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  • 201.
    Christiansson, Lisa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Myeloid-Derived Suppressor Cells and Other Immune Escape Mechanisms in Chronic Leukemia2013Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Chronic myeloid leukemia (CML) is characterized by the Philadelphia chromosome, a minute chromosome that leads to the creation of the fusion gene BCR/ABL and the transcription of the fusion protein BCR/ABL in transformed cells. The constitutively active tyrosine kinase BCR/ABL confers enhanced proliferation and survival on leukemic cells. CML has in only a few decades gone from being a disease with very bad prognosis to being a disease that can be effectively treated with oral tyrosine kinase inhibitors (TKIs). TKIs are drugs inhibiting BCR/ABL as well as other tyrosine kinases. In this thesis, the focus has been on the immune system of CML patients, on immune escape mechanisms present in untreated patients and on how these are affected by TKI therapy. We have found that newly diagnosed, untreated CML patients exert different kinds of immune escape mechanisms. Patients belonging to the Sokal high-risk group had higher levels of myeloid-derived suppressor cells (MDSCs) as well as high levels of the programmed death receptor 1 (PD-1)-expressing cytotoxic T cells compared to control subjects. Moreover, CML patients had higher levels of myeloid cells expressing the ligand for PD-1, PD-L1. CML patients as well as patients with B cell malignacies had high levels of soluble CD25 in blood plasma. In B cell malignacies, sCD25 was found to be released from T regulatory cells (Tregs). Treatment with the TKIs imatinib or dasatinib decreased the levels of MDSCs in peripheral blood. Tregs on the other hand increased during TKI therapy. The immunostimulatory molecule CD40 as well as NK cells increased during therapy, indicating an immunostimulatory effect of TKIs. When evaluating immune responses, multiplex techniques for quantification of proteins such as cytokines and chemokines are becoming increasingly popular. With these techniques a lot of information can be gained from a small sample volume and complex networks can be more easily studied than when using for example the singleplex ELISA. When comparing different multiplex platforms we found that the absolute protein concentration measured by one platform rarely correlated with the absolute concentration measured by another platform. However, relative quantification was better correlated.

  • 202.
    Christoffersson, Gustaf
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    von Herrath, Matthias
    La Jolla Inst Allergy & Immunol, Type Diabet Ctr 1, La Jolla, CA 92037 USA;Novo Nordisk Res Ctr, Seattle, WA 98109 USA.
    Regulatory Immune Mechanisms beyond Regulatory T Cells2019Ingår i: Trends in immunology, ISSN 1471-4906, E-ISSN 1471-4981, Vol. 40, nr 6, s. 482-491Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    In autoimmunity, aggressive immune responses are counteracted by suppressive rejoinders. For instance, FOXP3-expressing regulatory T cells (Tregs), have shown remarkable effects in limiting autoimmunity in preclinical models. However, early results from human Treg trials have not been as positive. Here, we highlight questions surrounding Treg transfers as putative treatments for autoimmunity. We discuss whether lack of antigenic recognition might be key to shifting cells from contributing to an aggressive autoresponse, to being part of a regulatory network. Moreover, we argue that identifying the physiological range of immunosuppression of Tregs might help potentiate their efficacy. We propose widening the view on immunoregulation by considering the participation of CD8(+) Tregs in this process, which could have major implications in autoimmunity.

  • 203.
    Christoffersson, Gustaf
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Vågesjö, Evelina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Vandooren, Jennifer
    Liden, Majken
    Massena, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Reinert, RB
    Brissova, M
    Powers, AC
    Opdenakker, Ghislain
    Phillipson, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    VEGF-A recruits a proangiogenic MMP-9-delivering neutrophil subset that induces angiogenesis in transplanted hypoxic tissue2012Ingår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 120, nr 23, s. 4653-4662Artikel i tidskrift (Refereegranskat)
    Abstract [sv]

    Recruitment and retention of leukocytes at a site of blood vessel growth are crucial for proper angiogenesis and subsequent tissue perfusion. Although critical for many aspects of regenerative medicine, the mechanisms of leukocyte recruitment to and actions at sites of angiogenesis are not fully understood. In this study, we investigated the signals attracting leukocytes to avascular transplanted pancreatic islets and leukocyte actions at the engraftment site. Expression of the angiogenic stimulus VEGF-A by mouse pancreatic islets was elevated shortly after syngeneic transplantation to muscle. High levels of leukocytes, predominantly CD11b+/Gr-1+/CXCR4hi neutrophils, were observed at the site of engraftment, whereas VEGF-A–deficient islets recruited only half of the amount of leukocytes when transplanted. Acute VEGF-A exposure of muscle increased leukocyte extravasation but not the levels of SDF-1α. VEGF-A–recruited neutrophils expressed 10 times higher amounts of MMP-9 than neutrophils recruited to an inflammatory stimulus. Revascularization of islets transplanted to MMP-9–deficient mice was impaired because blood vessels initially failed to penetrate grafts, and after 2 weeks vascularity was still disturbed. This study demonstrates that VEGF-A recruits a proangiogenic circulating subset of CD11b+/Gr-1+ neutrophils that are CXCR4hi and deliver large amounts of the effector protein MMP-9, required for islet revascularization and functional integration after transplantation.

  • 204. Chuangchaiya, S
    et al.
    Jangpatarapongsa, K
    Chootong, P
    Sirichaisinthop, J
    Sattabongkot, J
    Pattanapanyasat, K
    Chotivanich, K
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Cui, L
    Udomsangpetch, R
    Immune response to Plasmodium vivax has a potential to reduce malaria severity2010Ingår i: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 160, nr 2, s. 233-239Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Summary Plasmodium falciparum infection causes transient immunosuppression during the parasitaemic stage. However, the immune response during simultaneous infections with both P. vivax and P. falciparum has been investigated rarely. In particular, it is not clear whether the host's immune response to malaria will be different when infected with a single or mixed malaria species. Phenotypes of T cells from mixed P. vivax-P. falciparum (PV-PF) infection were characterized by flow cytometry, and anti-malarial antibodies in the plasma were determined by an enzyme-linked immunosorbent assay. We found the percentage of CD3(+)delta2(+)-T cell receptor (TCR) T cells in the acute-mixed PV-PF infection and single P. vivax infection three times higher than in the single P. falciparum infection. This implied that P. vivax might lead to the host immune response to the production of effector T killer cells. During the parasitaemic stage, the mixed PV-PF infection had the highest number of plasma antibodies against both P. vivax and P. falciparum. Interestingly, plasma from the group of single P. vivax or P. falciparum malaria infections had both anti-P. vivax and anti-P. falciparum antibodies. In addition, antigenic cross-reactivity of P. vivax or P. falciparum resulting in antibodies against both malaria species was shown in the supernatant of lymphocyte cultures cross-stimulated with either antigen of P. vivax or P. falciparum. The role of delta2 +/- TCR T cells and the antibodies against both species during acute mixed malaria infection could have an impact on the immunity to malaria infection.

  • 205. Clendenen, Tess V
    et al.
    Koenig, Karen L
    Arslan, Alan A
    Lukanova, Annekatrin
    Berrino, Franco
    Gu, Yian
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Idahl, Annika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Krogh, Vittorio
    Lokshin, Anna E
    Lundin, Eva
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Muti, Paola
    Marrangoni, Adele
    Nolen, Brian M
    Ohlson, Nina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Shore, Roy E
    Sieri, Sabina
    Zeleniuch-Jacquotte, Anne
    Factors associated with inflammation markers, a cross-sectional analysis2011Ingår i: Cytokine, ISSN 1043-4666, E-ISSN 1096-0023, Vol. 56, nr 3, s. 769-778Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Epidemiological studies have reported associations between circulating inflammation markers and risk of chronic diseases. It is of interest to examine whether risk factors for these diseases are associated with inflammation. We conducted a cross-sectional analysis to evaluate whether reproductive and lifestyle factors and circulating vitamin D were associated with inflammation markers, including C-reactive protein, cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p40, IL-12p70, IL-13, TNFα), and cytokine modulators (IL-1RA, sIL-1RII, sIL-2Ra, sIL-4R, sIL-6R, sTNF-R1/R2), among 616 healthy women. We confirmed associations of several inflammation markers with age and BMI. We also observed significantly higher levels of certain inflammation markers in postmenopausal vs. premenopausal women (TNFα, sIL-1RII, sIL-2Ra), with increasing parity (IL-12p40), and with higher circulating 25(OH) vitamin D (IL-13) and lower levels among current users of non-steroidal anti-inflammatory drugs (NSAIDs) (IL-1β, IL-2, IL-10, IL-12p70, and IL-12p40), current smokers (IL-4, IL-13, IL-12p40), and women with a family history of breast or ovarian cancer (IL-4, IL-10, IL-13). Our findings suggest that risk factors for chronic diseases (age, BMI, menopausal status, parity, NSAID use, family history of breast and ovarian cancer, and smoking) are associated with inflammation markers in healthy women.

  • 206. Codemo, Mario
    et al.
    Muschiol, Sandra
    Iovino, Federico
    Nannapaneni, Priyanka
    Plant, Laura
    Wai, Sun Nyunt
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Henriques-Normark, Birgitta
    Immunomodulatory Effects of Pneumococcal Extracellular Vesicles on Cellular and Humoral Host Defenses2018Ingår i: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 9, nr 2, artikel-id e00559-18Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Gram-positive bacteria, including the major respiratory pathogen Streptococcus pneumoniae, were recently shown to produce extracellular vesicles (EVs) that likely originate from the plasma membrane and are released into the extracellular environment. EVs may function as cargo for many bacterial proteins, however, their involvement in cellular processes and their interactions with the innate immune system are poorly understood. Here, EVs from pneumococci were characterized and their immunomodulatory effects investigated. Pneumococcal EVs were protruding from the bacterial surface and released into the medium as 25 to 250 nm lipid stained vesicles containing a large number of cytosolic, membrane, and surface-associated proteins. The cytosolic pore-forming toxin pneumolysin was significantly enriched in EVs compared to a total bacterial lysate but was not required for EV formation. Pneumococcal EVs were internalized into A549 lung epithelial cells and human monocyte-derived dendritic cells and induced proinflammatory cytokine responses irrespective of pneumolysin content. EVs from encapsulated pneumococci were recognized by serum proteins, resulting in C3b deposition and formation of C5b-9 membrane attack complexes as well as factor H recruitment, depending on the presence of the choline binding protein PspC. Addition of EVs to human serum decreased opsonophagocytic killing of encapsulated pneumococci. Our data suggest that EVs may act in an immunomodulatory manner by allowing delivery of vesicle-associated proteins and other macromolecules into host cells. In addition, EVs expose targets for complement factors in serum, promoting pneumococcal evasion of humoral host defense.

