centrala Östergötland, Länskliniken för Reumatologi i Östergötland.
    Nivåer av autoantikroppar mot CRP samvarierar med sjukdomsaktiviteten vid SLE2006Ingår i: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 103, nr 21-22, s. 1705-Artikel i tidskrift (Övrigt vetenskapligt)
  • 82.
    Sjöwall, Christoffer
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet.
    Bengtsson, Anders A
    Department of Rheumatology, Lund University Hospital, Sweden.
    Sturfelt, Gunnar
    Department of Rheumatology, Lund University Hospital, Sweden.
    Skogh, Thomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet.
    Serum levels of autoantibodies against monomeric C-reactive protein are correlated with disease activity in systemic lupus erythematosus2004Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 6, nr 2, s. R:87-94Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    This study was performed to investigate the relation between IgG autoantibodies against human C-reactive protein (anti-CRP) and disease activity measures in serial serum samples from 10 patients with systemic lupus erythematosus (SLE), of whom four had active kidney involvement during the study period. The presence of anti-CRP was analysed by enzyme-linked immunosorbent assay. The cut-off for positive anti-CRP test was set at the 95th centile of 100 healthy blood donor sera. Specificity of the anti-CRP antibody binding was evaluated by preincubating patient sera with either native or monomeric CRP. Disease activity was determined by the SLE disease activity index (SLEDAI), serum levels of CRP, anti-DNA antibodies, complement components and blood cell counts. Of 50 serum samples, 20 (40%) contained antibodies reactive with monomeric CRP, and 7 of 10 patients were positive on at least one occasion during the study. All patients with active lupus nephritis were positive for anti-CRP at flare. Frequent correlations between anti-CRP levels and disease activity measures were observed in anti-CRP-positive individuals. Accumulated anti-CRP data from all patients were positively correlated with SLEDAI scores and anti-DNA antibody levels, whereas significant inverse relationships were noted for complement factors C1q, C3 and C4, and for lymphocyte counts. This study confirms the high prevalence of anti-CRP autoantibodies in SLE and that the antibody levels are correlated with clinical and laboratory disease activity measures. This indicates that anti-CRP antibodies might have biological functions of pathogenetic interest in SLE. Further prospective clinical studies and experimental studies on effects mediated by anti-CRP antibodies are warranted.

  • 83.
    Sjöwall, Christoffer
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland.
    Cardell, Kristina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Infektionsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Infektionskliniken i Östergötland.
    Bokarewa, Maria I
    University of Gothenburg.
    Enocsson, Helena
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Ekstedt, Mattias
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Gastroenterologi och hepatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Endokrin- och magtarmmedicinska kliniken US.
    Lindvall, Liselott
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Infektionsmedicin. Linköpings universitet, Hälsouniversitetet.
    Frydén, Aril
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Infektionsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Infektionskliniken i Östergötland.
    Almer, Sven
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Gastroenterologi och hepatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Endokrin- och magtarmmedicinska kliniken US.
    High prevalence of autoantibodies to C-reactive protein in patients with chronic hepatitis C infection: association with liver fibrosis and portal inflammation2012Ingår i: Human Immunology, ISSN 0198-8859, E-ISSN 1879-1166, Vol. 73, nr 4, s. 382-388Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The presence of autoantibodies against C-reactive protein (anti-CRP) has been reported in association with autoimmunity and histopathology in chronic hepatitis C virus (HCV) infection. Resistin could play a role in the pathogenesis of hepatitis, although results on HCV infection are ambiguous. Here we retrospectively analyzed anti-CRP and resistin levels in the sera of 38 untreated and well-characterized HCV patients at the time of their first liver biopsy. HCV activity and general health were assessed by a physician at least yearly until follow-up ended. Anti-CRP and resistin were also measured in patients with autoimmune hepatitis (AIH) and nonalcoholic fatty liver disease (NAFLD). Anti-CRP antibodies were registered in all HCV patients, whereas only a few AIH (11%) and NAFLD (12%) sera were positive. Anti-CRP levels were related to histopathological severity and were highest in patients with cirrhosis at baseline. Resistin levels were similar in HCV, AIH, and NAFLD patients, but high levels of resistin were associated with early mortality in HCV patients. Neither anti-CRP nor resistin predicted a response to interferon-based therapy or cirrhosis development or was associated with liver-related mortality. We conclude that anti-CRP antibodies are frequently observed in chronic HCV infection and could be a useful marker of advanced fibrosis and portal inflammation.

