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Autoantigen BiP‐Derived HLA–DR4 Epitopes Differentially Recognized by Effector and Regulatory T Cells in Rheumatoid Arthritis
Author(s) -
Shoda Hirofumi,
Fujio Keishi,
Sakurai Keiichi,
Ishigaki Kazuyoshi,
Nagafuchi Yasuo,
Shibuya Mihoko,
Sumitomo Shuji,
Okamura Tomohisa,
Yamamoto Kazuhiko
Publication year - 2015
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.39054
Subject(s) - epitope , foxp3 , peripheral blood mononuclear cell , immunology , il 2 receptor , regulatory t cell , secretion , proinflammatory cytokine , cytokine , effector , t cell , medicine , rheumatoid arthritis , antibody , biology , inflammation , immune system , in vitro , biochemistry
Objective The balance between effector and regulatory CD4+ T cells plays a key role in the pathogenesis of rheumatoid arthritis (RA). The aim of this study was to examine whether the RA autoantigen BiP has epitopes for both effector and regulatory immunities. Methods The proliferation and cytokine secretion of peripheral blood mononuclear cells (PBMCs) from HLA–DR4–positive RA patients in response to BiP‐derived peptides were examined by 3 H‐thymidine uptake and enzyme‐linked immunosorbent assay. As a mouse therapeutic model, a BiP‐derived peptide was administered orally to mice with collagen‐induced arthritis (CIA). Results Among the peptides examined, BiP 336–355 induced the strongest proliferation of PBMCs from RA patients, but not from healthy donors. The proliferation of PBMCs in response to BiP 336–355 showed a correlation with clinical RA activity and serum anti‐BiP/citrullinated BiP antibodies. In contrast, BiP 456–475 induced interleukin‐10 (IL‐10) secretion from CD25‐positive PBMCs obtained from RA patients and healthy donors without inducing cell proliferation, and it actively suppressed the BiP 336–355 –induced proliferation and proinflammatory cytokine secretion by PBMCs. Oral administration of BiP 456–475 to mice with CIA reduced the severity of arthritis and T cell proliferation and increased the secretion of IL‐10 from T cells as well as the number of CD4+CD25+FoxP3+ regulatory T cells. Conclusion Effector and regulatory T cells recognized different BiP epitopes. The deviated balance toward BiP‐specific effector T cells in RA may be associated with disease activity; therefore, BiP‐specific effector or regulatory T cells could be a target of new RA therapies.