    Importance: Streptococcus pneumoniae is a major contributor to morbidity and mortality worldwide, being the major cause of milder respiratory tract infections such as otitis and sinusitis and of severe infections such as community-acquired pneumonia, with or without septicemia, and meningitis. More knowledge is needed on how pneumococci interact with the host, deliver virulence factors, and activate immune defenses. Here we show that pneumococci form extracellular vesicles that emanate from the plasma membrane and contain virulence properties, including enrichment of pneumolysin. We found that pneumococcal vesicles can be internalized into epithelial and dendritic cells and bind complement proteins, thereby promoting pneumococcal evasion of complement-mediated opsonophagocytosis. They also induce pneumolysin-independent proinflammatory responses. We suggest that these vesicles can function as a mechanism for delivery of pneumococcal proteins and other immunomodulatory components into host cells and help pneumococci to avoid complement deposition and phagocytosis-mediated killing, thereby possibly contributing to the symptoms found in pneumococcal infections.

  • 207. Cohen, Cheryl
    et al.
    Walaza, Sibongile
    Moyes, Jocelyn
    Groome, Michelle
    Tempia, Stefano
    Pretorius, Marthi
    Hellferscee, Orienka
    Dawood, Halima
    Chhagan, Meera
    Naby, Fathima
    Haffejee, Summaya
    Variava, Ebrahim
    Kahn, Kathleen
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och global hälsa.
    Nzenze, Susan
    Tshangela, Akhona
    von Gottberg, Anne
    Wolter, Nicole
    Cohen, Adam L.
    Kgokong, Babatyi
    Venter, Marietjie
    Madhi, Shabir A.
    Epidemiology of Viral-associated Acute Lower Respiratory Tract Infection Among Children < 5 Years of Age in a High HIV Prevalence Setting, South Africa, 2009-20122015Ingår i: The Pediatric Infectious Disease Journal, ISSN 0891-3668, E-ISSN 1532-0987, Vol. 34, nr 1, s. 66-72Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Data on the epidemiology of viral-associated acute lower respiratory tract infection (LRTI) from high HIV prevalence settings are limited. We aimed to describe LRTI hospitalizations among South African children aged < 5 years. Methods: We prospectively enrolled hospitalized children with physician-diagnosed LRTI from 5 sites in 4 provinces from 2009 to 2012. Using polymerase chain reaction (PCR), nasopharyngeal aspirates were tested for 10 viruses and blood for pneumococcal DNA. Incidence was estimated at 1 site with available population denominators. Results: We enrolled 8723 children aged < 5 years with LRTI, including 64% < 12 months. The case-fatality ratio was 2% (150/8512). HIV prevalence among tested children was 12% (705/5964). The overall prevalence of respiratory viruses identified was 78% (6517/8393), including 37% rhinovirus, 26% respiratory syncytial virus (RSV), 7% influenza and 5% human metapneumovirus. Four percent (253/6612) tested positive for pneumococcus. The annual incidence of LRTI hospitalization ranged from 2530 to 3173/100,000 population and was highest in infants (8446-10532/100,000). LRTI incidence was 1.1 to 3.0-fold greater in HIV-infected than HIV-uninfected children. In multivariable analysis, compared to HIV-uninfected children, HIV-infected children were more likely to require supplemental-oxygen [odds ratio (OR): 1.3, 95% confidence interval (CI): 1.1-1.7)], be hospitalized > 7 days (OR: 3.8, 95% CI: 2.8-5.0) and had a higher case-fatality ratio (OR: 4.2, 95% CI: 2.6-6.8). In multivariable analysis, HIV-infection (OR: 3.7, 95% CI: 2.2-6.1), pneumococcal coinfection (OR: 2.4, 95% CI: 1.1-5.6), mechanical ventilation (OR: 6.9, 95% CI: 2.7-17.6) and receipt of supplemental-oxygen (OR: 27.3, 95% CI: 13.2-55.9) were associated with death. Conclusions: HIV-infection was associated with an increased risk of LRTI hospitalization and death. A viral pathogen, commonly RSV, was identified in a high proportion of LRTI cases.

  • 208. Cohen, Cheryl
    et al.
    Walaza, Sibongile
    Moyes, Jocelyn
    Groome, Michelle
    Tempia, Stefano
    Pretorius, Marthi
    Hellferscee, Orienka
    Dawood, Halima
    Haffejee, Summaya
    Variava, Ebrahim
    Kahn, Kathleen
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och global hälsa.
    Tshangela, Akhona
    von Gottberg, Anne
    Wolter, Nicole
    Cohen, Adam L.
    Kgokong, Babatyi
    Venter, Marietjie
    Madhi, Shabir A.
    Epidemiology of Severe Acute Respiratory Illness (SARI) among Adults and Children Aged >= 5 Years in a High HIV-Prevalence Setting, 2009-20122015Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, nr 2, artikel-id e0117716Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective There are few published studies describing severe acute respiratory illness ( SARI) epidemiology amongst older children and adults from high HIV-prevalence settings. We aimed to describe SARI epidemiology amongst individuals aged >= 5 years in South Africa. Methods We conducted prospective surveillance for individuals with SARI from 2009-2012. Using polymerase chain reaction, respiratory samples were tested for ten viruses, and blood for pneumococcal DNA. Cumulative annual SARI incidence was estimated at one site with population denominators. Findings We enrolled 7193 individuals, 9% (621/7067) tested positive for influenza and 9%(600/6519) for pneumococcus. HIV-prevalence was 74% (4663/6334). Among HIV-infected individuals with available data, 41% of 2629 were receiving antiretroviral therapy (ART). The annual SARI hospitalisation incidence ranged from 325-617/100,000 population. HIV-infected individuals experienced a 13-19 times greater SARI incidence than HIV-uninfected individuals (p<0.001). On multivariable analysis, compared to HIV-uninfected individuals, HIV-infected individuals were more likely to be receiving tuberculosis treatment (odds ratio (OR): 1.7; 95% CI:1.1-2.7), have pneumococcal infection (OR 2.4; 95% CI: 1.7-3.3) be hospitalised for >7 days rather than <2 days (OR1.7; 95% CI: 1.2-2.2) and had a higher case-fatality ratio (8% vs 5%; OR1.7; 95% CI: 1.2-2.3), but were less likely to be infected with influenza (OR 0.6; 95% CI: 0.5-0.8). On multivariable analysis, independent risk indicators associated with death included HIV infection (OR 1.8; 95% CI: 1.3-2.4), increasing age-group, receiving mechanical ventilation (OR 6.5; 95% CI: 1.3-32.0) and supplemental-oxygen therapy (OR 2.6; 95% CI: 2.1-3.2). Conclusion The burden of hospitalized SARI amongst individuals aged >= 5 years is high in South Africa. HIV-infected individuals are the most important risk group for SARI hospitalization and mortality in this setting.

  • 209. Commins, Scott P.
    et al.
    James, Hayley R.
    Kelly, Libby A.
    Pochan, Shawna L.
    Workman, Lisa J.
    Perzanowski, Matthew S.
    Kocan, Katherine M.
    Fahy, John V.
    Nganga, Lucy W.
    Rönmark, Eva
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Yrkes- och miljömedicin.
    Cooper, Philip J.
    Platts-Mills, Thomas A. E.
    The relevance of tick bites to the production of IgE antibodies to the mammalian oligosaccharide galactose-alpha-1,3-galactose2011Ingår i: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 127, nr 5, s. 1286-1293.e6Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: In 2009, we reported a novel form of delayed anaphylaxis to red meat that is related to serum IgE antibodies to the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal). Most of these patients had tolerated meat for many years previously. The implication is that some exposure in adult life had stimulated the production of these IgE antibodies. Objectives: We sought to investigate possible causes of this IgE antibody response, focusing on evidence related to tick bites, which are common in the region where these reactions occur.

    Methods: Serum assays were carried out with biotinylated proteins and extracts bound to a streptavidin ImmunoCAP.

    Results: Prospective studies on IgE antibodies in 3 subjects after tick bites showed an increase in levels of IgE to alpha-gal of 20fold or greater. Other evidence included (1) a strong correlation between histories of tick bites and levels of IgE to alpha-gal (chi(2) = 26.8, P < .001), (2) evidence that these IgE antibodies are common in areas where the tick Amblyomma americanum is common, and (3) a significant correlation between IgE antibodies to alpha-gal and IgE antibodies to proteins derived from A americanum (r(s) = 0.75, P < .001).

    Conclusion: The results presented here provide evidence that tick bites are a cause, possibly the only cause, of IgE specific for alpha-gal in this area of the United States. Both the number of subjects becoming sensitized and the titer of IgE antibodies to alpha-gal are striking. Here we report the first example of a response to an ectoparasite giving rise to an important form of food allergy.

  • 210.
    Conlan, J Wayne
    et al.
    NRC, Kanada.
    Shen, Hua
    Golovliov, Igor
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Zingmark, Carl
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Oyston, Petra CF
    Chen, Wangxue
    House, Robert V
    Sjöstedt, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Differential ability of novel attenuated targeted deletion mutants of Francisella tularensis subspecies tularensis strain SCHU S4 to protect mice against aerosol challenge with virulent bacteria: effects of host background and route of immunization2010Ingår i: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 28, nr 7, s. 1824-1831Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Francisella tularensis subspecies tularensis is a highly virulent facultative intracellular pathogen of humans and a potential biological weapon. A live vaccine strain, F. tularensis LVS, was developed more than 50 years ago by pragmatic attenuation of a strain of the less virulent holarctica subspecies. LVS was demonstrated to be highly effective in human volunteers who were exposed to intradermal challenge with fully virulent subsp. tularensis, but was less effective against aerosol exposure. LVS faces regulatory hurdles that to date have prevented its licensure for general use. Therefore, a better defined and more effective vaccine is being sought. To this end we have created gene deletion mutants in the virulent subsp. tularensis strain and tested them for their ability to elicit a protective immune response against systemic or aerosol challenge with the highly virulent wild-type subsp. tularensis strain, SCHU S4. Both oral and intradermal (ID) primary vaccination routes were assessed in BALB/c and C3H/HeN mice as was oral boosting. One SCHU S4 mutant missing the heat shock gene, clpB, was significantly more attenuated than LVS whereas a double deletion mutant missing genes FTT0918 and capB was as attenuated as LVS. In general mice immunized with SCHU S4DeltaclpB were significantly better protected against aerosol challenge than mice immunized with LVS. A single ID immunization of BALB/c mice with SCHU S4DeltaclpB was at least as effective as any other regimen examined. Mice immunized with SCHU S4Delta0918DeltacapB were generally protected to a similar degree as mice immunized with LVS. A preliminary examination of immune responses to vaccination with LVS, SCHU S4DeltaclpB, or SCHU S4Delta0918DeltacapB provided no obvious correlate to their relative efficacies.

  • 211. Coppi, Alida
    et al.
    Natarajan, Ramya
    Pradel, Gabriele
    Bennett, Brandy L.
    James, Eric R.
    Roggero, Mario A.
    Corradin, Giampietro
    Persson, Cathrine
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Tewari, Rita
    Sinnis, Photini
    The malaria circumsporozoite protein has two functional domains, each with distinct roles as sporozoites journey from mosquito to mammalian host2011Ingår i: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 208, nr 2, s. 341-356Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Plasmodium sporozoites make a remarkable journey from the mosquito midgut to the mammalian liver. The sporozoite's major surface protein, circumsporozoite protein (CSP), is a multifunctional protein required for sporozoite development and likely mediates several steps of this journey. In this study, we show that CSP has two conformational states, an adhesive conformation in which the C-terminal cell-adhesive domain is exposed and a nonadhesive conformation in which the N terminus masks this domain. We demonstrate that the cell-adhesive domain functions in sporozoite development and hepatocyte invasion. Between these two events, the sporozoite must travel from the mosquito midgut to the mammalian liver, and N-terminal masking of the cell-adhesive domain maintains the sporozoite in a migratory state. In the mammalian host, proteolytic cleavage of CSP regulates the switch to an adhesive conformation, and the highly conserved region I plays a critical role in this process. If the CSP domain architecture is altered such that the cell-adhesive domain is constitutively exposed, the majority of sporozoites do not reach their target organs, and in the mammalian host, they initiate a blood stage infection directly from the inoculation site. These data provide structure-function information relevant to malaria vaccine development.

