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The role of anti-collagen type II antibodies in the pathogenesis and prognosis of rheumatoid arthritis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Rheumatoid arthritis (RA) which affects 0.5-1% of the world population and is characterised by joint erosions and presence of the autoantibodies anti-citrullinated protein antibodies (ACPA) and rheumatoid factor. Collagen II (CII) is a joint-specific antigen and we have shown that antibodies against CII (anti-CII) are present in around 8% of RA patients. RA patients with anti-CII are characterized by acute RA onset with elevated CRP and early joint erosions at the time of RA onset. Polymorphonuclear granulocytes (PMN) and peripheral blood mononuclear cells (PBMC) are abundant in RA synovial fluids, where they can interact with anti-CII, thus forming immune complexes (IC) with CII. In my thesis I have shown that PMN upregulated the cell surface markers CD66b and CD11b and downregulated CD16 and CD32 after stimulation with anti-CII IC. These changes in CD66b and CD16 associated to joint erosions to a larger extent than did PBMC responses to anti-CII IC. PMN cocultured with PBMC and stimulated with anti-CII IC showed augmented chemokine production that was dependent on TLR4 and functionally active PMN enzymes. This mechanism can lead to accumulation of inflammatory cells in joints of RA patients who are anti-CII positive around the time of RA diagnosis, and may thus help explain the acute onset RA phenotype associated with anti-CII.

In a large Swedish RA cohort, anti-CII associated with elevations in clinical and laboratory measures of disease activity at diagnosis and until 6 months, whereas ACPA associated with late inflammation. Anti-CII seropositive RA was associated with improvements in clinical measurements and was negatively associated with smoking in contrast to ACPA that was associated with worseneing of clinical symptoms and associated positively with smoking. Anti-CII levels associated to  HLADRB1*03 and  HLADRB1*01 whereas ACPA showed negative association to HLA-DRB1*03. In a Malaysian RA cohort anti-CII also associated to elevated CRP at the time of diagnosis.

Anti-CII seropositive RA represents a distinct phenotype, in many respects representing the converse  to the clinical, genetic and smoking associations described for ACPA. Early determinations of anti-CII in parallel to ACPA predict the inflammatory outcome in RA.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. , p. 62
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1289
Keywords [en]
Rheumatoid arthritis; Anti-collagen type II antibodies; HLADRB1*; Granulocytes; prognosis;
National Category
Rheumatology and Autoimmunity
Identifiers
URN: urn:nbn:se:uu:diva-311959ISBN: 978-91-554-9792-7 (print)OAI: oai:DiVA.org:uu-311959DiVA, id: diva2:1063747
Public defence
2017-02-28, Rudbecksalen, Daghammarskjölds väg 20, Uppsala, 09:00 (English)
Opponent
Supervisors
Funder
Swedish Research CouncilAvailable from: 2017-02-06 Created: 2017-01-03 Last updated: 2018-02-27
List of papers
1. Anti-type II collagen immune complex-induced granulocyte reactivity is associated with joint erosions in RA patients with anti-collagen antibodies
Open this publication in new window or tab >>Anti-type II collagen immune complex-induced granulocyte reactivity is associated with joint erosions in RA patients with anti-collagen antibodies
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2015 (English)In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 17, article id 8Article in journal (Refereed) Published
Abstract [en]

Introduction: Rheumatoid arthritis (RA) patients with autoantibodies against collagen type II (CII) are characterized by acute RA onset with elevated inflammatory measures and early joint erosions as well as increased production of tumor necrosis factor-alpha (TNF-alpha) by peripheral blood mononuclear cells (PBMC) stimulated by anti-CII immune complexes (IC) in vitro. Polymorphonuclear granulocytes (PMN) are abundant in RA synovial fluids, where they might interact directly with anti-CII IC in the articular cartilage, but no studies have investigated PMN responses towards anti-CII IC. The aim was to investigate whether PMN react towards anti-CII IC, and to what extent such reactivity might relate to the clinical acute onset RA phenotype associated with elevated levels of anti-CII. Methods: PMN and PBMC isolated from healthy donors were stimulated with IC made with a set of 72 baseline patient sera (24 anti-CII positive, 48 anti-CII negative) chosen from a clinically well-characterized RA cohort with two-year radiological follow-up with Larsen scoring. PMN expression of cluster of differentiation (CD) 11b, CD66b, CD16 and CD32 was measured by flow cytometry, whereas PMN production of myeloperoxidase (MPO) and interleukin (IL)-17, and PBMC production of TNF-alpha was measured with enzyme linked immunosorbent assay. Results: PMN expression of CD11b, CD66b and MPO, and PBMC production of TNF-alpha were upregulated whereas PMN expression of CD16 and CD32 were downregulated by anti-CII IC. CD16, CD66b, and MPO production correlated to serum anti-CII levels (Spearman's rho = 0.315, 0.675 and 0.253, respectively). CD16 was associated with early joint erosions (P = 0.024, 0.034, 0.046 at baseline, one and two years) and CD66b was associated with changes in joint erosions (P = 0.017 and 0.016, at one and two years compared to baseline, respectively). CD66b was associated with baseline C-reactive protein and PBMC production of TNF-alpha was associated with baseline erythrocyte sedimentation rate, in accordance with our earlier findings. No clinical associations were observed for MPO or IL-17. Conclusion: PMN responses against anti-CII IC are more closely associated with early joint erosions than are PBMC cytokine responses. PMN reactivity against anti-CII IC may contribute to joint destruction in newly diagnosed RA patients with high levels of anti-CII.

