HEAT-SHOCK (STRESS) PROTEINS AND AUTOIMMUNITY IN RHEUMATIC DISEASES

The rheumatic diseases (RDs) are characterized by acute and chronic inflammation, and autoimmunity plays a major role in their pathogenesis. RDs are for the most part of unknown etiology, but recent evidence indicates that heat shock or stress proteins (HSPs) may have an important role in the eitology / pathogenesis of RDs. HSPs are produced by prokaryotic and eukaryotic cells and are grouped according to molecular weight. Phylogenetically, HSPs are very old and are remarkably conserved molecules in evolution from bacteria to humans. HSPs are induced by a variety of cellular stresses in addition to heat; cognates are expressed constitutively and are essential in a number of normal functions. Some HSPs serve as molecular chaperones, the latter defined as proteins that mediate folding of other polypeptides and either promote their assembly into oligomeric structures or disassemble the final product. Conservation of structure and function of many HSPs may provide a link between immunity to infection and the autoimmune features of RDs. Evidence is reviewed from clinical and laboratory observations that diverse microbial agents, including viruses, bacteria, and parasites, may have putative roles in the development and pathogenesis of some RDs. HSPs also are discussed in relation to the major histocompatibility complex, HLA antigens, and disease associations and how they may alter the balance between tolerance and autoimmunity. Studies are reviewed that are supportive or nonsupportive of the concept of microbial infection associated with autoimmunity; individuals first react to microbial immunizations or infections with enhanced cellular/humoral responses to the agent's HSPs. With the enhanced immune response, cross-reactivity may occur with an HSP of the stressed host because of structural similarities to the microbial HSP. If all of these events occur, the host's homologous HSP or stressed cells now become true autoantigen(s). This sequence has implications for the etiology of immune-mediated RDs, the concept, of epitope sharing, and the accompanying autoimmunity. A recurring theme emphasized in some reports to understand better the role of HSPs in autoimmunity is the need to select patients with early-onset disease. A minor subpopulation of T lymphocytes express a CD3-associated T-cell receptor (TCR) heterodimer composed of γ and δ polypeptide chains. The γδ+ T cells have several unique features. When analyzed by the polymerase chain reaction, lymphocytes with TCR-γδ appear to reflect the polyclonal expansion of preexisting γδ clones. They are found in peripheral lymphoid tissue in very low percentage (<5%) but may represent the majority of T cells within epithelial tissue. Although the biological role of γδ+ T cells has yet to be established clearly, they may play a role in autoimmunity, possible through the production of HSP-inducing lymphokines. © 1993 W.B. Saunders Company. All rights reserved.