  • 212. Courtin, David
    et al.
    Milet, Jacqueline
    Bertin, Gwladys
    Vafa, Manijeh
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Sarr, Jean Birame
    Watier, Laurence
    Deloron, Philippe
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
    Garcia, André
    Migot-Nabias, Florence
    G6PD A-variant influences the antibody responses to Plasmodium falciparum MSP2.2011Ingår i: Infection, Genetics and Evolution, ISSN 1567-1348, E-ISSN 1567-7257, Vol. 11, nr 6, s. 1287-1292Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    High antibody levels directed to Plasmodium falciparum merozoite surface proteins (MSP), including MSP2, as well as genetically related red blood cell defects, have previously been found to be associated with protection against malaria. Here, our main objective was to study the changes in MSP2-specific total IgG, IgG1 and IgG3 responses during a malaria transmission season in order to assess the impact of sickle-cell, α(+)-thalassemia and G6PD variants on antibody kinetics. Repeated parasitological assessments of a cohort of children were conducted during an 8-month period. Antibody responses to recombinant MSP2/3D7 and MSP2/FC27 proteins were measured at the beginning and at the end of transmission season. We found that (i) the period of last Plasmodium falciparum infection during the transmission season was associated with IgG3 anti-MSP2 change. Compared to the IgG3 levels of children infected in January 2003 (end of transmission season), the IgG3 level of children decreased with the length of the period without infection, (ii) G6PD A- carriers had a lower increase of IgG3 levels to MSP2/FC27 and MSP2/3D7 during the transmission season than the noncarriers. This latter finding is suggestive of qualitative and/or quantitative reduction of exposure to malarial antigens related to this genetic variant, leading to weaker stimulation of specific antibody responses. We speculate that cell-mediated immune activity may explain the clinical protection afforded by this genetic trait.

  • 213.
    Crespo-Felez, I.
    et al.
    University of Leon, Spain.
    Castaneda-Sampedro, A.
    University of Leon, Spain.
    Sanchez, D. I.
    University of Leon, Spain.
    Fernandez-Alegre, E.
    University of Leon, Spain.
    Alvarez-Rodriguez, Manuel
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten.
    Dominguez, J. C.
    University of Leon, Spain.
    Morrell, J. M.
    Swedish University of Agriculture Science, Sweden.
    Martinez-Pastor, F.
    University of Leon, Spain; University of Leon, Spain.
    Effect of Single Layer Centrifugation Porcicoll (70%, 80% and 90%) or supplementation with reduced glutathione, seminal plasma and bovine serum albumin on frozen-thawed boar sperm2017Ingår i: Animal Reproduction Science, ISSN 0378-4320, E-ISSN 1873-2232, Vol. 187, s. 167-173Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Selecting the optimal sperm population is essential for success with reproductive techniques. Porcicoll (formerly Androcoll-P) is a colloid formulation for selection of high-quality boar spermatozoa by single layer centrifugation (SLC). To date, most studies have been carried out with fresh semen and large volumes. We carried out 2 experiments to test the use of Porcicoll for thawed boar semen in small volumes. In Experiment 1, cryopreserved semen doses were thawed, split in 200-pL aliquots and layered on 1 mL of Porcicoll 70%, 80% or 90%, or buffer without colloid. We assessed sperm recovery (the proportion of the loading dose that appeared in the pellet, %), and the physiology of the selected spermatozoa (flow cytometry: Viability, apoptotic changes, capacitation, mitochondrial activity, intracellular reactive oxygen species). The most suitable proportion was Porcicoll 80%, allowing acceptable sperm recovery (16.9 4.2%, compared to 70% (35.4% 3.0, p amp;lt; 0.001) and 90% (8.2% 3.0, P = 0.001), and improved quality (mitochondrial activity: Porcicoll 80%: 77.7 1% vs Control: 60.3 0.7%, P amp;lt; 0.05). In Experiment 2, we compared 3 supplements to Porcicoll 80%: 500 mM reduced glutathione (GSH), 20% seminal plasma (SP) and 0.5% bovine serum albumin (BSA). Supplementation with GSH or BSA did not cause relevant changes relative to Control. In contrast, SP induced membrane and acrosomal changes resembling capacitation, which might preclude its use in some applications, and decreased recovery (5.5% 1.9 vs. 24.3% 1.2 Control; P amp;lt; 0.001). However, it could be useful prior to other applications such as in vitro fertilisation. Overall, Porcicoll is an effective colloid for isolating a high-quality population from thawed boar sperm, 80% being a balanced option for good recovery and high quality. Supplements could be useful depending on the proposed use of the spermatozoa.

  • 214.
    Cros, Olivier
    Linköpings universitet, Institutionen för medicinsk teknik. Linköpings universitet, Tekniska fakulteten.
    Structural properties of the mastoid using image analysis and visualization2017Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The mastoid, located in the temporal bone, houses an air cell system whose cells have a variation in size that can go far below current conventional clinical CT scanner resolution. Therefore, the mastoid air cell system is only partially represented in a CT scan. Where the conventional clinical CT scanner lacks level of minute details, micro-CT scanning provides an overwhelming amount of ne details. The temporal bone being one of the most complex in the human body, visualization of micro-CT scanning of this boneawakens the curiosity of the experimenter, especially with the correct visualization settings.

    This thesis first presents a statistical analysis determining the surface area to volume ratio of the mastoid air cell system of human temporal bone, from micro-CT scanning using methods previously applied for conventional clinical CT scans. The study compared current results with previous studies, with successive downsampling the data down to a resolution found in conventional clinical CT scanning. The results from the statistical analysis showed that all the small mastoid air cells, that cannot be detected in conventional clinical CT scans, do heavily contribute to the estimation of the surface area, and in consequence to the estimation of the surface area to volume ratio by a factor of about 2.6. Such a result further strengthens the idea of the mastoid to play an active role in pressure regulation and gas exchange.

    Discovery of micro-channels through specific use of a non-traditional transfer function was then reported, where a qualitative and a quantitative pre-analysis were performed and reported. To gain more knowledge about these micro-channels, a local structure tensor analysis was applied where structures are described in terms of planar, tubular, or isotropic structures. The results from this structural tensor analysis suggest these microchannels to potentially be part of a more complex framework, which hypothetically would provide a separate blood supply for the mucosa lining the mastoid air cell system.

    The knowledge gained from analysing the micro-channels as locally providing blood to the mucosa, led to the consideration of how inflammation of the mucosa could impact the pneumatization of the mastoid air cell system. Though very primitive, a 3D shape analysis of the mastoid air cell system was carried out. The mastoid air cell system was first represented in a compact form through a medial axis, from which medial balls could be used. The medial balls, representative of how large the mastoid air cells can be locally, were used in two complementary clustering methods, one based on the size diameter of the medial balls and one based on their location within the mastoid air cell system. From both quantitative and qualitative statistics, it was possible to map the clusters based on pre-defined regions already described in the literature, which opened the door for new hypotheses concerning the effect of mucosal inflammation on the mastoid pneumatization.

    Last but not least, discovery of other structures, previously unreported in the literature, were also visually observed and briefly discussed in this thesis. Further analysis of these unknown structures is needed.

  • 215.
    Cui, Yue
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Dahlin, Joakim S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Feinstein, Ricardo
    Bankova, Lora G.
    Xing, Wei
    Shin, Kichul
    Gurish, Michael F.
    Hallgren, Jenny Martinsson
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Mouse Mast Cell Protease-6 and MHC Are Involved in the Development of Experimental Asthma2014Ingår i: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 193, nr 10, s. 4783-4789Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Allergic asthma is a complex disease with a strong genetic component where mast cells play a major role by the release of proinflammatory mediators. In the mouse, mast cell protease-6 (mMCP-6) closely resembles the human version of mast cell tryptase, beta-tryptase. The gene that encodes mMCP-6, Tpsb2, resides close by the H-2 complex (MHC gene) on chromosome 17. Thus, when the original mMCP-6 knockout mice were backcrossed to the BALB/c strain, these mice were carrying the 129/Sv haplotype of MHC (mMCP-6(-/-)/H-2bc). Further backcrossing yielded mMCP-6(-/-) mice with the BALB/c MHC locus. BALB/c mice were compared with mMCP-6(-/-) and mMCP-6(-/-)/H-2bc mice in a mouse model of experimental asthma. Although OVA-sensitized and challenged wild type mice displayed a striking airway hyperresponsiveness (AHR), mMCP-6(-/-) mice had less AHR that was comparable with that of mMCP-6(-/-)/H-2bc mice, suggesting that mMCP-6 is required for a full-blown AHR. The mMCP-6(-/-)/H-2bc mice had strikingly reduced lung inflammation, IgE responses, and Th2 cell responses upon sensitization and challenge, whereas the mMCP-6(-/-) mice responded similarly to the wild type mice but with a minor decrease in bronchoalveolar lavage eosinophils. These findings suggest that inflammatory Th2 responses are highly dependent on the MHC-haplotype and that they can develop essentially independently of mMCP-6, whereas mMCP-6 plays a key role in the development of AHR.

