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Immunological mechanisms in systemic autoimmunity: autoantibodies and chemokines in systemic lupus erythematosus and during treatment with TNF inhibitors in rheumatoid arthritis
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background. Rheumatoid Arthritis (RA) is an autoimmune inflammatory disease that, without powerful treatment, may lead to irreversible joint damage. During the past decade, anti-cytokine therapy has become available, e.g., infliximab, a chimeric antibody targeting the pro-inflammatory cytokine TNF that has a central role in the inflammatory process in RA patients. Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease that may affect all organs and is characterized by a massive antibody production. Chemokines, chemokine receptors and lipoprotein receptor-related protein 1(CD91) are regulators of inflammation in autoimmune diseases and T-cell migration.

Objectives. The aim of this study was to get a deeper understanding how TNF blocking treatment influences inflammatory mechanisms and autoantibody formation in RA with special reference to similarities and differences with SLE.

Methods. In patients with RA treated with anti-TNF, and in SLE patients (ACR criteria) clinical evaluation was performed and blood samples analyzed. Autoantibodies were analyzed using indirect immunofluorescence, ELISA and multiplex flow cytometry in samples from anti-TNF treated RA patients (n=59) followed longitudinally for 54 weeks, in pre-diseased samples from SLE patients (n=38) and matched population-based controls (n=152). T-cell expression of chemokine receptors and CD91 was analyzed by flow cytometry, whilst serum levels of chemokines were determined using ELISA in anti-TNF treated RA-patients (n=24) followed longitudinally (30 weeks), and cross-sectionally in SLE-patients (n=23). Expression of mRNA for chemokines was analyzed in T-cells from SLE-patients (n=10) using PCR.

Results. After treatment with infliximab, RA patients produced ANA, anti-dsDNA and anti-nucleosome antibodies, but not anti-ENA antibodies. Although these antibodies are considered typical for SLE only one patient developed a transient lupus-syndrome. Antibodies against cell nuclear antigens, including ENA, were detected several years before the first clinical symptom of SLE; anti-SSA was the earliest detectable antibody.

In RA-patients before infliximab treatment, the T-cell expression of several chemokine receptors was elevated compared with healthy controls. In contrast, only one soluble chemokine, IP-10 was elevated. After treatment the levels of soluble MIP-1β, MCP-1 and IP-10, and the T-cell expression of CCR2 were decreased. In SLE-patients MIP-1β, MCP-1, SDF-1, IP-10 and RANTES in blood were elevated, whilst expression of CXCR5 and CCR6 on T-cells was lower than in healthy controls. T-cell expression of CXCR2 and CCR1 was elevated in active disease (measured as SLEDAI index), whereas the CXCR5 and CCR2 expression was lower in inactive SLE. In SLE patients with nephritis IP-10 was lower and T-cell expression of CXCR3 and CCR3 elevated compared with patients without nephritis. The expression of CD91 was higher on T-cells from patients not responsive to infliximab treatment compared with responders.

Conclusion. These findings indicate that anti-TNF (infliximab) treatment in RA-patients has a major impact on the production of autoantibodies and chemokines. The autoantibody profile in infliximab-treated patients was similar to that predating disease onset in SLE patients with the exception of anti-ENA being detectable in SLE, but the development of lupus-syndromes was rare. The expression of CD91 on T-cells may predict responsiveness to infliximab. The expression of chemokine receptors in SLE- patients seemed to be related to disease activity. Anti-nuclear antibodies were detectable years before clinical disease onset in patients who developed SLE suggesting a gradual pathogenic process.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet , 2011. , 68 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1401
Keyword [en]
autoimmunity, chemokines, T-cells, autoantibodies, CD91
National Category
Immunology in the medical area Rheumatology and Autoimmunity
Research subject
Clinical Immunology; Medicine, rheumatology
Identifiers
URN: urn:nbn:se:umu:diva-42954ISBN: 978-91-7459-143-9OAI: oai:DiVA.org:umu-42954DiVA: diva2:410869
Public defence
2011-05-12, Betula, Norrlands universitetssjukhus, by 6M, Umeå, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2011-04-20 Created: 2011-04-15 Last updated: 2011-04-20Bibliographically approved
List of papers
1. Abnormal expression of chemokine receptors on T-cells from patients with systemic lupus erythematosus
Open this publication in new window or tab >>Abnormal expression of chemokine receptors on T-cells from patients with systemic lupus erythematosus
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2003 (English)In: Lupus, ISSN 0961-2033, E-ISSN 1477-0962, Vol. 12, no 10, 766-774 p.Article in journal (Refereed) Published
Abstract [en]

