Type II collagen-specific antibodies induce cartilage damage in mice independent of inflammation.

OBJECTIVE: Murine collagen antibody-induced arthritis (CAIA), like collagen-induced arthritis, has clinical and immunopathologic features that parallel those in human rheumatoid arthritis (RA). This study was undertaken to examine the effects of autoantibodies to type II collagen (CII) on articular cartilage in the paws of mice, under conditions in which other factors that may influence joint pathology could be excluded. METHODS: Mice of 2 different strains, B10.QC5δ and the parental strain B10.Q, were injected intravenously with either saline or arthritogenic monoclonal antibodies (mAb) to CII. B10.QC5δ mice lack complement factor C5 and do not develop CAIA when injected with arthritogenic mAb, whereas B10.Q mice have C5 and develop CAIA when administered the mAb and a subsequent injection of lipopolysaccharide. Three days after injection the paws of the mice were examined by standard histologic methods to assess morphologic appearance and proteoglycan loss, and by synchrotron-enhanced Fourier transform infrared microspectroscopy to assess chemical evidence of structural change. RESULTS: No macroscopic or microscopic signs of inflammation were evident in the mice. However, in contrast to the saline-injected controls, all mAb-injected mice exhibited cartilage damage in all joints, with loss of proteoglycans and collagen, chondrocyte hyperplasia and/or loss, and surface damage in the interphalangeal joints. CONCLUSION: The implication of these findings is that an autoimmune response to CII can disrupt articular cartilage, particularly that of the small joints, and the subsequent integrity of the cartilage depends on a balance between breakdown and repair. This has relevance with regard to RA, in which such autoantibodies occur but the inflammatory response may dominate clinically and mask underlying features of the autoimmune response.

Collagen Autoantibodies and Their Relationship to CCP Antibodies and Rheumatoid Factor in the Progression of Early Rheumatoid Arthritis.

Serum autoantibodies to cyclic citrullinated peptides (anti-CCP) and rheumatoid factor (RF) are important markers for diagnosis and prognosis of rheumatoid arthritis (RA), but their autoantigens are not cartilage-specific. Autoantibodies to joint-specific type II collagen (CII) also occur in RA, and monoclonal antibodies of similar specificity induce collagen antibody-induced arthritis in animals, but their role in RA is uncertain. We utilized an enzyme-linked immunosorbent assay (ELISA) with the CB10 peptide of CII to compare the frequency of autoantibodies with those of anti-CCP and RF in stored sera from a prospective study of 82 patients with early RA to examine the outcome, defined as remission (n = 23), persisting non-erosive arthritis (n = 27), or erosions (n = 32). Initial frequencies of anti-CB10, anti-CCP and RF were 76%, 54%, and 57% in RA, and 4%, 0%, and 9% in 136 controls. The frequency of anti-CB10 was unrelated to outcome, but anti-CCP and RF increased with increasing severity, and the number of autoantibodies mirrored the severity. We suggest RA is an immune complex-mediated arthritis in which the three antibodies interact, with anti-CII inducing localized cartilage damage and inflammation resulting in citrullination of joint proteins, neoepitope formation, and a strong anti-CCP response in genetically-susceptible subjects, all amplified and modified by RF.

Autoimmune gastritis: historical antecedents, outstanding discoveries, and unresolved problems.

The earliest recorded history of autoimmune gastritis can be traced to 1849 in London, when Thomas Addison described "a very remarkable form of anemia" later called pernicious (fatal) anemia (PA). This was followed by the recognition of a gastric mucosal defect suspected to have a nutritional basis, the discovery of the megaloblast that characterized the anemia, the insufficiency of a dietary extrinsic factor characterized as vitamin B12 (cobalamin), and a gastric-secreted intrinsic factor. Treatment with vitamin B12 proved curative. The link between PA and gastritis and atrophy was first confirmed histologically after immediate fixation of the stomach postmortem and later, in the 1940s, by peroral tube biopsy. The causes of gastritis remained enigmatic until the era of autoimmunity, when autoantibodies were detected first to gastric intrinsic factor and then to gastric parietal cells. Hints of a dichotomy in pathogenesis of gastritis were crystallized by the description in 1973 of Type A (Autoimmune) and Type B (later, Bacterial) gastritis. Clarification was enhanced by identification in Type A gastritis of the autoantigen of the parietal cell antibody, by the alpha and beta subunits of gastric H+/K+ ATPase, and by the highly informative experimental murine model of postneonatal thymectomy autoimmune gastritis, and in Type B of the causative role of gastric infection with Helicobacter pylori (H. pylori). A denouement will require a full understanding of (1) the origin and pathogenetic contribution of antibody to intrinsic factor; (2) the connection, if any, between H. pylori infection and Type A autoimmune gastritis; and (3) the genetic contributions to gastritis, whether due to autoimmunity or to H. pylori infection.

A tribute to an outstanding immunologist - Ian Reay Mackay.