  • 216.
    Cunningham, Anthony L.
    et al.
    Univ Sydney, Westmead Inst Med Res, Sydney, NSW, Australia.
    Heineman, Thomas C.
    GSK, King Of Prussia, PA USA;Genocea Biosci, Cambridge, MA USA.
    Lal, Himal
    GSK, King Of Prussia, PA USA;Pfizer Inc, Collegeville, PA USA.
    Godeaux, Olivier
    GSK, Wavre, Belgium;Janssen Vaccines & Prevent, Leiden, Netherlands.
    Chlibek, Roman
    Univ Def, Fac Mil Hlth Sci, Hradec Kralove, Czech Republic.
    Hwang, Shinn-Jang
    Taipei Vet Gen Hosp, Dept Family Med, Taipei, Taiwan;Natl Yang Ming Univ, Sch Med, Taipei, Taiwan.
    McElhaney, Janet E.
    Hlth Sci North Res Inst, Sudbury, ON, Canada.
    Vesikari, Timo
    Univ Tampere, Vaccine Res Ctr, Tampere, Finland.
    Andrews, Charles
    Diagnost Res Grp, San Antonio, TX USA.
    Choi, Won Suk
    Korea Univ, Coll Med, Dept Internal Med, Div Infect Dis, Seoul, South Korea.
    Esen, Meral
    Univ Clin Tuebingen, Inst Trop Med, Tubingen, Germany.
    Ikematsu, Hideyuki
    Japan Phys Assoc, Chiyoda Ku, Tokyo, Japan.
    Choma, Martina Kovac
    GSK, Rockville, MD USA.
    Pauksen, Karlis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionssjukdomar.
    Ravault, Stephanie
    GSK, Rixensart, Belgium.
    Salaun, Bruno
    GSK, Rixensart, Belgium.
    Schwarz, Tino F.
    Standort Juliusspital, Klinikum Wurzburg Mitte, Cent Lab & Vaccinat Ctr, Wurzburg, Germany.
    Smetana, Jan
    Univ Def, Fac Mil Hlth Sci, Hradec Kralove, Czech Republic.
    Vanden Abeele, Carline
    GSK, Wavre, Belgium.
    Van den Steen, Peter
    GSK, Wavre, Belgium.
    Vastiau, Ilse
    GSK, Wavre, Belgium.
    Weckx, Lily Yin
    Univ Fed Sao Paulo, Sao Paulo, Brazil.
    Levin, Myron J.
    Univ Colorado, Dept Pediat, Anschutz Med Campus, Aurora, CO USA;Univ Colorado, Dept Med, Anschutz Med Campus, Aurora, CO USA.
    Immune Responses to a Recombinant Glycoprotein E Herpes Zoster Vaccine in Adults Aged 50 Years or Older2018Ingår i: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 217, nr 11, s. 1750-1760Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background. The herpes zoster subunit vaccine (HZ/su), consisting of varicella-zoster virus glycoprotein E (gE) and AS01(B) Adjuvant System, was highly efficacious in preventing herpes zoster in the ZOE-50 and ZOE-70 trials. We present immunogenicity results from those trials. Methods. Participants (ZOE-50: >= 50; ZOE-70: >= 70 years of age) received 2 doses of HZ/su or placebo, 2 months apart. Serum anti-gE antibodies and CD4 T cells expressing >= 2 of 4 activation markers assessed (CD4(2+)) after stimulation with gE-peptides were measured in subcohorts for humoral (n = 3293) and cell-mediated (n = 466) immunogenicity. Results. After vaccination, 97.8% of HZ/su and 2.0% of placebo recipients showed a humoral response. Geometric mean anti-gE antibody concentrations increased 39.1-fold and 8.3-fold over baseline in HZ/su recipients at 1 and 36 months post-dose 2, respectively. A gE-specific CD4(2+) T-cell response was shown in 93.3% of HZ/su and 0% of placebo recipients. Median CD42+ T-cell frequencies increased 24.6-fold (1 month) and 7.9-fold (36 months) over baseline in HZ/su recipients and remained >= 5.6-fold above baseline in all age groups at 36 months. The proportion of CD4 T cells expressing all 4 activation markers increased over time in all age groups. Conclusions. Most HZ/su recipients developed robust immune responses persisting for 3 years following vaccination.

  • 217.
    Dadgar, Ashraf
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Methods for identification and diagnosis of amyloidosis2006Självständigt arbete på avancerad nivå (magisterexamen), 10 poäng / 15 hpStudentuppsats
    Abstract [sv]

    Amyloidos är ett sjukdomstillstånd där proteiner som normalt är lösliga i kroppen felveckas och formar långa olösliga fibriller som ansamlas i vävnader och organ såsom t.ex. hjärta, hjärna och lever. Det finns cirka 25 proteiner som kan ge upphov till amyloidos. Man kan skilja på två huvudgrupper av amyloidos, systemisk och lokaliserad. Vid lokal amyloidos kan inlagringar förekomma i specifika vävnader vid framför allt vissa åldersberoende sjukdomar som t.ex. Alzheimers sjukdom. Vid systemisk amyloidos förekommer inlagringar i praktiskt taget alla vävnader. Symtomatologin vid systemisk amyloidos är variabel och sjukdomsbilden kan vara svårtolkad men tidig och specifik diagnostik ger möjlighet till riktad terapi mot den bakomliggande sjukdomen. Syftet med denna studie var att utvärdera en Western blot metod som använts för typning av vanligaste formerna av systemisk amyloidos. De slutsatser som nåtts är att denna metod är snabbt, pålitligt och enkel att utföra. Diagnos erhölls med finnålsbiopsi av bukfettvävnad som är enkel, snabb och billig metod med liten risk för patienternas hälsa. Vi lyckades också med hjälp av immunhistokemisk infärgning titta på prevalens av amyloid i aortas intima.

  • 218.
    Dahlbom, I
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Olsson, M
    Forooz, NK
    Sjöholm, AG
    Truedsson, L
    Hansson, Tony
    Department of Rheumatology, Karolinska Institute.
    Immunoglobulin G (IgG) Anti-Tissue Transglutaminase Antibodies Used as Markers for IgA-Deficient Celiac Disease Patients.2005Ingår i: Clin Diagn Lab Immunol., Vol. 12, nr 2, s. 254-258Artikel i tidskrift (Refereegranskat)
  • 219.
    Dahlin, Joakim S
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Feinstein, Ricardo
    Statens veterinärmedicinska anstalt.
    Cui, Yue
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Heyman, Birgitta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Hallgren, Jenny
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    CD11c(+) Cells Are Required for Antigen-Induced Increase of Mast Cells in the Lung2012Ingår i: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 189, nr 8, s. 3869-3877Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Patients with allergic asthma have more lung mast cells, which likely worsens the symptoms. In experimental asthma, CD11c(+) cells have to be present during the challenge phase for several features of allergic inflammation to occur. Whether CD11c(+) cells play a role for Ag-induced increases of lung mast cells is unknown. In this study, we used diphtheria toxin treatment of sensitized CD11c-diphtheria toxin receptor transgenic mice to deplete CD11c(+) cells. We demonstrate that recruitment of mast cell progenitors to the lung is substantially reduced when CD11c(+) cells are depleted during the challenge phase. This correlated with an impaired induction of endothelial VCAM-1 and led to a significantly reduced number of mature mast cells 1 wk after challenge. Collectively, these data suggest that Ag challenge stimulates CD11c(+) cells to produce cytokines and/or chemokines required for VCAM-1 upregulation on the lung endothelium, which in turn is crucial for the Ag-induced mast cell progenitor recruitment and the increase in mast cell numbers.

  • 220.
    Dahlin, Joakim S
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Hallgren, Jenny
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Mast cell progenitors: Origin, development and migration to tissues2015Ingår i: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 63, nr 1, s. 9-17Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Mast cells in tissues are developed from mast cell progenitors emerging from the bone marrow in a process highly regulated by transcription factors. Through the advancement of the multicolor flow cytometry technique, the mast cell progenitor population in the mouse has been characterized in terms of surface markers. However, only cell populations with enriched mast cell capability have been described in human. In naïve mice, the peripheral tissues have a constitutive pool of mast cell progenitors. Upon infections in the gut and in allergic inflammation in the lung, the local mast cell progenitor numbers increase tremendously. This review focuses on the origin and development of mast cell progenitors. Furthermore, the evidences for cells and molecules that govern the migration of these cells in mice in vivo are described.

  • 221.
    Dahlin, Joakim S
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Heyman, Birgitta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Hallgren, Jenny
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Committed mast cell progenitors in mouse blood differ in maturity between Th1 and Th2 strains2013Ingår i: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 68, nr 10, s. 1333-1337Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Mast cell progenitors (MCp) leave the bone marrow and migrate to peripheral tissues where they mature. Although the existence of committed MCp in adult mouse and human blood has been postulated, they have never been found. We have isolated a rare population of cells in adult mouse blood, committed to the mast cell lineage. These were identified as lineage c-kithi ST2+ integrin β7hi CD16/32hi cells. Moreover, a major difference in maturity of these cells based on FcεRI expression was observed between the Th2-prone BALB/c strain and the Th1-prone C57BL/6 strain (66% vs 25% FcεRI+, respectively). Therefore, the choice of mouse strain is critical when studying disease models such as experimental asthma where mast cells and their progenitors are involved.

  • 222. Darsow, U.
    et al.
    Brockow, K.
    Pfab, F.
    Jakob, T.
    Petersson, C. J.
    Borres, M. P.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Pediatrik.
    Ring, J.
    Behrendt, H.
    Huss-Marp, J.
    Heterogeneity of molecular sensitization profiles in grass pollen allergy - implications for immunotherapy?2014Ingår i: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 44, nr 5, s. 778-786Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BackgroundData on molecular allergy diagnostics in adults with grass pollen allergy with regard to conjunctival and nasal provocation test outcome and specific immunotherapy are lacking to date. ObjectiveTo assess whether molecular allergy diagnostics for grass pollen allergens could help with predicting provocation test outcomes and serve as a basis for future component-resolved specific immunotherapy. MethodsSera of 101 adults with grass pollen allergy was analysed for IgE against timothy grass pollen (Phleum pratense), rPhl p 1, rPhl p 2, nPhl p 4, rPhl p 5b, rPhl p 6, rPhl p 7, rPhl p 11 and rPhl p12 and correlated with the individuals' outcome in the nasal and conjunctival provocation tests and investigated in regard to a potential component-resolved specific immunotherapy. ResultsAn increasing number of sensitizations to timothy grass allergens was correlated to a positive reaction in the conjunctival (4.9 vs. 3.6, P=0.003) and nasal provocation tests (4.5 vs. 2.2, P=0.0175). In molecular sensitization profiles, a substantial heterogeneity was detected, with none of the patients exactly matching the allergen composition of a previously published component-resolved specific immunotherapy containing Phl p 1, Phl p 2, Phl p 5a/b and Phl p 6. The results indicate that in 95% of the patients, a proportion of 50% of timothy-IgE would be targeted with such a specific immunotherapy, while in 50% and 10% of patients, 80% and 90% of timothy-IgE would be targeted, respectively. Conclusion and Clinical RelevanceMolecular allergy diagnostics is a prerequisite for future component-resolved specific immunotherapy due to the high heterogeneity of sensitization profiles. However, of current clinical relevance is the observed correlation between the number of sensitizations and provocation test outcome.

  • 223.
    Davey, Dvora Joseph
    et al.
    Mozambique HIV care and treatment - Ark, Maputo, Mozambique; Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles CA, USA.
    Nhavoto, José Antonio
    Örebro universitet, Handelshögskolan vid Örebro Universitet. Department of Mathematics and Informatics, Eduardo Mondlane University, Maputo, Mozambique.
    Augusto, Orvalho
    Department of Community Health, Eduardo Mondlane University, Maputo, Mozambique.
    Ponce, Walter
    Mozambique HIV care and treatment - Ark, Maputo, Mozambique.
    Traca, Daila
    Mozambique HIV care and treatment - Ark, Maputo, Mozambique.
    Nguimfack, Alexandre
    Mozambique HIV care and treatment - Ark, Maputo, Mozambique.
    de Sousa, Cesar Palha
    Department of Community Health, Eduardo Mondlane University, Maputo, Mozambique.
    SMSaude: Evaluating Mobile Phone Text Reminders to Improve Retention in HIV Care for Patients on Antiretroviral Therapy in Mozambique2016Ingår i: Journal of Acquired Immune Deficiency Syndromes, ISSN 1525-4135, E-ISSN 1944-7884, Vol. 73, nr 2, s. E23-E30Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: We evaluated whether regular mobile phone text reminders improved patients' retention in antiretroviral therapy (ART) care in Mozambique.

