T‐cell epitopes recognized within the 65 000 MW hsp in patients‘qc with IgA nephropathy

Abstract

SUMMARYIgA nephropathy (IgAN ) is the commonest cause of glomerulonephritis and clinical exacerbation of IgAN is frequently associated with mucosal infection. T-cell receptorcd ( TCRcd+) cells are increased in both the circulation and in renal biopsies of patients with progressive IgAN. We examined the hypothesis that specific peptides within the 65 000 MW heat-shock protein (hsp) might stimulate TCRcd cells and play a part in the immunopathogenesis of IgAN. We studied T-cell proliferative responses stimulated by overlapping peptides derived from the sequence of mycobacterial 65 000 MW hsp. Three T-cell epitopes have been identified ( peptides 51-65, 71-85 and 281-295). The three peptides have a synergistic eÂect and they stimulate significantly higher proliferation of T cells in patients with IgAN than in disease or healthy controls. This response was inhibited by monoclonal antibodies (mAb) to TCRcd+ and human leucocyte antigen (HLA) class I, but not by mAb to HLA class II. The involvement of TCRcd+ cells was confirmed by up-regulation of the proportion of TCRcd+ cells when stimulated with the three specific peptides. We suggest that IgAN might be associated with mucosal infection by a variety of micro-organisms and that peptides within the microbial hsp cross-react with the homologous human hsp which may stimulate TCRcd+ cells and play a part in the pathogenesis of IgAN.

Molecular Chaperones in the Kidney

“…Recent investigations also support a possible role for HSP 47, 65, 70, and 90 in the pathogenesis of some forms of glomerulopathy (122,123,125). Work by Warr and colleagues suggests that cross reactivity between microbial and human HSPs may stimulate a T cell subset that has been implicated in the pathogenesis of progressive IgA nephritis in humans (124). In this study, a peptide derived from mycobacterial HSP 65 stimulated T cell proliferation.…”

“…The presence of constitutive and inducible stress proteins has been demonstrated in animal kidneys with experimental GN (120)(121)(122). An increase in stress proteins was detected in human kidneys with various forms of acute GN (120,(123)(124)(125). Proteinuria, a potential cause of renal tubular injury that often accompanies GN, increases the expression of HSP 72 (123).…”

“…In sum, molecular chaperones may mediate glomerular injury via immune and non-immune mediated mechanisms. Some renal chaperones appear likely to alter the acute infiltration of pro-inflammatory cells, perhaps by inadvertently mimicking an invading micro-organism (124). Other chaperones modulate cell proliferation, determine the susceptibility to pro-apoptotic stimuli, or the propensity to undergo irreversible fibrosis.…”

T‐cell receptor repertoire in IgA nephropathy renal biopsies

“…There is evidence that γδ T cells in the gut of IgAN patients mainly use a subset of γδ T cells 21 . Furthermore three peptides within a 65 000‐MW heat shock protein were recognized by T cells from IgAN patients and also upregulated the T‐cell proliferative response by increasing the γδ T‐cell subsets 22 . In the present study we have further demonstrated an oligoclonal population of Vδ1 bearing a motif in their CDR3 region in most IgAN kidneys examined.…”

Oligoclonally expandingγδT lymphocytes induce IgA switching in IgA nephropathy

“…It has been reported that V γ 9+ T cells proliferated in response to various antigens, including mycobacterium tuberculosis, staphylococcus enterotoxin B, and bacterial heat shock protein (hsp) [31]. It has also been reported that a subset of γδ T cells in IgAN patients could recognize the epitopes of the human hsp65 [32]. Since human hsp shares a high degree of homology with hsp of microorganisms, it is likely that V γ 9+ T cells in IgAN patients proliferate in response to bacterial hsp delivered from mucosal infection by microorganisms.…”