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A Shared Epitope of Collagen Type XI and Type II Is Recognized by Pathogenic Antibodies in Mice and Human with Arthritis

Journal article
Authors D. M. Tong
E. Lonnblom
A. C. Y. Yau
K. S. Nandakumar
B. B. Liang
C. R. Ge
J. Viljanen
L. Li
M. Balan
L. Klareskog
A. S. Chagin
Inger Gjertsson
J. Kihlberg
M. Zhao
R. Holmdahl
Published in Frontiers in Immunology
Volume 9
ISSN 1664-3224
Publication year 2018
Published at Institute of Medicine, Department of Rheumatology and Inflammation Research
Language en
Keywords rheumatoid arthritis, arthritis, autoantibody, collagen XI, CII, cross-reactive, rheumatoid-arthritis, cartilage, gene, fibrils, ix, chondrosarcoma, mutations, reveals, col11a1, rats, Immunology
Subject categories Immunology in the medical area


Background: Collagen XI (CXI) is a heterotrimeric molecule with triple helical structure in which the alpha 3(XI) chain is identical to the alpha 1(II) chain of collagen II (CII), but with extensive posttranslational modifications. CXI molecules are intermingled in the cartilage collagen fibers, which are mainly composed of CII. One of the alpha chains in CXI is shared with CII and contains the immunodominant T cell epitope, but it is unclear whether there are shared B cell epitopes as the antibodies tend to recognize the triple helical structures. Methods: Mice expressing the susceptible immune response gene A(q) were immunized with CII or CXI. Serum antibody responses were measured, monoclonal antibodies were isolated and analyzed for specificity to CII, CXI, and triple helical collagen peptides using bead-based multiplex immunoassays, enzyme-linked immunosorbent assays, and Western blots. Arthritogenicity of the antibodies was investigated by passive transfer experiments. Results: Immunization with CII or CXI leads to a strong T and B cell response, including a cross-reactive response to both collagen types. Immunization with CII leads to severe arthritis in mice, with a response toward CXI at the chronic stage, whereas CXI immunization induces very mild arthritis only. A series of monoclonal antibodies to CXI were isolated and of these, the L10D9 antibody bound to both CXI and CII equally strong, with a specific binding for the D3 epitope region of alpha 3(XI) or alpha 1(II) chain. The L10D9 antibody binds cartilage in vivo and induced severe arthritis. In contrast, the L5F3 antibody only showed weak binding and L7D8 antibody has no binding to cartilage and did not induce arthritis. The arthritogenic L10D9 antibody bound to an epitope shared with CII, the triple helical D3 epitope. Antibody levels to the shared D3 epitope were elevated in the sera from mice with arthritis as well as in rheumatoid arthritis. Conclusion: CXI is immunologically not exposed in healthy cartilage but contains T and B cell epitopes cross-reactive with CII, which could be activated in both mouse and human arthritis and could evoke an arthritogenic response.

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