Abstract
Heat shock proteins (Hsps) are highly conserved, and their expression is upregulated in cells by heat and other stressful stimuli. These proteins play a vital role in preserving the structural and functional integrity of cells under stress. Despite the ubiquitous expression of Hsps in an individual, the immune system is not fully tolerant to them. In fact, Hsps are highly immunogenic in nature, and immune response to these proteins is observed in various inflammatory and autoimmune diseases. Studies on the immunopathogenesis of autoimmune arthritis in the rat adjuvant arthritis (AA) model of human rheumatoid arthritis (RA) as well as observations in patients with RA and juvenile idiopathic arthritis (JIA) have unraveled immunoregulatory attributes of self-Hsp65-directed immunity. Notable features of Hsp65 immunity in AA include protection rather than disease induction following immunization of Lewis rats with self (rat)-Hsp65; the diversification of T cell response to mycobacterial Hsp65 during the course of AA and its association with spontaneous induction of response to self-Hsp65; the cross-reactive T cells recognizing foreign and self homologs of Hsp65 and their role in disease suppression in rats; the suppressive effect of antibodies to Hsp65 in AA; and the use of Hsp65, its peptides, or altered peptide ligands in controlling autoimmune pathology. The results of studies in the AA model have relevance to RA and JIA. We believe that these insights into Hsp65 immunity would not only advance our understanding of the disease process in RA/JIA, but also lead to the development of novel therapeutic approaches for autoimmune arthritis.
Highlights
Reviewed by: Beatrice Jahn-Schmid, Medical University of Vienna, Austria Elizabeth Ann Repasky, Roswell Park Cancer Institute, USA
Are Lewis rats tolerant to self-Hsp65?; how does activation of self-Hsp65-reactive T cells affect the development of arthritis?; how does immune response to foreign Hsp65 evolve during the course of adjuvant arthritis (AA)?; what is the significance of the T cell repertoire against foreign Hsp65 that is cross-reactive with self-Hsp65?; what role do antibodies to Hsp65 play in AA?; and does Hsp65 treatment influence arthritis induced by a non-antigenic compound? These aspects of cellular and humoral immunity to Hsp65 are elaborated below, based on results of studies by others and us
We further suggested that inflammation upregulates the display of cryptic BCTD, which can induce T cells that cooperate with Rhsp65 C-terminal determinants (RCTD)-primed T cells in suppressing pathogenic T cell response, leading to natural recovery from acute AA (Figure 1)
Summary
Reviewed by: Beatrice Jahn-Schmid, Medical University of Vienna, Austria Elizabeth Ann Repasky, Roswell Park Cancer Institute, USA. These results showed that immune response to systemically administered self-Hsp65 is protective against arthritis instead of being pathogenic (Figure 1).
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