    Design: SMSaude was a randomized control trial of HIV-infected patients on ART who received regular text message reminder vs. standard of care at 3 public health facilities in Maputo Province, Mozambique. The primary outcome was retention in HIV care. Between November 2011 and March 2012, 830 eligible HIV-infected patients on ART were randomized 1: 1 to the text reminder intervention or standard of care.

    Methods: We used Kaplan-Meier estimators and log-rank tests to compare proportions of patients who received SMS reminders who were retained in HIV care compared to the control group who received standard of care. Post hoc analyses were performed using Cox proportional hazards models stratified by urban/rural facility and when initiated ART (<= 3 months vs. >3 months). Hazard ratios and confidence intervals (CIs) are reported. Analysis was with intention to treat.

    Results: Patients who received text messages had lower attrition from HIV care at 12 months, though the difference was nonsignificant (RR: 0.68, 95% CI: 0.41 to 1.13). Among urban patients, text messages improved retention in HIV care (RR: 0.54, 95% CI: 0.31 to 0.95). Intervention patients newly initiated on ART (<3 months) had lower attrition than control patients (HR: 0.54; 95% CI: 0.23 to 0.91), especially urban newly initiated patients (HR: 0.20, 95% CI: 0.06 to 0.64). Text messages had no effect on retention among rural patients.

    Conclusions: Text messages did not improve retention in HIV care for all patients on ART but improved retention in care of urban patients and those who recently started ART and received text reminders compared with standard of care.

  • 224.
    Davidsson, Sabina
    et al.
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Urology, Örebro University Hospital, Örebro, Sweden; A Member of the Transdisciplinary Prostate Cancer Partnership (TopCaP), Örebro, Sweden .
    Mölling, Paula
    Department of Laboratory Medicine, Clinical Microbiology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Rider, Jennifer R.
    Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.
    Unemo, Magnus
    Örebro universitet, Institutionen för hälsovetenskaper. Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Karlsson, Mats G.
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Laboratory Medicine, Pathology, Örebro University Hospital, Örebro, Sweden.
    Carlsson, Jessica
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Urology, Örebro University Hospital, Örebro, Sweden; A Member of the Transdisciplinary Prostate Cancer Partnership (TopCaP), Örebro, Sweden.
    Andersson, Swen-Olof
    Örebro universitet, Institutionen för hälsovetenskaper. Department of Urology, Örebro University Hospital, Örebro, Sweden; A Member of the Transdisciplinary Prostate Cancer Partnership (TopCaP), Örebro, Sweden.
    Elgh, Fredrik
    Department of Clinical Microbiology, Umeå University, Umeå, Sweden.
    Söderquist, Bo
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Andrén, Ove
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Urology, Örebro University Hospital, Örebro, Sweden; A Member of the Transdisciplinary Prostate Cancer Partnership (TopCaP), Örebro, Sweden.
    Erratum to: Frequency and typing of Propionibacterium acnes in prostate tissue obtained from men with and without prostate cancer2016Ingår i: Infectious Agents and Cancer, ISSN 1750-9378, E-ISSN 1750-9378, Vol. 11, artikel-id 36Artikel i tidskrift (Refereegranskat)
  • 225. Dawoodji, Amina
    et al.
    Chen, Ji-Li
    Shepherd, Dawn
    Dalin, Frida
    Centre of Molecular Medicine, Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden.
    Tarlton, Andrea
    Alimohammadi, Mohammad
    Penna-Martinez, Marissa
    Meyer, Gesine
    Mitchell, Anna L.
    Gan, Earn H.
    Bratland, Eirik
    Bensing, Sophie
    Husebye, Eystein S.
    Pearce, Simon H.
    Badenhoop, Klaus
    Kämpe, Olle
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Autoimmunitet. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Cerundolo, Vincenzo
    High Frequency of Cytolytic 21-Hydroxylase-Specific CD8(+) T Cells in Autoimmune Addison's Disease Patients2014Ingår i: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 193, nr 5, s. 2118-2126Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The mechanisms behind destruction of the adrenal glands in autoimmune Addison's disease remain unclear. Autoantibodies against steroid 21-hydroxylase, an intracellular key enzyme of the adrenal cortex, are found in >90% of patients, but these autoantibodies are not thought to mediate the disease. In this article, we demonstrate highly frequent 21-hydroxylase-specific T cells detectable in 20 patients with Addison's disease. Using overlapping 18-aa peptides spanning the full length of 21-hydroxylase, we identified immunodominant CD8(+) and CD4(+) T cell responses in a large proportion of Addison's patients both ex vivo and after in vitro culture of PBLs <= 20 y after diagnosis. In a large proportion of patients, CD8(+) and CD4(+) 21-hydroxylase-specific T cells were very abundant and detectable in ex vivo assays. HLA class I tetramer guided isolation of 21-hydroxylase-specific CD8(+) T cells showed their ability to lyse 21-hydroxylase-positive target cells, consistent with a potential mechanism for disease pathogenesis. These data indicate that strong CTL responses to 21-hydroxylase often occur in vivo, and that reactive CTLs have substantial proliferative and cytolytic potential. These results have implications for earlier diagnosis of adrenal failure and ultimately a potential target for therapeutic intervention and induction of immunity against adrenal cortex cancer.

  • 226. de Sandt, Carolien E. van
    et al.
    Kreijtz, Joost H. C. M.
    Geelhoed-Mieras, Martina M.
    Vogelzang-van Trierum, Stella E.
    Nieuwkoop, Nella J.
    van de Vijver, David A. M. C.
    Fouchier, Ron A. M.
    Osterhaus, Albert D. M. E.
    Morein, Bror
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionssjukdomar.
    Rimmelzwaan, Guus F.
    Novel G3/DT adjuvant promotes the induction of protective T cells responses after vaccination with a seasonal trivalent inactivated split-virion influenza vaccine2014Ingår i: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 32, nr 43, s. 5614-5623Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Vaccines used against seasonal influenza are poorly effective against influenza A viruses of novel subtypes that may have pandemic potential. Furthermore, pre(pandemic) influenza vaccines are poorly immunogenic, which can be overcome by the use of adjuvants. A limited number of adjuvants has been approved for use in humans, however there is a need for alternative safe and effective adjuvants that can enhance the immunogenicity of influenza vaccines and that promote the induction of broad-protective T cell responses. Here we evaluated a novel nanoparticle, G3, as an adjuvant for a seasonal trivalent inactivated influenza vaccine in a mouse model. The G3 adjuvant was formulated with or without steviol glycosides (DT, for diterpenoid). The use of both formulations enhanced the virus-specific antibody response to all three vaccine strains considerably. The adjuvants were well tolerated without any signs of discomfort. To assess the protective potential of the vaccine-induced immune responses, an antigenically distinct influenza virus strain, A/Puerto Rico/8/34 (A/PR/8/34), was used for challenge infection. The vaccine-induced antibodies did not cross-react with strain A/PR/8/34 in HI and VN assays. However, mice immunized with the G3/DT-adjuvanted vaccine were partially protected against A/PR/8/34 infection, which correlated with the induction of anamnestic virus-specific CD8(+) T cell responses that were not observed with the use of G3 without DT. Both formulations induced maturation of human dendritic cells and promoted antigen presentation to a similar extent. In conclusion, G3/DT is a promising adjuvant formulation that not only potentiates the antibody response induced by influenza vaccines, but also induces T cell immunity which could afford broader protection against antigenically distinct influenza viruses.

  • 227.
    Demirel, Isak
    et al.
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Persson, Alexander
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Brauner, Annelie
    Department of Microbiology, Tumor and Cell Biology, Division of Clinical Microbiology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Särndahl, Eva
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Kruse, Robert
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Clinical Research Laboratory, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Persson, Katarina
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Activation of the NLRP3 Inflammasome Pathway by Uropathogenic Escherichia coli Is Virulence Factor-Dependent and Influences Colonization of Bladder Epithelial Cells2018Ingår i: Frontiers in Cellular and Infection Microbiology, E-ISSN 2235-2988, Vol. 8, artikel-id 81Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The NLRP3 inflammasome and IL-1 beta release have recently been suggested to be important for the progression of urinary tract infection (UTI). However, much is still unknown regarding the interaction of UPEC and the NLRP3 inflammasome. The purpose of this study was to elucidate what virulence factors uropathogenic Escherichia coil (UPEC) use to modulate NLRP3 inflammasome activation and subsequent IL-1 beta release and the role of NLRP3 for UPEC colonization of bladder epithelial cells. The bladder epithelial cell line 5637, CRISPR/Cas9 generated NLRP3, caspase-1 and mesotrypsin deficient cell lines and transformed primary bladder epithelial cells (HBLAK) were stimulated with UPEC isolates and the non-pathogenic MG1655 strain. We found that the UPEC strain CFT073, but not MG1655, induced an increased caspase-1 activity and IL-1 beta release from bladder epithelial cells. The increase was shown to be mediated by et-hemolysin activation of the NLRP3 inflammasome in an NE-kappa B-independent manner. The effect of-hemolysin on IL-1 beta release was biphasic, initially suppressive, later inductive. Furthermore, the phase-locked type-1-fimbrial ON variant of CFT073 inhibited caspase-1 activation and IL-1 beta release. In addition, the ability of CFT073 to adhere to and invade NLRP3 deficient cells was significantly reduced compare to wild-type cells. The reduced colonization of NLRP3-deficient cells was type-1 fimbriae dependent. In conclusion, we found that the NLRP3 inflammasome was important for type-1 fimbriae-dependent colonization of bladder epithelial cells and that both type-1 fimbriae and alpha-hemolysin can modulate the activity of the NLRP3 inflammasome.