  • 84.
    Sjöwall, Christoffer
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Medicincentrum, Länskliniken för Reumatologi i Östergötland.
    Ernerudh, Jan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk immunologi. Linköpings universitet, Hälsouniversitetet.
    Bengtsson, Anders A
    Department of Rheumatology, Lund University Hospital, Lund, Sweden.
    Sturfelt, Gunnar
    Department of Rheumatology, Lund University Hospital, Lund, Sweden.
    Skogh, Thomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Medicincentrum, Länskliniken för Reumatologi i Östergötland.
    Reduced anti-TNFα autoantibody levels coincide with flare in systemic lupus erythematosus2004Ingår i: Journal of Autoimmunity, ISSN 0896-8411, Vol. 22, nr 4, s. 315-323Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Deviating cytokine patterns, as a consequence of aberrant immunoregulation, is implicated to be of aetiopathogenetic importance in systemic lupus erythematosus (SLE). To evaluate the possibility of anti-cytokine autoantibody-mediated cytokine regulation/dysregulation, IgG class autoantibodies against cytokines (IL-1β, IL-6, IL-10, TNFα and TGFβ1) were analysed by enzyme-linked immunosorbent assay (ELISA) in serial serum samples from clinically well-characterized SLE patients and in normal human sera (NHS). Anti-TNFα autoantibody levels were lower in patients with active disease compared to inactive disease (P<0.001) as well as to NHS (P<0.001). The anti-TNFα antibody levels correlated inversely to the SLE disease activity index (SLEDAI) (r2=0.07, P<0.01), whereas anti-TGFβ antibodies were raised in SLE and correlated positively to levels of complement factor C1q (r2=0.08, P<0.005). Generally raised anti-cytokine antibody levels and correlations to disease activity measures were found in one individual. Inverse correlations were found comparing SLEDAI scores and autoantibodies to TNFα (r2=0.92) and IL-6 (r2=0.86) and positive correlations were found between levels of anti-TNFα and C1q (r2=0.86) and C3 (r2=0.90). We show, for the first time, a coincidence between reduced anti-TNFα autoantibody levels and disease exacerbation in SLE, which is of interest regarding aetiopathogenesis and disease control.

  • 85.
    Sjöwall, Christoffer
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland.
    Kastbom, Alf
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland.
    Almroth, Gunnel
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet.
    Wetterö, Jonas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet.
    Skogh, Thomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland.
    Beware of Antibodies to Dietary Proteins in "Antigen-specific" Immunoassays! Falsely Positive Anticytokine Antibody Tests Due to Reactivity with Bovine Serum Albumin in Rheumatoid Arthritis (The Swedish TIRA Project)2011Ingår i: JOURNAL OF RHEUMATOLOGY, ISSN 0315-162X, Vol. 38, nr 2, s. 215-220Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective. To evaluate (1) to what extent sera from healthy subjects and patients with rheumatoid arthritis (RA) contain antibodies to bovine serum albumin (BSA); and (2) if anti-BSA antibodies interfere with results of enzyme-linked immunoassays (ELISA) containing BSA. Methods. The ELISA used was a previously developed in-house assay of autoantibodies to tumor necrosis factor (TNF). Anti-TNF and anti-BSA antibodies were analyzed by ELISA in 189 patients with early RA and 186 healthy blood donors. TNF preparations containing either BSA or human serum albumin (HSA) as carrier proteins were used as antigens in the anti-TNF assay. The presence and levels of antibodies were analyzed in relation to disease course and to the presence/absence of rheumatoid factor (RF). Results. In patients with RA, anti-TNF/BSA levels strongly correlated with anti-BSA levels (r = 0.81, p andlt; 0.001), whereas anti-TNF/HSA did not (r = -0.09). Neither the presence nor the levels of anti-BSA in RA patients were associated with disease progression, and antibody levels were not significantly altered compared to controls (p = 0.11). IgG reactivity with TNF/HSA was neglible. In paired sera, preincubation with BSA abolished the anti-TNF/BSA reactivity. There were no indications of RF interference with anti-BSA or anti-TNF reactivity. Conclusion. Antibodies to BSA are common in patients with RA as well as in healthy individuals. Their presence does not seem to be associated with RA disease activity or disease course, but may severely interfere with ELISA containing BSA. The use of BSA as a "blocking agent" or carrier protein in immunoassays should therefore be avoided.

