Background/Purpose: Molecular mimicry is believed to be an important mechanism of autoimmunity development. We previously demonstrated that imbalance between effector and regulatory T cells specific for BiP, a member of heat shock protein 70 family, induced autoimmne responses in rheumtaoid arthritis (RA). However, the reason why BiP-specific effector T cells developed in RA remains unclear. Here, we examined the immunological linkages between human heat shock proteins (HSPs) and Mycobacterium (Myc) HSPs in RA because the sequences of HSPs are preserved through the species.

Methods: Serum antibodies to bacteria (Mycobacterium and E.Coli) and human HSPs (HSP10, HSP40, HSP60, HSP70) in RA were measured by ELISA. Proliferation of peripheral blood mononuclear cells (PBMCs) from HLA-DR4-positive RA patients in response to MycHSP70-derived and BiP-derived peptides was examined using ³H-thymidine uptake. The effect of immunity on MycHSP70, was evaluated by immunizing HLA-DR4-trangenic mice with MycHSP70 and CFA, and measuring serum antibodies by ELISA. CD4⁺ T cell proliferation in response to MycHSP70 and BiP epitopes was measured by ³H-thymidine uptake. MycHSP70-derived peptide was orally administered to collagen-induced arthritis (CIA) and scores were observed.

Results:  Serum titers of antibodies against MycHSP70 were significantly elevated in RA patients and correlated with serum anti-BiP and anti-ciurullinated BiP antibody titers. A MycHSP70-derived HLA-DR4 major epitope was identified using proliferative capasity of RA PBMCs as an indicator. The major T-cell epitope, MycHSP70^287-306, was located at the corresponding position in the major epitope for human BiP^336-355, and PBMC proliferations in response to MycHSP70^287-306 and BiP^336-355 were highly correlated. These two peptides shared the common amino acid sequences which were important for HLA-DR4 binding. Immunization with MycHSP70 induced BiP-specific T cell proliferation, and development of anti-BiP antibodies. Moreover, oral administration of MycHSP70^287-306resulted in amelioration of CIA and inhibition of BiP and collagen-specific T cell proliferations .

Conclusion: Immune responses to MycHSP70 were associated with adaptive immunity against BiP in RA. Mycobacterium exposure in the daily environment could trigger the immune responses. Further examination of the immune response against BiP could reveal a mechanism for the development of related autoantibodies including ACPA upon exposure to a certain spectrum of microbes.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/immune-responses-to-mycobacterium-heat-shock-protein-70-accompany-self-reactivity-to-human-bip-in-rheumatoid-arthritis/