  • 228. Demirel, Isak
    et al.
    Vumma, Ravi
    Mohlin, Camilla
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Svensson, Lovisa
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Säve, Susanne
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Persson, Katarina
    Linnéuniversitetet, Fakultetsnämnden för naturvetenskap och teknik, Institutionen för naturvetenskap, NV.
    Nitric Oxide Activates IL-6 Production and Expression in Human Renal Epithelial Cells2012Ingår i: American Journal of Nephrology, ISSN 0250-8095, E-ISSN 1421-9670, Vol. 36, nr 6, s. 524-530Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background/Aims: Increased nitric oxide (NO) production or inducible form of NO synthase activity have been documented in patients suffering from urinary tract infection (UTI), but the role of NO in this infection is unclear. We investigated whether NO can affect the host response in human renal epithelial cells by modulating IL-6 production and mRNA expression. Methods: The human renal epithelial cell line A498 was infected with a uropathogenic Escherichia coli (UPEC) strain and/or the NO donor DETA/NO. The IL-6 production and mRNA expression were evaluated by ELISA and real-time RT-PCR. IL-6 mRNA stability was evaluated by analyzing mRNA degradation by real-time RT-PCR. Results: DETA/NO caused a significant (p < 0.05) increase in IL-6 production. Inhibitors of p38 MAPK and ERK1/2 signaling, but not JNK, were shown to significantly suppress DETA/NO-induced IL-6 production. UPEC-induced IL-6 production was further increased (by 73 +/- 23%, p < 0.05) in the presence of DETA/NO. The IL-6 mRNA expression increased 2.1 +/- 0.17-fold in response to DETA/NO, while the UPEC-evoked increase was pronounced (20 +/- 4.5-fold). A synergistic effect of DETA/NO on UPEC-induced IL-6 expression was found (33 +/- 7.2-fold increase). The IL-6 mRNA stability studies showed that DETA/NO partially attenuated UPEC-induced degradation of IL-6 mRNA. Conclusions: NO was found to stimulate IL-6 in renal epithelial cells through p38 MAPK and ERK1/2 signaling pathways and also to increase IL-6 mRNA stability in UPEC-infected cells. This study proposes a new role for NO in the host response during UTI by modulating the transcription and production of the cytokine IL-6. Copyright (C) 2012 S. Karger AG, Basel

  • 229.
    Dernstedt, Andy
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Serotonin stimulates survival and proliferation of B-cell lymphomas: Effect on proliferation and expression of oncogenes upon inhibition of serotonin signaling in B-cell lymphoma cell lines2016Självständigt arbete på grundnivå (kandidatexamen), 10 poäng / 15 hpStudentuppsats (Examensarbete)
  • 230.
    Desbiens, Louisane
    et al.
    Univ Sherbrooke, Med Sch, Dept Pharmacol & Physiol, Sherbrooke, PQ, Canada.
    Lapointe, Catherine
    Univ Sherbrooke, Med Sch, Dept Pharmacol & Physiol, Sherbrooke, PQ, Canada.
    Gendron, Louis
    Univ Sherbrooke, Med Sch, Dept Pharmacol & Physiol, Sherbrooke, PQ, Canada.
    Gharagozloo, Marjan
    Univ Sherbrooke, Med Sch, Dept Pharmacol & Physiol, Sherbrooke, PQ, Canada.
    Vincent, Laurence
    Univ Sherbrooke, Med Sch, Dept Pharmacol & Physiol, Sherbrooke, PQ, Canada.
    Pejler, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, Uppsala, Sweden.
    Gris, Denis
    Univ Sherbrooke, Med Sch, Dept Pharmacol & Physiol, Sherbrooke, PQ, Canada.
    D'Orleans-Juste, Pedro
    Univ Sherbrooke, Med Sch, Dept Pharmacol & Physiol, Sherbrooke, PQ, Canada.
    Experimental Autoimmune Encephalomyelitis Potentiates Mouse Mast Cell Protease 4-Dependent Pressor Responses to Centrally or Systemically Administered Big Endothelin-12019Ingår i: Journal of Pharmacology and Experimental Therapeutics, ISSN 0022-3565, E-ISSN 1521-0103, Vol. 370, nr 3, s. 437-446Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Multiple sclerosis is a neurodegenerative disease affecting predominantly female patients between 20 and 45 years of age. We previously reported the significant contribution of mouse mast cell protease 4 (mMCP-4) in the synthesis of endothelin-1 (ET-1) in healthy mice and in a murine model of experimental autoimmune encephalomyelitis (EAE). In the current study, the cardiovascular effects of ET-1 and big endothelin-1 (big-ET-1) administered systemically or intrathecally were assessed in the early preclinical phase of EAE in telemetry instrumented/conscious mice. Chymase-specific enzymatic activity was also measured in the lung, brain, and mast cell extracts in vitro. Finally, the impact of EAE immunization was studied on the pulmonary and brain mRNA expression of different genes of the endothelin pathway, interleukin-33 (IL-33), and monitoring of immunoreactive tumor necrosis factor-α (TNF-α). Systemically or intrathecally administered big-ET-1 triggered increases in blood pressure in conscious mice. One week post-EAE, the pressor responses to big-ET-1 were potentiated in wild-type (WT) mice but not in mMCP-4 knockout (KO) mice. EAE triggered mMCP-4–specific activity in cerebral homogenates and peritoneal mast cells. Enhanced pulmonary, but not cerebral preproendothelin-1 and IL-33 mRNA were found in KO mice and further increased 1 week post-EAE immunization, but not in WT animals. Finally, TNF-α levels were also increased in serum from mMCP-4 KO mice, but not WT, 1 week post-EAE. Our study suggests that mMCP-4 activity is enhanced both centrally and systemically in a mouse model of EAE.

  • 231.
    Desbiens, Louisane
    et al.
    Univ Sherbrooke, Sch Med, Dept Pharmacol, 3001 12th Ave North, Sherbrooke, PQ J1H 5N4, Canada..
    Lapointe, Catherine
    Univ Sherbrooke, Sch Med, Dept Pharmacol, 3001 12th Ave North, Sherbrooke, PQ J1H 5N4, Canada..
    Gharagozloo, Marjan
    Univ Sherbrooke, Sch Med, Dept Pediat, Program Immunol & Allergol, 3001 12th Ave North, Sherbrooke, PQ J1H 5N4, Canada..
    Mahmoud, Shaimaa
    Univ Sherbrooke, Sch Med, Dept Pediat, Program Immunol & Allergol, 3001 12th Ave North, Sherbrooke, PQ J1H 5N4, Canada..
    Pejler, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, POB 7070, S-75007 Uppsala, Sweden..
    Gris, Denis
    Univ Sherbrooke, Sch Med, Dept Pediat, Program Immunol & Allergol, 3001 12th Ave North, Sherbrooke, PQ J1H 5N4, Canada..
    D'Orleans-Juste, Pedro
    Univ Sherbrooke, Sch Med, Dept Pharmacol, 3001 12th Ave North, Sherbrooke, PQ J1H 5N4, Canada..
    Significant Contribution of Mouse Mast Cell Protease 4 in Early Phases of Experimental Autoimmune Encephalomyelitis2016Ingår i: Mediators of Inflammation, ISSN 0962-9351, E-ISSN 1466-1861, artikel-id 9797021Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Experimental autoimmune encephalomyelitis (EAE) is a mouse model that reproduces cardinal signs of clinical, histopathological, and immunological features found in Multiple Sclerosis (MS). Mast cells are suggested to be involved in the main inflammatory phases occurring during EAE development, possibly by secreting several autacoids and proteases. Among the latter, the chymase mouse mast cell protease 4 (mMCP-4) can contribute to the inflammatory response by producing endothelin-1 (ET-1). The aim of this study was to determine the impact of mMCP-4 on acute inflammatory stages in EAE. C57BL/6 wild type (WT) or mMCP-4 knockout (KO) mice were immunized with MOG(35-55) plus complete Freund's adjuvant followed by pertussis toxin. Immunized WT mice presented an initial acute phase characterized by progressive increases in clinical score, which were significantly reduced in mMCP-4 KO mice. In addition, higher levels of spinal myelin were found in mMCP-4 KO as compared with WT mice. Finally, whereas EAE triggered significant increases in brain levels of mMCP-4 mRNA and immunoreactive ET-1 in WT mice, the latter peptide was reduced to basal levels in mMCP-4 KO congeners. Together, the present study supports a role form MCP-4 in the early inflammatory phases of the disease in a mouse model of MS.

  • 232.
    Devito, Claudia
    et al.
    Swedish Inst Infect Dis Control, Sweden; HD Dept Clin Virol, Sweden.
    Ellegård, Rada
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk genetik.
    Falkeborn, Tina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk mikrobiologi.
    Svensson, Lennart
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Ohlin, Mats
    Lund Univ, Sweden.
    Larsson, Marie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Broliden, Kristina
    Karolinska Inst, Sweden.
    Hinkula, Jorma
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten.
    Human IgM monoclonal antibodies block HIV-transmission to immune cells in cervico-vaginal tissues and across polarized epithelial cells in vitro2018Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, artikel-id 10180Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The importance of natural IgM antibodies in protection against infections is still emerging and these antibodies have a potential role in the maintenance of homeostasis through clearance of apoptotic bodies, complement-dependent mechanisms, inflammation and exclusion of misfolded proteins. Natural IgM act as a first line of defence against unknown hazardous factors and are present in most vertebrates. We investigated the functional capacity of anti-HIV-1 IgM monoclonal antibodies, from a combinatorial Fab library derived from healthy individuals, and evaluated their protective role in inhibiting HIV-1 in vitro when passing across the human mucosal epithelial barrier. Primary HIV-1 isolates were efficiently transmitted over the tight polarized epithelial cells when added to their apical surface. Efficient inhibition of HIV-1 transmission was achieved when anti-HIV-1 IgM monoclonal antibodies were added to the basolateral side of the cells. Two of these human IgM MoAbs had the ability to neutralize HIV and reduced infection of dendritic cells in primary cervico-vaginal tissue biopsies in vitro. This indicates a potential role of natural IgM antibodies in the reduction of HIV-1 transmission in mucosal tissues and improve our understanding of how natural IgM antibodies against a neutralizing epitope could interfere with viral transmission.

  • 233.
    Di Giuseppe, Daniela
    et al.
    Karolinska Inst, Sweden.
    Frisell, Thomas
    Karolinska Inst, Sweden.
    Ernestam, Sofia
    Karolinska Univ Hosp, Sweden.
    Forsblad-DElia, Helena
    Umea Univ, Sweden.
    Lindqvist, Elisabet
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Lindstrom, Ulf
    Gothenburg Univ, Sweden.
    Sjöwall, Christopher
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland.
    Askling, Johan
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Uptake of rheumatology biosimilars in the absence of forced switching2018Ingår i: Expert Opinion on Biological Therapy, ISSN 1471-2598, E-ISSN 1744-7682, Vol. 18, nr 5, s. 499-504Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: To describe the uptake and system-level effects of the introduction of biosimilars in a setting without forced switching.Research design and methods: We used data from the Swedish Rheumatology Quality register from start of marketing of infliximab (Remsima (R) and Inflectra (R)) and etanercept (Benepali (R)) biosimilars until 31 December 2016. We compared users of each originator-product and its biosimilar(s) by line of treatment: bDMARD-naive patients, non-medical switchers (vs. matched patients remaining on originator), and patients switching from a previous bDMARD of another type.Results: From the start of marketing 1343 patients started an infliximab biosimilar (22 months) and 2691 started etanercept (9months). Overall, the introduction of these biosimilars resulted in an increase of the total number of ongoing infliximab and etanercept treatments (originator + biosimilar) . At the end of the study period, biosimilars accounted for 31% of all infliximab treatments and 31% of all etanercept-treated patients. For each line of therapy, we noted only small differences in patient characteristics between those starting the originator product vs. its biosimilar(s).Conclusions: Introduction of biosimilars have effects beyond replacement of the originator product, in terms of an increased rate of bDMARD initiation. Selection to non-medical switching displayed no particular disease- or patient-characteristics.