  • 86.
    Sjöwall, Christoffer
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland.
    Olin, Anders I.
    Infection Medicine, Department of Clinical Sciences, Lund University, Lund, Sweden.
    Skogh, Thomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland.
    Wetterö, Jonas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland.
    Mörgelin, Matthias
    Infection Medicine, Department of Clinical Sciences, Lund University, Lund, Sweden.
    Nived, Ola
    Rheumatology, Department of Clinical Sciences, Lund University, Lund, Sweden.
    Sturfelt, Gunnar
    Rheumatology, Department of Clinical Sciences, Lund University, Lund, Sweden.
    Bengtsson, Anders A.
    Rheumatology, Department of Clinical Sciences, Lund University, Lund, Sweden.
    C-reactive protein, immunoglobulin G and complement co-localize in renal immune deposits of proliferative lupus nephritis2013Ingår i: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 46, nr 3, s. 205-214Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The pattern recognition molecules C-reactive protein (CRP) and C1q are of big interest in relation to the pathogenesis of systemic lupus erythematosus (SLE). Circulating autoantibodies against CRP and C1q are frequently found in SLE patients with active disease, particularly in lupus nephritis (LN), and rising levels reportedly relate to disease activity and outcome. If CRP-, or dsDNA- and/or C1q-containing immune complexes (ICs) are pathogenic in LN, glomerular IgG-deposits would be expected to co-localize with these antigens. In search for proof of this concept, renal biospsies from patients with active LN (n=5) were examined with high-resolution immunogold electron microscopy. Renal biopsies from patients with Henoch-Schönlein purpura, pauci-immune nephritis and renal cancer served as controls. IgG antibodies against CRP, C1q and nucleosomes were analyzed in pre–post flare sera. We could demonstrate that CRP, C1q, C3c and dsDNA were co-localized with IgG in electron dense deposits in the glomerular basement membrane/subendothelial space in all of the 5 LN patients. Deposits of IgG, CRP, complement and dsDNA were 10-fold higher in LN compared to controls. All SLE patients had circulating anti-nucleosome antibodies; 4/5 had serum antibodies against CRP, dsDNA, and C1q at biopsy/flare. Despite a limited number of cases, the results support the notion of a pathogenic role not only for anti-dsDNA antibodies, but also for anti-CRP and anti-C1q in LN. The glomerular ICs may have been generated by deposition of circulating ICs or by in situ IC formation.

  • 87.
    Sjöwall, Christoffer
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Medicincentrum, Länskliniken för Reumatologi i Östergötland.
    Wetterö, Jonas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet.
    Bengtsson, Torbjörn
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Askendal, Agneta
    Linköpings universitet, Institutionen för fysik, kemi och biologi. Linköpings universitet, Tekniska högskolan.
    Skogh, Thomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Tekniska högskolan. Östergötlands Läns Landsting, Medicincentrum, Länskliniken för Reumatologi i Östergötland.
    Tengvall, Pentti
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Tillämpad Fysik. Linköpings universitet, Tekniska högskolan.
    Solid-phase classical complement activation by C-reactive protein (CRP) is inhibited by fluid-phase CRP-C1q interaction2007Ingår i: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 352, nr 1, s. 251-258Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    C-reactive protein (CRP) interacts with phosphorylcholine (PC), Fcγ receptors, complement factor C1q and cell nuclear constituents, yet its biological roles are insufficiently understood. The aim was to characterize CRP-induced complement activation by ellipsometry. PC conjugated with keyhole limpet hemocyanin (PC-KLH) was immobilized to cross-linked fibrinogen. A low-CRP serum with different amounts of added CRP was exposed to the PC-surfaces. The total serum protein deposition was quantified and deposition of IgG, C1q, C3c, C4, factor H, and CRP detected with polyclonal antibodies. The binding of serum CRP to PC-KLH dose-dependently triggered activation of the classical pathway. Unexpectedly, the activation was efficiently down-regulated at CRP levels >150 mg/L. Using radial immunodiffusion, CRP–C1q interaction was observed in serum samples with high CRP concentrations. We propose that the underlying mechanism depends on fluid-phase interaction between C1q and CRP. This might constitute another level of complement regulation, which has implications for systemic lupus erythematosus where CRP is often low despite flare-ups.

  • 88.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet.
    C-reactive protein (CRP) and anti-CRP autoantibodies in systemic lupus erythematosus: a study on the occurrence and clinical implications of anti-CRP antibodies and CRP-mediated complement activation2006Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by production of a wide range of autoantibodies, multiple organ involvement and by local formation or tissue deposition of immune complexes (ICs) in the inflamed organs. In contrast to most systemic inflammatory conditions, and despite raised levels of pro-inflammatory cytokines, SLE flares are rarely reflected by elevated C-reactive protein (CRP), an important acute-phase reactant in man with homologs in vertebrates and several invertebrates. As a part of the innate immune system, CRP binds certain molecules exposed on the surface of dying cells/apoptotic bodies and on the surface of pathogens and mediates their elimination by uptake in the reticuloendothelial system. CRP also interacts with IgG-containing immune complexes, binds Fc receptors and activates the complement system via C1q.

    The aims of this thesis were to investigate the complement activation properties of CRP; to elucidate if anti-CRP antibodies occur in SLE and, if so, whether anti-CRP antibody levels correlate with disease activity in SLE; to test the hypothesis that autoantibodies to pro-inflammatory cytokines prevent rise of CRP; and to survey if autoantibodies to certain nuclear antigens or to CRP correlate with cytokine-inducing properties of ICs from SLE sera.