The expression of chemokine receptors on T-cells and chemokine levels in the blood was studied in 23 patients with SLE (ACR criteria), seven patients with rheumatoid arthritis (RA) and in 15 healthy controls using flow cytometry, RT-PCR and ELISA. The cell surface expression of the chemokine receptors CXCR5 and CCR6 was decreased in SLE patients compared with controls (P = 0.051 and P = 0.002, respectively). The decrease of CXCR5 was confined to SLE patients with inactive disease (SLEDAI < 6) compared with active disease (SLEDAI &GE; 6) and controls. CXCR2 and CCR1 were increased in patients with active SLE compared with patients with inactive disease (P = 0.001 and P = 0.01, respectively) and with controls ( P = 0.02 and P = 0.053, respectively). The levels of the chemokines MIP-1β MCP-1, SDF-1α, IP-10 and RANTES were significantly elevated in SLE patients compared with controls. Patients with renal involvement had increased surface expression of CXCR3 and CCR3 (P = 0.04 in both) and a lower level of soluble IP-10 compared with patients without renal disease (P = 0.025) and compared with controls (P = 0.001). The ratio between CCR5 and CCR3 was significantly increased in RA patients compared with SLE patients and controls supporting a Th1 overweight in RA. In conclusion, patients with SLE showed abnormal T-cell expression of several chemokine receptors and levels of soluble chemokines in their plasma/ serum.

Keyword
chemokines; chemokine receptors; SLE; T-lymphocytes
National Category
Immunology in the medical area Rheumatology and Autoimmunity
Research subject
Clinical Immunology; Medicine, rheumatology
Identifiers
urn:nbn:se:umu:diva-39152 (URN)10.1191/0961203303lu467oa (DOI)
Available from: 2011-01-18 Created: 2011-01-18 Last updated: 2011-04-20Bibliographically approved
2. Autoantibody formation in patients with rheumatoid arthritis treated with anti-TNF alpha
Open this publication in new window or tab >>Autoantibody formation in patients with rheumatoid arthritis treated with anti-TNF alpha
2005 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 64, no 3, 403-407 p.Article in journal (Refereed) Published
Abstract [en]

Background: Research on autoantibody formation in patients treated with TNFα inhibitors has produced contradictory results.

Objective: To study the prevalence of autoantibodies in patients with rheumatoid arthritis treated with the TNFα inhibitor infliximab.

Methods: 53 patients (48 female, 11 male) treated with infliximab for rheumatoid arthritis were followed for autoantibody production before treatment and after 14, 30, and 54 weeks. Six patients treated with etanercept were studied for comparison. The analyses included antibodies against nuclear antigens (ANA), extractable nuclear antigens, double stranded (ds)DNA (by ELISA, IIF on Crithidia luciliae for IgM and IgG, and Farr assay), nucleosomes, cardiolipin, smooth muscle, mitochondria, proteinase 3, and myeloperoxidase antigens.

Results: The number of patients treated with infliximab who developed antibodies against dsDNA of both IgG and IgM class (tested by IIF) increased significantly. The prevalence of patients positive for IgG class increased to 66% at 30 weeks and 45% at 54 weeks, and of IgM class to 85% and 70%, respectively. The titre and number of patients expressing antibodies against nucleosomes and ANA also increased significantly. The number of rheumatoid factor or anticardiolipin positive patients was stable and there was no increase in antibodies against the other antigens. A lupus-like syndrome was seen in one patient. No patient treated with etanercept developed any of these autoantibodies.

Conclusions: Patients treated with infliximab may develop anti-dsDNA antibodies of both IgM and IgG class, anti-nucleosome antibodies, and ANA, with a gradual increase until 30 weeks.