  • 234.
    Dige, Anders
    et al.
    Gastro-Immuno Research Laboratory (GIRL), Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
    Magnusson, Maria K.
    Department of Microbiology and Immunology, Institute for Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden / Department of Internal Medicine and Clinical Nutrition, Institute for Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Öhman, Lena
    Department of Microbiology and Immunology, Institute for Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden / Department of Internal Medicine and Clinical Nutrition, Institute for Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Hvas, Christian Lodberg
    Gastro-Immuno Research Laboratory (GIRL), Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
    Kelsen, Jens
    Gastro-Immuno Research Laboratory (GIRL), Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
    Wick, Mary Jo
    Department of Microbiology and Immunology, Institute for Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Agnholt, Jørgen
    Gastro-Immuno Research Laboratory (GIRL), Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
    Reduced numbers of mucosal DR(int) macrophages and increased numbers of CD103(+) dendritic cells during anti-TNF-α treatment in patients with Crohn's disease2016Ingår i: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 51, nr 6, s. 692-699Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE: Anti-TNF-α treatment constitutes a mainstay in the treatment of Crohn's disease (CD), but its mechanisms of action are not fully understood. We aimed to investigate the effects of adalimumab, a human monoclonal TNF-α antibody, on macrophage (MQ) and dendritic cell (DC) subsets in mucosal biopsies and peripheral blood.

    MATERIAL AND METHODS: Intestinal biopsies and blood samples were obtained from 12 different CD patients both before and 4 weeks after the initiation of the induction of adalimumab treatment. Endoscopic disease activity was estimated by the Simple Endoscopic Score for Crohn's Disease. Biopsies were obtained from inflamed and non-inflamed areas. The numbers of lamina propria CD14 (+) DR(int) and CD14 (+) DR(hi) MQs, CD141(+), CD141(-) and CD103(+ )DCs subsets, and circulating monocytes and DCs were analyzed using flow cytometry.

    RESULTS: At baseline, we observed higher numbers of DR(int) MQs and lower numbers of CD103(+ )DCs in inflamed versus non-inflamed mucosa [843 vs. 391/10(5) lamina propria mononuclear cells (LPMCs) (p < 0.05) and 9 vs. 19 × 10(5) LPMCs (p = 0.01), respectively]. After four weeks of adalimumab treatment, the numbers of DR(int) MQs decreased [843 to 379/10(5) LPMCs (p = 0.03)], whereas the numbers of CD103(+ )DCs increased [9-20 × 10(5) LPMCs (p = 0.003)] compared with baseline. In peripheral blood, no alterations were observed in monocyte or DC numbers between baseline and week 4.

    CONCLUSIONS: In CD, mucosal inflammation is associated with high numbers of DR(int) MQs and low numbers of CD103(+ )DCs. This composition of intestinal myeloid subsets is reversed by anti-TNF-α treatment. These results suggest that DR(int) MQs play a pivotal role in CD inflammation.

  • 235.
    Digre, Andreas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Singh, Kailash
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Åbrink, Magnus
    Swedish Univ Agr Sci, Immunol Sect, Dept Biomed Sci & Vet Publ Hlth, VHC, Box 7028, Uppsala, Sweden.
    Reijmers, Rogier M.
    Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
    Sandler, Stellan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Vlodavsky, Israel
    Cancer and Vascular Biology Research Center, The Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.
    Li, Jin-Ping
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Overexpression of heparanase enhances T lymphocyte activities and intensifies the inflammatory response in a model of murine rheumatoid arthritis2017Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, artikel-id 46229Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Heparanase is an endo-glucuronidase that degrades heparan sulfate chains. The enzyme is expressed at a low level in normal organs; however, elevated expression of heparanase has been detected in several inflammatory conditions, e.g. in the synovial joints of rheumatoid arthritis (RA) patients. Herein, we have applied the model of collagen-induced arthritis (CIA) to transgenic mice overexpressing human heparanase (Hpa-tg) along with wildtype (WT) mice. About 50 % of the induced animals developed clinical symptoms, i.e. swelling of joints, and there were no differences between the Hpa-tg and WT mice in the incidence of disease. However, Hpa-tg mice displayed an earlier response and developed more severe symptoms. Examination of cells from thymus, spleen and lymph nodes revealed increased innate and adaptive immune responses of the Hpa-tg mice, reflected by increased proportions of macrophages, antigen presenting cells and plasmacytoid dendritic cells as well as Helios-positive CD4+ and CD8+ T cells. Furthermore, splenic lymphocytes from Hpa-tg mice showed higher proliferation activity. Our results suggest that elevated expression of heparanase augmented both the innate and adaptive immune system and propagated inflammatory reactions in the murine RA model.

  • 236. Dinarello, Charles
    et al.
    Arend, William
    Sims, John
    Smith, Dirk
    Blumberg, Hal
    O'Neill, Luke
    Goldbach-Mansky, Raphaela
    Pizarro, Theresa
    Hoffman, H.
    Bufler, Philip
    Nold, Marcel
    Ghezzi, Pietro
    Mantovani, Alberto
    Garlanda, Cecilia
    Boraschi, Diana
    Rubartelli, Anna
    Netea, Mihai
    van der Meer, Jos
    Joosten, Leo
    Mandrup-Poulsen, Tom
    Donath, Marc
    Lewis, Eli
    Pfeilschifter, Josef
    Martin, Michael
    Kracht, Michael
    Muehl, H
    Novick, Daniela
    Lukic, Miodrag
    Conti, Bruno
    Solinger, Alan
    Kelk, Peyman
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi. Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    van de Veerdonk, Frank
    Gabel, Chiristopher
    IL-1 family nomenclature2010Ingår i: Nature Immunology, ISSN 1529-2908, E-ISSN 1529-2916, Vol. 11, nr 11, s. 973-973Artikel i tidskrift (Refereegranskat)
  • 237.
    Ding, Zhoujie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Feedback Enhancement of Immune Responses by IgE, IgM, and IgG3 Antibodies2015Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Antibodies can enhance or suppress the immune responses against their specific antigens. This phenomenon is known as antibody-mediated feedback regulation. We have studied the mechanisms underlying IgE-, IgM-, and IgG3-mediated enhancement of immune responses in mouse models using intravenous immunization. We attempted to answer the following questions: 1) Which cell type presents IgE-complexed antigens to CD4+ T cells? 2) Is complement activation required for specific IgM to enhance antibody responses? 3) Does IgM enhance CD4+ T-cell responses? 4) How are IgG3-antigen complexes transported into B-cell follicles?

    We found that CD23+ B cells transporting IgE-antigen complexes into B-cell follicles were not required to prime the antigen-specific CD4+ T cells in vivo, whereas CD11c+ cells were indispensable. After examining the three most common subpopulations of CD11c+ cells in the spleen, we determined that it was CD8α- conventional dendritic cells migrating into the T-cell zone following immunization that presented IgE-complexed antigens to CD4+ T cells.

    Next, we showed that specific IgM from Cµ13 mice, which is unable to activate complement, failed to enhance either antibody or germinal center responses whereas wild-type IgM enhanced both responses. Therefore, specific IgM must activate complement to enhance humoral responses. In addition, wild-type IgM did not up-regulate CD4+ T-cell responses.

    Finally, we showed that IgG3-antigen complexes were transported by marginal zone B cells into B-cell follicles via binding to complement receptors 1 and 2 (CR1/2) on those cells. The immune complexes were captured by follicular dendritic cells as early as 2 h after immunization. Germinal center responses were also enhanced by IgG3. Using bone marrow chimeric mice, we found that CR1/2 expression was required on both marginal zone B cells and follicular dendritic cells to provide an optimal enhancement of antibody responses.

  • 238.
    Ding, Zhoujie
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Dahlin, Joakim S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Heyman, Birgitta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    CD8αconventional dendritic cells are the dominant cells presenting IgE-complexed Ag to CD4+ T cellsManuskript (preprint) (Övrigt vetenskapligt)
  • 239.
    Ding, Zhoujie
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Dahlin, Joakim S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Xu, Hui
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Heyman, Birgitta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    IgE-mediated enhancement of CD4(+) T cell responses requires antigen presentation by CD8 alpha(-) conventional dendritic cells2016Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, artikel-id 28290Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    IgE, forming an immune complex with small proteins, can enhance the specific antibody and CD4(+) T cell responses in vivo. The effects require the presence of CD23 (Fc epsilon-receptor II)(+) B cells, which capture IgE-complexed antigens (Ag) in the circulation and transport them to splenic B cell follicles. In addition, also CD11c(+) cells, which do not express CD23, are required for IgE-mediated enhancement of T cell responses. This suggests that some type of dendritic cell obtains IgE-Ag complexes from B cells and presents antigenic peptides to T cells. To elucidate the nature of this dendritic cell, mice were immunized with ovalbumin (OVA)-specific IgE and OVA, and different populations of CD11c(+) cells, obtained from the spleens four hours after immunization, were tested for their ability to present OVA. CD8 alpha(-) conventional dendritic cells (cDCs) were much more efficient in inducing specific CD4(+) T cell proliferation ex vivo than were CD8 alpha(+) cDCs or plasmacytoid dendritic cells. Thus, IgE-Ag complexes administered intravenously are rapidly transported to the spleen by recirculating B cells where they are delivered to CD8 alpha(-) cDCs which induce proliferation of CD4(+) T cells.

  • 240.
    Ding, Zhoujie
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Heyman, Birgitta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    The Role of CD23 Expression on Follicular Dendritic Cells in IgE-mediated Enhancement2014Ingår i: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 80, nr 3, s. 215-215Artikel i tidskrift (Övrigt vetenskapligt)
  • 241.
    Ding, Zhoujie
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Zhang, Lu
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Xu, Hui
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Heyman, Birgitta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    IgG3-mediated enhancement of antibody responses is dependent on expression of complement receptors 1 and 22014Ingår i: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 61, nr 2, s. 277-278Artikel i tidskrift (Övrigt vetenskapligt)
  • 242.
    Domsgen, Erna
    et al.
    Karolinska Univ Hosp, Karolinska Inst, Dept Med HS, Ctr Infect Med, S-14186 Stockholm, Sweden..
    Lind, Katharina
    Karolinska Univ Hosp, Karolinska Inst, Dept Med HS, Ctr Infect Med, S-14186 Stockholm, Sweden..
    Kong, Lingjia
    Univ Turku, Turku Ctr Biotechnol, FIN-20520 Turku, Finland.;Abo Akad Univ, FIN-20520 Turku, Finland..
    Huhn, Michael H.
    Karolinska Univ Hosp, Karolinska Inst, Dept Med HS, Ctr Infect Med, S-14186 Stockholm, Sweden.;Astra Zeneca AB R&D, Pepparedsleden 1, S-43150 Molndal, Sweden..
    Rasool, Omid
    Univ Turku, Turku Ctr Biotechnol, FIN-20520 Turku, Finland.;Abo Akad Univ, FIN-20520 Turku, Finland..
    van Kuppeveld, Frank
    Univ Utrecht, Div Virol, Dept Infect Dis & Immunol, Fac Vet Med, NL-3584 Utrecht, Netherlands..
    Korsgren, Olle
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Lahesmaa, Riitta
    Univ Turku, Turku Ctr Biotechnol, FIN-20520 Turku, Finland.;Abo Akad Univ, FIN-20520 Turku, Finland..
    Flodstrom-Tullberg, Malin
    Karolinska Univ Hosp, Karolinska Inst, Dept Med HS, Ctr Infect Med, S-14186 Stockholm, Sweden.;Univ Tampere, Inst Biosci & Med Technol, Tampere 33520, Finland..
    An IFIH1 gene polymorphism associated with risk for autoimmunity regulates canonical antiviral defence pathways in Coxsackievirus infected human pancreatic islets2016Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, artikel-id 39378Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The IFIH1 gene encodes the pattern recognition receptor MDA5. A common polymorphism in IFIH1 (rs1990760, A946T) confers increased risk for autoimmune disease, including type 1-diabetes (T1D). Coxsackievirus infections are linked to T1D and cause beta-cell damage in vitro. Here we demonstrate that the rs1990760 polymorphism regulates the interferon (IFN) signature expressed by human pancreatic islets following Coxsackievirus infection. A strong IFN signature was associated with high expression of IFN lambda 1 and IFN lambda 2, linking rs1990760 to the expression of type III IFNs. In the highresponding genotype, IRF-1 expression correlated with that of type III IFN, suggesting a positivefeedback on type III IFN transcription. In summary, our study uncovers an influence of rs1990760 on the canonical effector function of MDA5 in response to an acute infection of primary human parenchymal cells with a clinically relevant virus linked to human T1D. It also highlights a previously unrecognized connection between the rs1990760 polymorphism and the expression level of type III IFNs.