    We have demonstrated that CRP bound to phosphorylcholine is a powerful activator of the classical complement pathway already in the CRP concentration range 4 to 10 mg/L, but with a marked inhibition at CRP levels above 150 mg/L. Autoantibodies to the monomeric form of CRP were found in approximately 40 percent of SLE patients and in a few sera from patients with primary Sjögren’s syndrome, but not in rheumatoid arthritis or in inflammatory bowel disease. The anti-CRP antibody levels showed significant correlations to several laboratory and clinical measurements, and anti-CRP positivity was associated with renal involvement in SLE. Native CRP levels were not correlated with anti-CRP or anti-cytokine antibody levels. Hence, the presence of antibodies to monomeric CRP or to CRP-inducing cytokines is an unlikely explanation to the relative failure of CRP response in patients with active lupus. However, antibodies to TNFα were found in subnormal levels at disease flares, whereas antibodies to TGFβ were found in supranormal levels as compared to healthy subjects. In contrast to antibodies against CRP and DNA, anti-SSA and anti-SSB antibodies may regulate the inflammatory process in SLE by enhancing IC formation and subsequent production of cytokines such as IL-6, IL-10 and IL-12p40. Hypothetically, anti-CRP autoantibodies may be of pathogenic importance, for instance by binding to monomeric CRP on cell and tissue surfaces and thereby increasing the risk of extrahepatic deposition of apoptotic material and in situ formation of ICs.

  • 89.
    Sjöwall, Christopher
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Medicincentrum, Länskliniken för Reumatologi i Östergötland.
    Eriksson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Medicincentrum, Länskliniken för Reumatologi i Östergötland.
    Almer, Sven
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Gastroenterologi och hepatologi. Linköpings universitet, Hälsouniversitetet.
    Skogh, Thomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Medicincentrum, Länskliniken för Reumatologi i Östergötland.
    Autoantibodies to C-reactive protein is a common finding in SLE, but not in primary Sjögren’s syndrome, rheumatoid arthritis or inflammatory bowel disease2002Ingår i: Journal of Autoimmunity, ISSN 0896-8411, Vol. 19, nr 3, s. 155-160Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The occurrence of antibodies to human C-reactive protein (CRP) was analysed by enzyme-linked immunosorbent assay (ELISA) in 56 patient sera known to contain antibodies to double-stranded DNA (dsDNA) and in 16 sera from patients with primary Sjögren's syndrome (SS), 15 rheumatoid arthritis, 31 Crohn's disease, and 37 ulcerative colitis. Eighty-seven per cent of the patients with anti-dsDNA antibodies had systemic lupus erythematosus (SLE) and the remaining had autoimmune hepatitis. The cut-off for positive anti-CRP test was set at the 95th percentile of 100 healthy blood donors. Twenty of 56 anti-dsDNA sera (36%) and two of 16 SS sera (13%) had antibodies reactive with human CRP, whereas all other samples were negative. Thirteen of 27 SLE patients (48%) were positive on at least one occasion. The sera containing anti-CRP antibodies only reacted with surface-bound antigen, but not with native CRP in solution. In conclusion, we found that autoantibodies to CRP are common in sera from patients with anti-dsDNA antibodies. It is not likely that this explains the relative failure of CRP response in patients with active SLE. However, it cannot be excluded that anti-CRP autoantibodies have other biological potentials of pathophysiological interest in SLE, for instance by binding to CRP deposited on cell and tissue surfaces.

  • 90.
    Sjöwall, Christopher
    et al.
    Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Medicincentrum, Länskliniken för Reumatologi i Östergötland.
    Sturm, Martin
    Dahle, Charlotte
    Linköpings universitet, Hälsouniversitetet.
    Bengtsson, Anders A
    Jönsen, Andreas
    Sturfelt, Gunnar
    Skogh, Thomas
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Östergötlands Läns Landsting, Medicincentrum, Länskliniken för Reumatologi i Östergötland.
    Abnormal Antinuclear Antibody Titers Are Less Common Than Generally Assumed in Established Cases of Systemic Lupus Erythematosus2008Ingår i: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 35, s. 1994-2000Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE: To evaluate antinuclear antibody (ANA) tests in established cases of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) by indirect immunofluorescence microscopy (F-ANA) and enzyme-immunoassays detecting antinucleosomal antibodies (ANSA-EIA). METHODS: Sera from 50 patients with SLE and 65 patients with RA were analyzed regarding abnormal concentrations of F-ANA (serum dilution >/= 1:200 = 95th percentile among 300 healthy blood donors). The sera were also analyzed with 2 commercial ANSA-EIA kits. RESULTS: An abnormal F-ANA titer occurred in 76% of the SLE sera compared to 23% in RA, and was not related to present use of antirheumatic drugs. At dilution 1:50, 84% of the SLE sera were F-ANA-positive compared to 20% of healthy women. Forty percent and 56%, respectively, of the SLE sera tested positive in the 2 ANSA-EIA kits. By the most sensitive assay, 96% of the ANSA-positive SLE sera produced a homogenous (chromosomal) F-ANA staining pattern compared to 18% of the ANSA-negative SLE sera. Ten of the 15 F-ANA-positive RA sera (63%) generated homogenous F-ANA staining and 13 (20%) tested positive in the most sensitive ANSA-EIA, but with no correlation to the F-ANA staining pattern. CONCLUSION: The sensitivity of F-ANA at an abnormal titer was surprisingly low (76%) in established cases of SLE. ANSA occurred in 56% of the SLE sera, but also in a fair number (20%) of RA sera. Practically all ANSA-positive SLE sera were identified by chromosomal F-ANA staining. We conclude that the antigen-specific antinucleosomal EIA does not have high enough diagnostic specificity to justify use of this analysis for routine diagnostic purposes.  