Keyword
Adult, Aged, Antibodies; Antinuclear/biosynthesis, Antibodies; Monoclonal/adverse effects/*immunology/therapeutic use, Antirheumatic Agents/adverse effects/*immunology/therapeutic use, Arthritis; Rheumatoid/drug therapy/*immunology, Autoantibodies/*biosynthesis, DNA/immunology, Drug Hypersensitivity/etiology, Drug Therapy; Combination, Female, Humans, Immunoglobulin G/biosynthesis, Immunoglobulin M/biosynthesis, Male, Middle Aged
National Category
Immunology in the medical area Rheumatology and Autoimmunity
Research subject
Clinical Immunology; Medicine, rheumatology
Identifiers
urn:nbn:se:umu:diva-12934 (URN)10.1136/ard.2004.024182 (DOI)15297281 (PubMedID)
Available from: 2007-04-25 Created: 2007-04-25 Last updated: 2011-04-20Bibliographically approved
3. T-cell expression of CD91: a marker of unresponsiveness to anti-TNF therapy in rheumatoid arthritis
Open this publication in new window or tab >>T-cell expression of CD91: a marker of unresponsiveness to anti-TNF therapy in rheumatoid arthritis
2010 (English)In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 118, no 11, 837-845 p.Article in journal (Refereed) Published
Abstract [en]

The aim of this study was to investigate the expression of thrombospondin-1 (TSP-1) and its receptors, lipoprotein receptor-related protein/cluster of differentiation (CD)91, calreticulin (CRT), and CD47, on T cells and monocytes from patients with rheumatoid arthritis (RA) treated with anti-tumor necrosis factor (TNF) therapy. The surface expression of CD91 and associated components on CD3- and CD14-positive cells was examined using flow cytometry in 12 patients with established RA before and after beginning therapy and compared with that of 9 healthy controls and 12 patients with early RA treated with conventional therapies. CD3-positive cells from anti-TNF non-responders showed significantly greater expression of CD91 expression than those from responders (p<0.05) after 6 weeks and when all measurements were pooled (p<0.001). CD91 expression on CD3-positive cells from non-responders to other therapies was at the same level as in healthy controls. In contrast, CD14-positive cells showed no differences in CD91 expression between patients and controls or between responders and non-responders to anti-TNF therapy. The expression of TSP-1, CRT, and CD47 showed no differences between responders and non-responders. The results suggest T-lymphocyte expression of CD91 to be a biomarker that signifies unresponsiveness to anti-TNF therapy in patients with RA and may be used to identify potential responders and non-responders.

Keyword
Rheumatoid arthritis; infliximab; anti-TNF; CD91; T cells
National Category
Immunology in the medical area Rheumatology and Autoimmunity
Research subject
Clinical Immunology; Medicine, rheumatology
Identifiers
urn:nbn:se:umu:diva-38723 (URN)10.1111/j.1600-0463.2010.02677.x (DOI)20955456 (PubMedID)
Available from: 2010-12-23 Created: 2010-12-23 Last updated: 2011-04-20Bibliographically approved
4. Autoantibodies predate the onset of Systemic Lupus Erythematosus in northern Sweden
Open this publication in new window or tab >>Autoantibodies predate the onset of Systemic Lupus Erythematosus in northern Sweden
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2011 (English)In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 13, no 1, R30- p.Article in journal (Refereed) Published
Abstract [en]

INTRODUCTION: Autoantibodies have a central role in systemic lupus erythematosus (SLE). The presence of autoantibodies preceding disease onset by years has been reported both in patients with SLE and those with rheumatoid arthritis, suggesting a gradual development of these diseases. To identify autoantibodies in a Northern European population predating the onset of symptoms of SLE and their relationship to presenting symptoms.

METHODS: The register of patients fulfilling the American College of Rheumatology (ACR) criteria for SLE and with a given date for the onset of symptoms was co-analysed with the register of the Medical Biobank, Umea, Sweden. Thirty-eight patients were identified as having donated blood samples prior to symptom onset. A nested case-control study (1:4) was performed with 152 age- and sex-matched controls identified from within the Biobank register. Antibodies against anti- Sjogren's syndrome antigen A (Ro/SSA) (60 and 52 kDa), anti- Sjogren's syndrome antigen B (La/SSB), anti-Smith antibody (Sm), ribonucleoprotein (RNP), scleroderma-70 (Scl-70), anti- histidyl-tRNA synthetase antibody (Jo-1), double-stranded DNA (dsDNA); Centromere protein B and histones were analysed using the anti-nuclear antibody test II (ANA-II) Plus Test System (Athena Multi-Lyte(R)) on a Bio-Plex Array Reader (Luminex200). ANA were analysed using indirect immunofluorescence on Human Epidermal cells-2 (HEp2-cells) at a sample dilution of 1:100.

