Regulation of autoimmune arthritis by self–heat-shock proteins

Abstract

Heat-shock proteins (hsps) are highly conserved and immunogenic, and they are generally perceived to be attractive initiators or targets of a pathogenic immune response and as such have been implicated in the pathogenesis of autoimmune arthritis. However, studies in animal models and arthritis patients have unraveled the disease-regulating attributes of self hsp65. We propose that the self hsp65 induces a protective and beneficial immune response owing to its ubiquitous distribution, stress-inducibility, and participation in tolerogenic processes. In contrast, the foreign hsp65 that does not influence the above processes, and which resides admixed with microbial ligands for innate receptors, generates an inflammatory pathogenic response. The regulatory properties of self hsps need be fully explored and might be utilized for therapeutic purposes.

Heat-shock proteins can promote as well as regulate autoimmunity

“…However, the precise conditions controlling these differential outcomes of the immune response to Hsps are not fully defined. In this regard, some of the factors proposed and elaborated by others and us [7-10] include the induction of T cell tolerance by self Hsp leading to pre-emptive deletion of potentially autoreactive T cells; the contribution of microbial toll-like receptors (TLR) and other ligands of innate immune receptors to the pathogenicity of foreign (microbial) Hsps; and the differential activation of DCs by foreign versus self Hsp leading to the generation of a pro-inflammatory versus a regulatory response, respectively. Furthermore, molecular mimicry or enhanced expression of Hsps and their antigenic determinants can contribute not only to pathogenic mechanisms (described in section 1), but also to regulation of autoimmunity.…”

“…These self Hsps may further propagate the ongoing inflammation, and also constitute an attractive target for T cells and antibodies induced by foreign Hsps. In addition, inflammation can alter the antigen processing of Hsps to reveal certain epitopes more efficiently or display neodeterminants, including hidden (cryptic) epitopes [7], which can prime an immune response leading to immune pathology.…”

“…Furthermore, molecular mimicry or enhanced expression of Hsps and their antigenic determinants can contribute not only to pathogenic mechanisms (described in section 1), but also to regulation of autoimmunity. Broadly, the regulatory effector mechanisms recruited to control pathogenic responses include [7, 8, 10-13] the induction of immune tolerance, deviation of the cytokine response from Th1 to Th2 type, suppression of IL-17 response, apoptosis of pathogenic T cells, and activation and expansion of regulatory T cells (e.g., CD4+CD25+ (Treg)-, IL-10-secreting (Tr1)-, or TGF-β-secreting (Th3)- regulatory T cells).…”

The HSP60 immune system network

“…The immune response to HSP in general, and the role of other self-molecules in immune regulation has been discussed elsewhere [16,17]. This review focuses on the ability of extracellular HSP60 to link immune cells to infectious agents and to provide communication between immune cells and other cells of the body.…”

“…In the extracellular environment, HSP60 alone or in combination with self or microbial proteins, acts as a link between immune cells, and can coordinate the activity of the immune system. This ability to behave as a link between components of the immune system is shared by other chaperones, such as HSP70 and HSP90 [13][14][15].The immune response to HSP in general, and the role of other self-molecules in immune regulation has been discussed elsewhere [16,17]. This review focuses on the ability of extracellular HSP60 to link immune cells to infectious agents and to provide communication between immune cells and other cells of the body.…”