National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-251853 (URN)10.1186/s13075-015-0523-7 (DOI)000351573200001 ()25598326 (PubMedID)
Available from: 2015-04-28 Created: 2015-04-24 Last updated: 2018-02-27Bibliographically approved
2. Granulocyte-augmented chemokine production induced by type II collagen containing immune complexes is mediated via TLR4 in rheumatoid arthritis patients
Open this publication in new window or tab >>Granulocyte-augmented chemokine production induced by type II collagen containing immune complexes is mediated via TLR4 in rheumatoid arthritis patients
2016 (English)In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 46, no 12, p. 2822-2834Article in journal (Refereed) Published
Abstract [en]

Rheumatoid arthritis (RA) patients with early elevations of antibodies against collagen type II (CII) have a distinct acute onset phenotype, associated with cytokine induction by surface-bound anti-CII-containing immune complexes (ICs) and high C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Polymorphonuclear granulocytes (PMNs) and peripheral blood mononuclear cells (PBMCs) are abundant in the vicinity of CII in RA joints, and both PMN and PBMC reactivity against anti-CII IC individually relate to early joint destruction and early elevation of CRP and ESR in RA. We searched for CII-dependent mechanisms that might attract PMNs and PBMCs to RA joints. Human PBMCs and PMNs were stimulated with anti-CII ICs and control ICs, either individually or in cocultures. Cocultured PMNs and PBMCs stimulated with anti-CII ICs synergistically augmented production of the chemokines CXCL8, RANTES and MCP-1, whereas downregulation was seen with control IC. This upregulation was unique to chemokines, as TNF-α, IL-1β, and GM-CSF were downregulated in anti-CII IC-stimulated cocultures. The coculture-associated chemokine upregulation depended on endogenous TLR4 ligand(s) and functionally active PMN enzymes, and was partially mediated by GM-CSF. As anti-CII levels peak around the time of RA diagnosis, this mechanism can attract inflammatory cells to joints in early RA and intensify the anti-CII-associated acute onset RA phenotype.

Place, publisher, year, edition, pages
Wiley-VCH Verlagsgesellschaft, 2016
Keywords
Anticollagen antibodies, Chemokine, Collagen type II, Immune complexes, Polymorphonuclear granulocytes, Rheumatoid arthritis, TLR4
National Category
Immunology
Identifiers
urn:nbn:se:uu:diva-308558 (URN)10.1002/eji.201646496 (DOI)000392940400021 ()27621106 (PubMedID)
Funder
Swedish Research CouncilSwedish Rheumatism Association
Available from: 2016-11-28 Created: 2016-11-28 Last updated: 2018-02-27Bibliographically approved
3. Anticollagen type II antibodies are associated with an acute onset rheumatoid arthritis phenotype and prognosticate lower degree of inflammation during 5 years follow-up
Open this publication in new window or tab >>Anticollagen type II antibodies are associated with an acute onset rheumatoid arthritis phenotype and prognosticate lower degree of inflammation during 5 years follow-up
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2017 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 76, no 9, p. 1529-1536Article in journal (Refereed) Published
Abstract [en]

Objective

Antifibrillar collagen type II (anti-CII) antibody-positive patients with rheumatoid arthritis (RA) have early but not late signs of increased inflammation and joint erosions. We wanted to replicate this in a large RA cohort, and to relate to human leukocyte antigen (HLA)-DRB1* alleles.

Methods

Anti-CII and anti-cyclic citrullinated peptide (CCP)2 were measured at baseline in 773 patients with RA from the Swedish Epidemiological Investigation in Rheumatoid Arthritis (EIRA) study with clinical follow-up data from the Swedish Rheumatology Quality Register (SRQ) registry, and 1476 with HLA-DRB1* information. Comparisons were done concerning C reactive protein (CRP), erythrocyte sedimentation rate (ESR), tender joint count (TJC), swollen joint count (SJC), Disease Activity Score encompassing 28 joints based on ESR (DAS28), DAS28CRP, pain-Visual Analogue Scale (VAS), global-VAS and Health Assessment Questionnaire Score (HAQ) at eight occasions during 5 years, and association with HLA-DRB1* alleles.

Results

Anti-CII associated with elevated CRP, ESR, SJC, DAS28 and DAS28CRP at diagnosis and up to 6 months, whereas anti-CCP2 associated with SJC and DAS28 from 6 months to 5 years, but not earlier. The anti-CII-associated phenotype was strong, and predominated in anti-CII/anti-CCP2 double-positive patients. Anti-CII was associated with improvements in CRP, ESR, SJC, TJC and DAS28, whereas anti-CCP2 was associated with deteriorations in SJC and DAS28 over time. Anti-CII-positive patients achieved European League Against Rheumatism good or moderate response more often than negative patients. Anti-CII was positively associated with HLA-DRB1*01 and HLA-DRB1*03, with significant interaction, and double-positive individuals had >14 times higher mean anti-CII levels than HLA double negatives. Whereas smoking was associated with elevated anti-CCP2 levels, smokers had lower anti-CII levels.

Conclusions

Anti-CII seropositive RA represents a distinct phenotype, in many respects representing the converse to the clinical, genetic and smoking associations described for anticitrullinated protein peptide autoantibodies. Although not diagnostically useful, early anti-CII determinations predict favourable inflammatory outcome in RA.

National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-311956 (URN)10.1136/annrheumdis-2016-210873 (DOI)000407833100022 ()28336519 (PubMedID)
Available from: 2017-01-03 Created: 2017-01-03 Last updated: 2018-02-27Bibliographically approved
4. Anti-collagen type II antibodies are associated with an acute onset  rheumatoid arthritis phenotype
Open this publication in new window or tab >>Anti-collagen type II antibodies are associated with an acute onset  rheumatoid arthritis phenotype
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-311958 (URN)
Available from: 2017-01-03 Created: 2017-01-03 Last updated: 2018-02-27

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