Immune responses to Mycobacterial heat shock protein 70 accompany self-reactivity to human BiP in rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease, and a member of human heat shock protein (HSP) 70 protein family, Binding Immunoglobulin Protein (BiP), has been identified as an important autoantigen for T and B cells. We herein focused on Mycobacterial (Myc) HSPs and immune responses to MycHSPs in RA patients. Serum titers of antibodies against MycHSP70 were significantly elevated in RA patients and correlated with serum anti-BiP antibody titers. A MycHSP70-derived HLA-DR4 major epitope was identified using the proliferative capacity of RA PBMCs as an indicator. The major epitope, MycHSP70287–306, was located at the corresponding position in the major epitope for human BiP336–355, and a strong correlation was found between the proliferation of PBMCs in response to MycHSP70287–306 and BiP336–355. The immunization of HLA-DR4 transgenic mice with MycHSP70 induced the proliferation of T cells and development of anti-BiP antibodies. In contrast, the oral administration of MycHSP70287–306 resulted in the amelioration of collagen-induced arthritis, serum antibody responses, and T cell proliferation. In conclusion, immune responses to MycHSP70 were associated with adaptive immunity against BiP in RA, and could be an important mechanism underlying the development of autoimmunity.

Role of Infections in the Pathogenesis of Rheumatoid Arthritis: Focus on Mycobacteria

“…Autoimmune response to Mycobacterial (Myc) HSP70 and human binding immunoglobulin protein (Bip), a member of the human HSP70 family, has also been reported in RA patients [ 102 ]. Shoda’s study showed that the similarity between Myc HSP70 287–306 and human Bip 336–355 epitopes can lead to a broken immune tolerance, triggering an auto-immune response as a result of the T cells’ inability to distinguish between self- and pathogens’ antigens [ 103 ] ( Figure 1 ).…”

Autoantibodies in the Pathogenesis, Diagnosis, and Prognosis of Juvenile Idiopathic Arthritis

“…Immunization of HLA-DR4 transgenic mice with HSP70 287−306 derived from Mycobacterium leporae induced the development of BiP autoantibodies. In the collagen-induced arthritis model, oral administration of this mycobacterial peptide induced tolerance, blunting the development of arthritis and reducing anti-BiP autoantibody production (132). Thus, tolerance against BiP, a common autoantigen in RA and JIA, may be broken by immune responses directed against a mycobacterial pathogen.…”

Ts-Hsp70 induces protective immunity against Trichinella spiralis infection in mouse by activating dendritic cells through TLR2 and TLR4

“…Some Hsps have been reported to play important roles in antigen presentation and maturation of dendritic cells [ 9 , 10 ]. Recently, many studies have showed that Hsps from parasites [ 11 , 12 ] or bacteria [ 13 ] exhibited potent immunogenicity and induced protective immunity against specific infections, thus these proteins have become momentous target proteins in vaccine development against various infections. Heat shock protein-70 of Trichinella spiralis ( Ts -Hsp70) is a member of Hsp70 family with molecular weight of about 70 kDa and an immunodominant antigen during infection.…”