  • 91.
    Sjöwall, Christopher
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Östergötlands Läns Landsting, Medicincentrum, Länskliniken för Reumatologi i Östergötland. Linköpings universitet, Hälsouniversitetet.
    Zickert, Agneta
    Karolinska University Hospital, Solna, Sweden.
    Skogh, Thomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Östergötlands Läns Landsting, IC - I-centrum, Länskliniken för Reumatologi i Östergötland. Linköpings universitet, Hälsouniversitetet.
    Wetterö, Jonas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet.
    Gunnarsson, Iva
    Karolinska University Hospital, Solna, Sweden.
    Serum levels of autoantibodies against C-reactive protein correlate with renal disease activity and response to therapy in lupus nephritis2009Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 11, nr 6, s. R188-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction

    Serum levels of C-reactive protein (CRP) seldom reflect disease activity in systemic lupus erythematosus (SLE). We have previously shown that autoantibodies against neo-epitopes of CRP often occur in SLE, but that this does not explain the modest CRP response seen in flares. However, we have repeatedly found that anti-CRP levels parallel lupus disease activity, with highest levels in patients with renal involvement; thus, we aimed to study anti-CRP in a material of well-characterized lupus nephritis patients.

    Methods

    Thirty-eight patients with lupus nephritis were included. Treatment with corticosteroids combined with cyclophosphamide, mycophenolate mofetil or rituximab was started after baseline kidney biopsy. A second biopsy was taken after ≥ 6 months. Serum creatinine, cystatin C, complement, anti-dsDNA, anti-CRP and urinalysis were done on both occasions. Biopsies were evaluated regarding World Health Organisation (WHO) class and indices of activity and chronicity. Renal disease activity was estimated using the British Isles Lupus Assessment Group (BILAG) index.

    Results

    At baseline, 34/38 patients had renal BILAG-A; 4/38 had BILAG-B. Baseline biopsies showed WHO class III (n = 8), IV (n = 19), III to IV/V (n = 3) or V (n = 8) nephritis. Seventeen out of 38 patients were anti-CRP-positive at baseline, and six at follow-up. Overall, anti-CRP levels had dropped at follow-up (P < 0.0001) and anti-CRP levels correlated with renal BILAG (r = 0.29, P = 0.012). A positive anti-CRP test at baseline was superior to anti-dsDNA and C1q in predicting poor response to therapy as judged by renal BILAG. Baseline anti-CRP levels correlated with renal biopsy activity (r = 0.33, P = 0.045), but not with chronicity index. Anti-CRP levels were positively correlated with anti-dsDNA (fluorescence-enhanced immunoassay: r = 0.63, P = 0.0003; Crithidia luciliae immunofluorescence microscopy test: r = 0.44, P < 0.0001), and inversely with C3 (r = 0.35, P = 0.007) and C4 (r = 0.29, P = 0.02), but not with C1q (r = 0.14, P = 0.24). No associations with urinary components, creatinine, cystatin C or the glomerular filtration rate were found.

    Conclusions

    In the present study, we demonstrate a statistically significant correlation between anti-CRP levels and histopathological activity in lupus nephritis, whereas a baseline positive anti-CRP test predicted poor response to therapy. Our data also confirm previous findings of associations between anti-CRP and disease activity. This indicates that anti-CRP could be helpful to assess disease activity and response to therapy in SLE nephritis, and highlights the hypothesis of a pathogenetic role for anti-CRP antibodies in lupus nephritis.