The 11th Australasian Autoimmunity Workshop was held in Melbourne, Australia from July 6-8, 2007 organized by the Monash University Autoimmunity Network. The workshops, founded by the late Kevin Lafferty, are a chance for Australasians interested in research into autoimmune disease to present and discuss their work. This workshop also was a chance to acknowledge Ian Mackay, a pioneer clinician-scientist who has made major contributions to our understanding of autoimmune diseases. Friends, colleagues and former students attended the Workshop and acknowledged Ian's expertise and mentorship. This edition of the Journal of Autoimmunity pays tribute to Ian Mackay. It features articles from attendees at the workshop, and contributions from some of Ian's past students and past and current collaborators.

Arthritogenic anti-type II collagen antibodies are pathogenic for cartilage-derived chondrocytes independent of inflammatory cells.

OBJECTIVE: Some monoclonal antibodies (mAb) to type II collagen (CII) are arthritogenic upon passive transfer to mice. We undertook this study to investigate whether such mAb are pathogenic in the absence of mediators of inflammation. METHODS: The arthritogenic mAb CIIC1 and M2139, and the nonarthritogenic mAb CIIF4, each reactive with a distinct and well-defined conformational epitope on CII, were compared with control mAb GAD6. Bovine chondrocytes were cultured with one of the mAb, and on days 3, 6, and 9, antibody binding by chondrocytes and newly synthesized extracellular matrix (ECM) was examined by immunofluorescence, morphologic effects were studied by electron microscopy, and synthesis of matrix components was determined by metabolic labeling with (3)H-proline for collagen and (35)S-sulfate for proteoglycans. RESULTS: All 3 mAb to CII bound to the matrix. CIIC1 and M2139 adversely affected the cultures, whereas CIIF4 did not. CIIC1 caused disorganization of CII fibrils in the ECM without affecting chondrocyte morphology, and increased matrix synthesis. M2139 caused thickening and aggregation of CII fibrils in the ECM and abnormal chondrocyte morphology but matrix synthesis was unaffected. CONCLUSION: The unique arthritogenic capacity of particular anti-CII mAb upon passive transfer could be explained by their adverse, albeit differing, effects in primary cultures of chondrocytes. Such effects occur independent of inflammation mediators and are related to the epitope specificity of the mAb. Interference with the structural integrity of CII could precede, and even initiate, the inflammatory expression of disease.

Autoantibodies to the transcriptional factor SOX13 in primary biliary cirrhosis compared with other diseases.

The molecule SOX13 was initially identified as an autoantigen (ICA12) in Type 1 diabetes. SOX13 is a member of the SOX family of transcriptional regulatory proteins that contain a high mobility group (HMG) motif with structural similarity to HMG proteins 1 and 2. Antibodies to HMG 1 and 2 occur in autoimmune diseases of the liver and in ulcerative colitis. We measured the occurrence and levels of anti-SOX13 by radioimmunoprecipitation in primary biliary cirrhosis (PBC) and other diseases, and compared frequencies with anti-HMG measured by ELISA. Anti-SOX13 was detected in 18% of patients with PBC, 13% with autoimmune hepatitis, 18% with Type 1 diabetes, at lower frequencies in other conditions including the multisystem autoimmune diseases, systemic lupus erythematosus and rheumatoid arthritis, and in 1% of normal sera. Anti-HMG1 and anti-HMG2 occurred at frequencies of 30% and 35% respectively in PBC. Serum levels of anti-SOX13 and anti-HMG correlated significantly for PBC although not for Type 1 diabetes. Anti-SOX13 in PBC may occur merely as an immune response to products of damage to parenchymal tissue, or may be illustrative of a general proclivity of transcriptional regulatory proteins to elicit autoimmune responses.

An arthritogenic monoclonal antibody to type II collagen, CII-C1, impairs cartilage formation by cultured chondrocytes.

Antibodies to type II collagen (CII) cause articular damage in collagen-induced arthritis (CIA) in mice as judged by passive transfer to naive animals of mAb to CII. We tested the hypothesis that mAb degrade cartilage structure by reacting with functionally important regions of the collagen molecule by examining the effects of an arthritogenic mAb to CII, CII-C1, on cultured bovine chondrocytes at high density, at days 7 and 14. The effects were compared of CII-C1, an isotype-matched control mAb, or medium alone, on chondrocyte proliferation and viability, cell morphology, matrix structure by light and electron microscopy, and matrix synthesis by metabolic labelling with 3H-proline for collagen or 35SO4 for proteoglycans. Chondrocytes in culture remained viable, proliferated, and produced an extracellular matrix in which CII was the major collagen. The addition of CII-C1, but not a control mAb, increased the synthesis of CII and proteoglycan, and caused disorganization of the extracellular matrix and thin collagen fibrils ultrastructurally. Moreover, using a cell-free assay, CII-C1 inhibited the normal self-assembly of collagen fibrils from CII in solution. The finding that the mAb to CII, CII-C1 has striking degradative effects in vitro on cartilage synthesis suggests that antibodies to collagen perpetuate the chronic phase of CIA and that, in mice at least, such antibodies are an important component of pathogenesis.