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      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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          Abstract

          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-α (ΤΝF-α) 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 ΤΝF-α was measured with enzyme linked immunosorbent assay.

          Results

          PMN expression of CD11b, CD66b and MPO, and PBMC production of ΤΝF-α 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 ρ = 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 ΤΝF-α 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.

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          Most cited references45

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          The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis.

          The revised criteria for the classification of rheumatoid arthritis (RA) were formulated from a computerized analysis of 262 contemporary, consecutively studied patients with RA and 262 control subjects with rheumatic diseases other than RA (non-RA). The new criteria are as follows: 1) morning stiffness in and around joints lasting at least 1 hour before maximal improvement; 2) soft tissue swelling (arthritis) of 3 or more joint areas observed by a physician; 3) swelling (arthritis) of the proximal interphalangeal, metacarpophalangeal, or wrist joints; 4) symmetric swelling (arthritis); 5) rheumatoid nodules; 6) the presence of rheumatoid factor; and 7) radiographic erosions and/or periarticular osteopenia in hand and/or wrist joints. Criteria 1 through 4 must have been present for at least 6 weeks. Rheumatoid arthritis is defined by the presence of 4 or more criteria, and no further qualifications (classic, definite, or probable) or list of exclusions are required. In addition, a "classification tree" schema is presented which performs equally as well as the traditional (4 of 7) format. The new criteria demonstrated 91-94% sensitivity and 89% specificity for RA when compared with non-RA rheumatic disease control subjects.
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            IL-17 produced by neutrophils regulates IFN-gamma-mediated neutrophil migration in mouse kidney ischemia-reperfusion injury.

            The IL-23/IL-17 and IL-12/IFN-gamma cytokine pathways have a role in chronic autoimmunity, which is considered mainly a dysfunction of adaptive immunity. The extent to which they contribute to innate immunity is, however, unknown. We used a mouse model of acute kidney ischemia-reperfusion injury (IRI) to test the hypothesis that early production of IL-23 and IL-12 following IRI activates downstream IL-17 and IFN-gamma signaling pathways and promotes kidney inflammation. Deficiency in IL-23, IL-17A, or IL-17 receptor (IL-17R) and mAb neutralization of CXCR2, the p19 subunit of IL-23, or IL-17A attenuated neutrophil infiltration in acute kidney IRI in mice. We further demonstrate that IL-17A produced by GR-1+ neutrophils was critical for kidney IRI in mice. Activation of the IL-12/IFN-gamma pathway and NKT cells by administering alpha-galactosylceramide-primed bone marrow-derived DCs increased IFN-gamma production following moderate IRI in WT mice but did not exacerbate injury or enhance IFN-gamma production in either Il17a-/- or Il17r-/- mice, which suggested that IL-17 signaling was proximal to IFN-gamma signaling. This was confirmed by the finding that IFN-gamma administration reversed the protection seen in Il17a-/- mice subjected to IRI, whereas IL-17A failed to reverse protection in Ifng-/- mice. These results demonstrate that the innate immune component of kidney IRI requires dual activation of the IL-12/IFN-gamma and IL-23/IL-17 signaling pathways and that neutrophil production of IL-17A is upstream of IL-12/IFN-gamma. These mechanisms might contribute to reperfusion injury in other organs.
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              Collagen type II-specific monoclonal antibody-induced arthritis in mice: description of the disease and the influence of age, sex, and genes.

              Transfer of collagen type II (CII)-specific monoclonal antibodies induces an acute form of arthritis (collagen type II antibody-induced arthritis, CAIA) in naïve mice. Arthritis was induced using a pair of monoclonal antibodies M2139 and CIIC1, binding to J1 and C1(I) epitopes of CII, respectively. Thereafter, lipopolysaccharide injection was used to increase the incidence and severity of the disease. This model was used to investigate the effect of genes, age, and sex as well as effector cells in the end-stage effector phase of arthritis pathogenesis. Injection of a single monoclonal antibody induced arthritis only after lipopolysaccharide stimulation. CAIA showed differences in disease penetration among the susceptible strains indicating the importance of non-major histocompatibility complex genes on the antibody effector pathway. B-cell-deficient mice were susceptible to CAIA and in some genetic backgrounds B-cell deficiency leads to enhanced arthritis. Histology of the affected paws revealed massive infiltrations of neutrophils along with bone and cartilage erosion, pannus formation, and fibrin deposition. Depletion of neutrophils significantly reduced the incidence and severity of the disease. CAIA susceptibility increased with age. Males were more susceptible than females and estrogen treatment decreased the development of arthritis. We conclude that CAIA is an acute arthritis triggered by antibody binding and neutrophils bypassing immune activation but with many characteristics in common with collagen-induced arthritis.
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                Author and article information

                Contributors
                vivek.anand@igp.uu.se
                azita.sohrabian@igp.uu.se
                marius.wick@karolinska.se
                mmullazehi@yahoo.se
                lena.douhan-hakansson@medsci.uu.se
                johan.ronnelid@igp.uu.se
                Journal
                Arthritis Res Ther
                Arthritis Research & Therapy
                BioMed Central (London )
                1478-6354
                1478-6362
                19 January 2015
                19 January 2015
                2015
                : 17
                : 1
                : 8
                Affiliations
                [ ]Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
                [ ]Department of Radiology, Karolinska University Hospital, Stockholm, Sweden
                [ ]Department of Medical Sciences, Uppsala University, Uppsala, Sweden
                [ ]Unit of Rheumatology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
                Article
                523
                10.1186/s13075-015-0523-7
                4349301
                25598326
                2e44b336-7fea-4f07-955f-4ae8cf1ef292
                © Manivel et al.; licensee BioMed Central. 2015

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 3 June 2014
                : 8 January 2015
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                © The Author(s) 2015

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