  • 92.
    Skogh, Thomas
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet.
    Bengtsson, Anders A
    Landstinget i Östergötland.
    Dahle, Charlotte
    Lund University Hospital.
    Jonsen, Andreas
    Landstinget i Östergötland.
    Sjöwall, Christoffer
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Medicincentrum, Länskliniken för Reumatologi i Östergötland.
    Sturfelt, Gunnar
    Landstinget i Östergötland.
    Sturm, Martin
    Landstinget i Östergötland.
    Limitations of Antinuclear Antibody Tests (HEp-2) Are Overcome with the Autoimmune Target Test (IT-1) in Systemic Lupus Erythematosus Reply2009Ingår i: British Journal of Rheumatology, ISSN 0263-7103, E-ISSN 1460-2172, Vol. 36, nr 8, s. 1834-1835Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    n/a

  • 93.
    Skogh, Thomas
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Medicincentrum, Länskliniken för Reumatologi i Östergötland.
    Dahle, Charlotte
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk immunologi. Linköpings universitet, Hälsouniversitetet.
    Letter: Comment on: Clinical utility of ANA measured by ELISA compared with ANA measured by immunofluorescence2010Ingår i: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 49, nr 2, s. 396-397Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    n/a

  • 94.
    Skogh, Thomas
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Östergötlands Läns Landsting, Medicincentrum, Länskliniken för Reumatologi i Östergötland.
    Kastbom, Alf
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Östergötlands Läns Landsting, Medicincentrum, Länskliniken för Reumatologi i Östergötland.
    Sjöwall, Christoffer
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Östergötlands Läns Landsting, Medicincentrum, Länskliniken för Reumatologi i Östergötland.
    The B cells are back!2005Ingår i: Drug Discovery Today: Disease Mechanisms, ISSN 1740-6765, Vol. 2, nr 3, s. 351-357Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    New interest has emerged regarding the central roles of B cells in physiological immunoregulation and immunopathogenesis of rheumatoid arthritis (RA), a condition traditionally viewed as T-cell mediated. Thus, B cells, autoantibodies, immune complexes, complement and their cellular receptors are experiencing renewed interest concerning their roles in the initiation and propagation of arthritis. The discovery of citrullinated proteins as targets of autoimmune response in RA has implications regarding aetiopathogenesis, prediction of future disease, diagnosis of recent onset and established arthritis and prediction of disease course and disease outcome. Antibody-based therapies against cytokines, cytokine receptors and B cells contribute to the important advances in antirheumatic therapy. © 2005 Elsevier Ltd. All rights reserved.

  • 95.
    Skoglund, Caroline
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för fysik, kemi och biologi, Molekylär ytfysik och nanovetenskap.
    Wetterö, Jonas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet.
    Bengtsson, Torbjorn
    University of Örebro.
    C1q regulates collagen-dependent production of reactive oxygen species, aggregation and levels of soluble P-selectin in whole blood2012Ingår i: Immunology Letters, ISSN 0165-2478, E-ISSN 1879-0542, Vol. 142, nr 1-2, s. 28-33Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Blood platelets express several receptors involved in immunity (e.g. complement-, toll-like- and Fc gamma-receptors) and release inflammatory mediators. Furthermore, formation of platelet-leukocyte aggregates has an important role during inflammatory conditions such as coronary artery disease. Thus, apart from their well-known role in haemostasis, platelets are today also recognized as cells with immunomodulatory properties. less thanbrgreater than less thanbrgreater thanWe have previously reported regulatory effects of complement protein 1q (C1q) on platelet activation in experimental setups using isolated cells. In the present study we have proceeded by investigating effects of C1q on collagen-induced aggregation, production of reactive oxygen species (ROS), formation of platelet-leukocyte aggregates and levels of soluble P-selectin in whole blood. less thanbrgreater than less thanbrgreater thanImpedance measurements showed that C1q inhibited collagen-induced aggregation whereas it potentiated the collagen-provoked production of ROS in a luminol-dependent chemiluminescence assay. The effects of C1q on aggregation and ROS-production were dependent upon platelets, as they were no longer observed in presence of the platelet (GpIIb/IIIa) inhibitor Reopro. Furthermore, the levels of soluble P-selectin were found to be lowered upon treatment with C1q prior to addition of collagen. There was also a trend towards a decreased formation of large platelet-leukocyte aggregates in collagen-stimulated whole blood following C1q treatment. In conclusion, our data indicate that C1q could have a role in regulating platelet activation and associated leukocyte recruitment during vessel wall injury. This has implications for inflammatory disorders such as coronary artery disease.

