The Human Endoplasmic Reticulum Molecular Chaperone BiP Is an Autoantigen for Rheumatoid Arthritis and Prevents the Induction of Experimental Arthritis

Abstract

Rheumatoid arthritis (RA) is the most common, crippling human autoimmune disease. Using Western blotting and tandem mass spectroscopy, we have identified the endoplasmic reticulum chaperone BiP, a 78-kDa glucose-regulated protein, as a possible autoantigen. It preferentially stimulated increased proliferation of synovial T cells from patients with RA but not from patients with other arthritides. Mice with established collagen- or pristane-induced arthritis developed IgG Abs to BiP. Although BiP injected in CFA failed to induce arthritis in several strains of rats and mice, including HLA-DR4+/−- and HLA-DR1+/+-transgenic animals, it completely inhibited the development of arthritis when given i.v. 1 wk before the injection of type II collagen arthritis. Preimmunization with BiP suppressed the development of adjuvant arthritis in Lewis rats in a similar manner. This is the first report of a mammalian chaperone that is an autoantigen in human RA and in experimental arthritis and that can also prevent the induction of experimental arthritis. These findings may stimulate the development of new immunotherapies for the treatment of RA.

Treatment of murine collagen‐induced arthritis by the stress protein BiP via interleukin‐4–producing regulatory T cells: A novel function for an ancient protein

“…Previously, we and other investigators have identified the immunoglobulin binding protein, BiP, alternatively known as glucose-regulated protein 78, as a putative autoantigen in RA (11,12). BiP is an endoplasmic reticulum chaperone and stress protein belonging to the Hsp70 family.…”

“…BiP is an endoplasmic reticulum chaperone and stress protein belonging to the Hsp70 family. We previously demonstrated that patients with RA have anti-BiP antibodies in their serum (11). In addition, mice with CIA or pristane-induced arthritis produce anti-BiP antibodies.…”

“…In addition, mice with CIA or pristane-induced arthritis produce anti-BiP antibodies. Furthermore, patients with RA were shown to harbor BiP-specific T cells in synovial fluid, in contrast to that found in other inflamed joints (11). These T cells were observed to have unusual properties, in that they proliferated poorly and produced only low levels of interferon-␥ (IFN␥).…”

Serologic changes following B lymphocyte depletion therapy for rheumatoid arthritis

“…The most prevalent autoantibody reactivity in RA is RF, with IgG-RF being particularly implicated in the formation of small immune complexes (2,22), but a significant proportion of patients also have raised levels of antibodies to cyclic citrullinated peptides (anti-CCP) (23) and to proteins such as the immunoglobulin heavy-chain binding protein (anti-BiP) (24). In the absence of T cell responses to IgG, there is particular interest in the possible roles of T cell responses to these other antigens and their interrelationships with RF B cells.…”

Integrating the cell stress response: a new view of molecular chaperones as immunological and physiological homeostatic regulators

“…Thus HSPA1 is well recognised as a proinflammatory ligand causing activation of human and murine monocytes [25]. In contrast, HSPA5, which has 64% sequence identity to HSPA1, is a potent monocyte inhibitor and anti-inflammatory protein which is starting trials as a therapy for the chronic inflammatory disease, rheumatoid arthritis [26,27]. Mycobacterium tuberculosis is one of a proportion of bacteria that have more than one gene coding for chaperonin 60 proteins and in this organism the proteins are termed chaperonin 60.1 and 60.2 (Hsp65).…”