  • 243. Dreborg, S
    et al.
    Holgersson, M
    Basomba, A
    Löfkvist, T
    Möller, Christian
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Evaluation of skin reactivity during (immuno) therapy validation of methods for estimation of changes in skin reactivity and correlation to shock organ sensitivity. Proposal of two simple methods2014Ingår i: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 69, s. 613-613Artikel i tidskrift (Övrigt vetenskapligt)
  • 244.
    Dreborg, Sten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Pediatrik.
    Allergen skin prick test results should be adjusted to the histamine reactivity2015Ingår i: International Archives of Allergy and Immunology, ISSN 1018-2438, E-ISSN 1423-0097, Vol. 166, nr 1, s. 77-80Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Skin prick test results are mostly reported as mean wheal diameter obtained with one concentration of allergen. Differences in technique between personnel causes variation in wheal size. The research question was whether the influence of differences in skin prick test technique among assistants and centers can be reduced by relating the allergen wheal response to that of histamine. Methods: Two methods for estimating skin reactivity, the method of Nordic Guidelines using histamine as a reference and the method of Brighton et al. [Clin Allergy 1979; 9: 591-596] not using histamine as a reference, were applied to data from two biological standardization trials, using the same batch of freeze-dried timothy pollen preparation. Results: The concentration defining the Nordic biological unit, defined as a concentration of allergen eliciting a wheal of the same size as that of histamine dihydrochloride 10 mg/ml, did not differ between the centers. When not using histamine as a reference, applying the method of Brighton et al., there was a 15-fold difference in the estimate of the biological activity between the trials that was eliminated by adjusting the allergen response to that of the histamine reference. Conclusions: To reduce the influence of differences in test technique among assistants and centers responses to allergen-induced skin prick tests should be compared to that of histamine.

  • 245.
    Dreborg, Sten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Evaluation of Allergen Immunotherapy2015Ingår i: JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE, ISSN 2213-2198, Vol. 3, nr 2, s. 267-268Artikel i tidskrift (Övrigt vetenskapligt)
  • 246.
    Dreborg, Sten
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Pediatrik.
    Holgersson, Margareta
    Pharmacia Diagostics AB, Uppsala, Sweden.
    Evaluation of methods for estimation of threshold concentrations by the skin prick test2015Ingår i: International Archives of Allergy and Immunology, ISSN 1018-2438, E-ISSN 1423-0097, Vol. 166, nr 1, s. 71-76Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The allergen dose-response curve is flat; thus, small changes in wheal size reflect large differences in skin sensitivity. The sensitivity as measured by provocation tests is given by the threshold concentration that causes symptoms and/or objective signs. The threshold concentrations differ by several magnitudes between the most and the least sensitive individuals clinically allergic to the same allergen. Variation in technique can be minimized by relating allergen responses to that to histamine. The aim here is to present and validate simple methods for estimation of the skin sensitivity given as the concentration inducing a wheal of the same size as that with the positive reference, 10 mg/ml of histamine HCl, in the same patient. Methods: Data from previously reported trials on the biological equilibration of allergen extracts were used to document a method to calculate the concentration of allergen required to induce a wheal of the same size as that with 10 mg/ml of histamine dihydrochloride in the same patient, and to validate the methods using the parallel line bioassay as the gold standard. Results: The validated methods correlated well with the results obtained using the gold standard method and provide results of skin prick testing based on threshold concentrations of allergen. Conclusions: The validated methods reduce the error of differences in testing techniques and make it possible to report skin sensitivity at threshold concentrations. A simple method to be used in clinical practice and a method suitable to describe changes in skin reactivity over time or during treatment are proposed.

  • 247.
    Dreborg, Sten
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Kim, Harold
    Western Univ, Dept Med, London, ON, Canada;McMaster Univ, Dept Med, Hamilton, ON, Canada.
    Pressure, trigger forces, and epinephrine auto-injectors Response2018Ingår i: Annals of Allergy, Asthma & Immunology, ISSN 1081-1206, E-ISSN 1534-4436, Vol. 121, nr 5, s. 644-645Artikel i tidskrift (Övrigt vetenskapligt)
  • 248.
    Dreborg, Sten
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Pediatrisk inflammationsforskning.
    Kim, Harold
    Western Univ, Div Clin Immunol & Allergy, London, ON, Canada;McMaster Univ, Hamilton, ON, Canada.
    Tissue compression and epinephrine deposition2019Ingår i: Journal of Allergy and Clinical Immunology: In Practice, ISSN 2213-2198, E-ISSN 2213-2201, Vol. 7, nr 6, s. 2096-2097Artikel i tidskrift (Övrigt vetenskapligt)
  • 249.
    Drobin, Kimi
    et al.
    Affinity Proteomics, SciLifeLab, School of Biotechnology, KTH, Royal Institute of Technology, Stockholm, Sweden.
    Assadi, Ghazaleh
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
    Hong, Mun-Gwan
    Affinity Proteomics, SciLifeLab, School of Biotechnology, KTH, Royal Institute of Technology, Stockholm, Sweden.
    Andersson, Eni
    Affinity Proteomics, SciLifeLab, School of Biotechnology, KTH, Royal Institute of Technology, Stockholm, Sweden.
    Fredolini, Claudia
    Affinity Proteomics, SciLifeLab, School of Biotechnology, KTH, Royal Institute of Technology, Stockholm, Sweden.
    Forsström, Björn
    Affinity Proteomics, SciLifeLab, School of Biotechnology, KTH, Royal Institute of Technology, Stockholm, Sweden.
    Reznichenko, Anna
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
    Akhter, Tahmina
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
    Ek, Weronica E.
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Bonfiglio, Ferdinando
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden; Department of Gastrointestinal and Liver Diseases, Biodonostia Health Research Institute, San Sebastián, Spain.
    Hansen, Mark Berner
    AstraZeneca R&D Mölndal, Innovative and Global Medicines, Mölndal, Sweden; Digestive Disease Center, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark.
    Sandberg, Kristian
    Science for Life Laboratory, Drug Discovery & Development Platform & Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala Biomedical Center, Uppsala University, Uppsala, Sweden; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Greco, Dario
    Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
    Repsilber, Dirk
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Schwenk, Jochen M.
    Affinity Proteomics, SciLifeLab, School of Biotechnology, KTH, Royal Institute of Technology, Stockholm, Sweden.
    D'Amato, Mauro
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden; BioDonostia Health Research Institute, San Sebastian, Spain; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
    Halfvarson, Jonas
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Gastroenterology.
    Targeted Analysis of Serum Proteins Encoded at Known Inflammatory Bowel Disease Risk Loci2019Ingår i: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 25, nr 2, s. 306-316Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Few studies have investigated the blood proteome of inflammatory bowel disease (IBD). We characterized the serum abundance of proteins encoded at 163 known IBD risk loci and tested these proteins for their biomarker discovery potential.

    Methods: Based on the Human Protein Atlas (HPA) antibody availability, 218 proteins from genes mapping at 163 IBD risk loci were selected. Targeted serum protein profiles from 49 Crohn's disease (CD) patients, 51 ulcerative colitis (UC) patients, and 50 sex- and age-matched healthy individuals were obtained using multiplexed antibody suspension bead array assays. Differences in relative serum abundance levels between disease groups and controls were examined. Replication was attempted for CD-UC comparisons (including disease subtypes) by including 64 additional patients (33 CD and 31 UC). Antibodies targeting a potentially novel risk protein were validated by paired antibodies, Western blot, immuno-capture mass spectrometry, and epitope mapping.

    Results: By univariate analysis, 13 proteins mostly related to neutrophil, T-cell, and B-cell activation and function were differentially expressed in IBD patients vs healthy controls, 3 in CD patients vs healthy controls and 2 in UC patients vs healthy controls (q < 0.01). Multivariate analyses further differentiated disease groups from healthy controls and CD subtypes from UC (P < 0.05). Extended characterization of an antibody targeting a novel, discriminative serum marker, the laccase (multicopper oxidoreductase) domain containing 1 (LACC1) protein, provided evidence for antibody on-target specificity.

    Conclusions: Using affinity proteomics, we identified a set of IBD-associated serum proteins encoded at IBD risk loci. These candidate proteins hold the potential to be exploited as diagnostic biomarkers of IBD.

  • 250.
    Drobni, Mirva
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Kariologi.
    Li, Tong
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Kariologi.
    Krüger, Karina
    Loimaranta, Vuokko
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Kariologi.
    Kilian, Mogens
    Hammarström, Lennart
    Jörnvall, Hans
    Bergman, Tomas
    Strömberg, Nicklas
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Kariologi.
    A host-derived pentapeptide enhancing host-bacteria commensalisms and communication2006Ingår i: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 74, nr 11, s. 6293-6299Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Salivary proline-rich proteins (PRPs) attach commensal Actinomyces and Streptococcus species to teeth. Here, gel filtration, mass spectrometry and Edman degradation were applied to show the release of a pentapeptide, RGRPQ, from PRP-1 upon proteolysis by Streptococcus gordond. Moreover, synthetic RGRPQ and derivatives were used to investigate associated innate properties and responsible motifs. The RGRPQ peptide increased 2.5-fold the growth rate of S. gordonii via a Q-dependent sequence motif and selectively stimulated oral colonization of this organism in a rat model in vivo. In contrast, the growth of Streptococcus mutans, implicated in caries, was not affected. While the entire RGRPQ sequence was required to block sucrose-induced pH-decrease by S. gordonii and S. mutans, the N-terminal Arg residue mediated the pH increase (i.e., ammonia production) by S. gordonii alone (which exhibits Arg catabolism to ammonia). Strains of commensal viridans streptococci exhibited PR-P degradation and Arg catabolism, whereas cariogenic species did not. The RGRPQ peptide mediated via a differential Q-dependent sequence motif, adhesion inhibition, and desorption of PRP-1-binding strains of A. naeslundii genospecies 2 (5 of 10 strains) but not of S. gordonii (n = 5). The inhibitable A. naeslundii strains alone displayed the same binding profile as S. gordond to hybrid peptides terminating in RGRPQ or GQSPQ, derived from the middle or C-terminal segments of PRP-1. The present findings indicate the presence of a host-bacterium interaction in which a host peptide released by bacterial proteolysis affects key properties in biofilm formation.

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