  • 96.
    Skoglund, Caroline
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Wetterö, Jonas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet.
    Bengtsson, Torbjörn
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet.
    C1q regulates collagendependentproduction of reactive oxygen species, formation of plateletleukocyteaggregates and levels of soluble Pselectinin whole blood2010Manuskript (preprint) (Övrig (populärvetenskap, debatt, mm))
    Abstract [en]

    Blood platelets are nowadays recognized as cells with immuno‐modulatory properties as they express receptors involved in immunity (e.g. complement‐, toll‐like‐ and Fcγ‐receptors) and release inflammatory mediators. Furthermore, formation of plateletleukocyte aggregates has an important role during inflammatory conditions, e.g. coronary artery disease. We have previously reported regulatory effects of complement protein 1q (C1q) on platelet activation in experimental setups using isolated cells. In the present study we have continued by investigating the effect of C1q on collagen‐induced aggregation and production of reactive oxygen species (ROS), formation of plateletleukocyte aggregates and levels of soluble P‐selectin in whole blood. Impedance measurements showed that C1q, at physiological concentrations, inhibited collageninduced aggregation in whole blood, whereas it potentiated the collagen‐provoked production of ROS in a luminal‐dependent chemiluminescence assay. The potentiation was dependent on platelets, as the effect was not seen when the platelet fibrinogen binding receptor GpIIb/IIIa was blocked by Reopro. Moreover, the formation of large platelet‐leukocyte aggregates in collagen‐stimulated whole blood was inhibited by C1q. This may be explained by the finding that C1q antagonized the collagen‐induced activation, revealed by lowered levels of soluble P‐selectin. In conclusion, C1q may have an important role in regulating platelet activation and associated leukocyte recruitment during vessel wall injury and thus be involved in inflammatory disorders such as coronary artery disease.

  • 97.
    Skoglund, Caroline
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi.
    Wetterö, Jonas
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi.
    Skogh, Thomas
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Östergötlands Läns Landsting, Medicincentrum, Länskliniken för Reumatologi i Östergötland.
    Sjöwall, Christopher
    Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Medicincentrum, Länskliniken för Reumatologi i Östergötland.
    Tengvall, Pentti
    Linköpings universitet, Tekniska högskolan. Linköpings universitet, Institutionen för fysik, kemi och biologi, Tillämpad Fysik.
    Bengtsson, Torbjörn
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    C-reactive protein and C1q regulate platelet adhesion and activation on adsorbed immunoglobulin G and albumin2008Ingår i: Immunology and Cell Biology, ISSN 0818-9641, E-ISSN 1440-1711, Vol. 86, nr 5, s. 466-474Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Blood platelets and C-reactive protein (CRP) are both used clinically as markers of ongoing inflammation, and both participate actively in inflammatory responses, although the biological effects are still incompletely understood. Rapidly adhering platelets express receptors for complement factor 1q (C1q) and the Fc part of immunoglobulin G (IgG), and CRP is known to activate/regulate complement via C1q binding, and to ligate FcγRs. In the present study, we used normal human IgG pre-adsorbed to a well-characterized methylated surface as a model solid-phase immune complex when investigating the effects of CRP and C1q on platelet adhesion and activation. Protein adsorption was characterized using ellipsometry and polyclonal antibodies, and human serum albumin (HSA) and non-coated surfaces were used as reference surfaces. Platelet adhesion to IgG and HSA was inhibited by both C1q and CRP. Furthermore, CRP (moderately) and C1q (markedly) decreased the spreading of adhering platelets. The combination of C1q and CRP was slightly more potent in reducing cell adhesion to IgG, and also impaired the adhesion to HSA and non-coated surfaces. Platelet production of thromboxane B2 (TXB2) was also reduced by C1q both in the presence and absence of CRP, whereas CRP alone had no effect on TXB2 production. We conclude that CRP and C1q regulate the behaviour of platelets, and that this may be an important immunoregulatory mechanism during inflammatory conditions. © 2008 Australasian Society for Immunology Inc. All rights reserved.

  • 98.
    Skoglund, Caroline
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Wetterö, Jonas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet.
    Tengvall, Pentti
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Tillämpad Fysik. Linköpings universitet, Tekniska högskolan.
    Bengtsson, Torbjörn
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    C1q induces a rapid up-regulation of P-selectin and modulates collagen- and collagen-related peptide-triggered activation in human platelets2010Ingår i: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 215, nr 12, s. 987-995Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Blood platelets are emerging as important immunomodulatory cells, but complement interaction with platelets is not well understood. Several platelet structures have been described as complement protein 1q (C1q) binding receptors, such as C1qRp/CD93 and gC1qR. However, there are conflicting results whether these receptors are C1q binding structures, or even at all expressed on the cell surface. Recently, the collagen-binding integrin alphaIIbetaI was reported to bind C1q on mast cells, and this receptor is also present on platelets. The aim of this study was to further characterize the effects of C1q on platelets, by quantifying the platelet surface expression of P-selectin (CD62P) and monitoring the formation of platelet-neutrophil aggregates. Using flow cytometry, we found that C1q dose-dependently triggered a rapid but moderate and transient up-regulation of P-selectin already within 5s of C1q exposure. Pre-incubation with an antibody directed against gC1qR significantly inhibited (with 57% compared to control) the up-regulation, whereas an antibody towards the alphaIIbetaI-integrin showed no effect. Stimulation with C1q did not change the cytosolic calcium-levels, as measured with the fluorescent ratiometric probe Fura-2, however, a protein kinase C inhibitor (GF109203x) blocked the C1q-induced P-selectin expression. Furthermore, pre-incubation of platelets with C1q diminished both the collagen as well as the collagen-related peptide-induced up-regulation of P-selectin, most evident after 90s of stimulation. This indicates that C1q may regulate platelet activation via the GPVI receptor, which is a novel finding. Moreover, C1q antagonized the collagen-induced formation of platelet-neutrophil aggregates, indicating a reduced interaction between platelet P-selectin and neutrophil P-selectin glycoprotein ligand-1(PSGL-1/CD162). In summary, C1q induces a moderate rapid platelet P-selectin expression, modulates subsequent collagen and collagen-related peptide stimulation of platelets, and inhibits the formation of platelet-neutrophil aggregates. These immuno-regulatory effects of C1q may have a crucial role in innate immunity and inflammation.