RESULTS: Autoantibodies against nuclear antigens were detected 5.6 (+/- 4.7; mean +/- SD) years before the onset of symptoms and 8.7 (+/- 5.6) years before diagnosis in 63% of the individuals who subsequently developed SLE. The sensitivity (45.7%) was highest for ANA with a specificity of 95%, followed by anti-dsDNA and anti-Ro/SSA antibodies both with sensitivities of 20.0% at specificities of 98.7% and 97.4%, respectively. The odds ratio (OR) for anti-dsDNA predicting disease was 18.13 (CI 95%; 3.58-91.84), and for ANA 11.5 (CI 95%; 4.54-28.87). Anti-Ro/SSA antibodies appeared first, 6.6 (+/- 2.5) years prior to symptom onset. The mean number of autoantibodies in pre-diseased individuals was 1.4 and after disease onset 3.1 (P< 0.0005). The time predating disease was shorter, and the number of autoantibodies greater, in those individuals with serositis as a presenting symptom in comparison to those with arthritis and skin manifestations.

CONCLUSIONS: Autoantibodies against nuclear antigens were detected in individuals developing SLE several years before the onset of symptoms and diagnosis. The most sensitive autoantibodies were ANA, Ro/SSA and dsDNA, with the highest predictive OR for anti-dsDNA antibodies. The first autoantibodies detected were anti-Ro/SSA.

National Category
Immunology in the medical area Rheumatology and Autoimmunity
Research subject
Clinical Immunology; Medicine, rheumatology
Identifiers
urn:nbn:se:umu:diva-41159 (URN)10.1186/ar3258 (DOI)21342502 (PubMedID)
Available from: 2011-03-18 Created: 2011-03-18 Last updated: 2016-05-23Bibliographically approved
5. Changes in chemokines and their receptors in blood during treatment with the TNF inhibitor infliximab in patients with rheumatoid arthritis
Open this publication in new window or tab >>Changes in chemokines and their receptors in blood during treatment with the TNF inhibitor infliximab in patients with rheumatoid arthritis
2013 (English)In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, Vol. 42, no 4, 260-265 p.Article in journal (Refereed) Published
Abstract [en]

Background. Chemokines are involved in leucocyte recruitment into inflammatory sites, such as the synovial tissue of patients with rheumatoid arthritis (RA). The release of certain chemokines is augmented by pro-inflammatory cytokines, such as tumor necrosis factor (TNF). Infliximab, a monoclonal antibody against TNF that blocks the biological effects of TNF, is used in the treatment of chronic inflammatory diseases. The effect of blocking TNF activity on chemokines is not fully understood.

Aim. The aim of this study was to analyse the effects on chemokines and their receptors on peripheral mononuclear cells of anti-TNF treatment in RA-patients.

Material and methods. Twelve patients with established RA who began treatment with infliximab, and nine patients with early RA treated with traditional disease-modifying anti-rheumatic drugs, were followed clinically for 30 weeks and chemokine levels in blood samples and chemokine receptor expression on the surface of T-cells and monocytes analysed. Three SLE-patients, as a small control group of another inflammatory disease, and nine healthy subjects were also included in the study.

Result. CXCL10/IP-10 was significantly higher in RA-patients compared with healthy controls and decreased significantly two weeks after infliximab infusion. CCL2/MCP-1 and CCL4/MIP-1β decreased significantly after infliximab treatment although the concentrations were not significantly elevated at baseline compared with controls. There was an inverse correlation between the chemokine cleaving molecule dipeptidyl peptidase-IV/CD26 and CCL5/RANTES. Several chemokine receptors on T-cells were elevated in RA patients at inclusion into the study. The CCR2 expression on T-cells decreased significantly after infliximab treatment.

Conclusion. The chemokines CXCL10/IP-10, CCL2/MCP-1 and CCL4/MIP-1β, mainly targeting the Th1 immune response, decreased after treatment with anti-TNF suggesting a more pronounced effect onTh1 activity than on the Th2 mediated response. Several chemokine receptors on blood T-cells were elevated in RA-patients, suggesting that they may be involved in the recruitment of T-lymphocytes from the blood to affected tissues.

National Category
Immunology in the medical area Rheumatology and Autoimmunity
Research subject
Clinical Immunology; Medicine, rheumatology
Identifiers
urn:nbn:se:umu:diva-39809 (URN)10.3109/03009742.2012.754937 (DOI)978-91-7459-143-9 (ISBN)
Available from: 2011-04-15 Created: 2011-02-09 Last updated: 2013-08-20Bibliographically approved

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