  • 99.
    Sverker, Annette
    et al.
    Linköpings universitet, Institutionen för samhälls- och välfärdsstudier, Socialt arbete. Linköpings universitet, Filosofiska fakulteten.
    Östlund, Gunnel
    Linköpings universitet, Institutionen för samhälls- och välfärdsstudier, Socialt arbete. Linköpings universitet, Filosofiska fakulteten.
    Thyberg, Mikael
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Rehabiliteringsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Smärt och rehabiliteringscentrum.
    Waltersson, Eva
    Östergötlands Läns Landsting.
    Björk, Matilda
    School of Health Sciences, Jönköping University.
    Thyberg, Ingrid
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Smärt och rehabiliteringscentrum.
    Dilemmas of participation in everyday life in early rheumatoid arthritis (RA): A qualitative interview study (the Swedish TIRA study)2012Ingår i: Health professionals reumatology: EULAR12-2344, 2012Konferensbidrag (Övrigt vetenskapligt)
  • 100.
    Svärd, Anna
    et al.
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet.
    Kastbom, Alf
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet.
    Reckner Olsson, Åsa
    Linköpings universitet, Institutionen för molekylär och klinisk medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet.
    Skogh, Thomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Reumatologi. Linköpings universitet, Hälsouniversitetet.
    Presence and utility of IgA-class antibodies to cyclic citrullinated peptides in early rheumatoid arthritis: the Swedish TIRA project2008Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 10, nr 4Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction

    The present study was carried out to assess whether IgA-class antibodies against cyclic citrullinated peptides (IgA anti-CCP) in recent-onset rheumatoid arthritis add diagnostic and/or prognostic information to IgG anti-CCP analysis.

    Methods

    Serum samples were obtained from 228 patients with recent-onset (<12 months) rheumatoid arthritis at the time of inclusion in the Swedish TIRA cohort (Swedish Early Intervention in Rheumatoid Arthritis). Sera from 72 of these patients were also available at the 3-year follow-up. Disease activity and functional ability measures (erythrocyte sedimentation rate, serum C-reactive protein, 28-joint count Disease Activity Score, physician's assessment of disease activity, and the Swedish version of the Health Assessment Questionnaire) were registered at inclusion and at regular follow-ups during 3 years. An IgA anti-CCP assay was developed based on the commercially available IgG-specific enzyme immunoassay from EuroDiagnostica (Arnhem, the Netherlands), replacing the detection antibody by an anti-human-IgA antibody. A positive IgA anti-CCP test was defined by the 99th percentile among healthy blood donors.

    Results

    At baseline, a positive IgA anti-CCP test was observed in 29% of the patient sera, all of which also tested positive for IgG anti-CCP at a higher average level than sera containing IgG anti-CCP alone. The IgA anti-CCP-positive patients had significantly higher disease activity over time compared with the IgA anti-CCP-negative patients. After considering the IgG anti-CCP level, the disease activity also tended to be higher in the IgA anti-CCP-positive cases – although this difference did not reach statistical significance. The proportion of IgA anti-CCP-positive patients was significantly larger among smokers than among nonsmokers.

    Conclusion

    Anti-CCP antibodies of the IgA class were found in about one-third of patients with recent-onset rheumatoid arthritis, all of whom also had IgG anti-CCP. The occurrence of IgA-class antibodies was associated with smoking, and IgA anti-CCP-positive patients had a more severe disease course over 3 years compared with IgA anti-CCP-negative cases. Although IgA anti-CCP analysis does not seem to offer any diagnostic information in addition to IgG anti-CCP analysis, further efforts are justified to investigate the prognostic implications.

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