Association between the 65-kilodalton heat shock protein, Streptococcus sanguis, and the corresponding antibodies in Behçet's syndrome

Abstract

The etiology of Behcet's syndrome (BS) is unknown, but a number of streptococcal species have been implicated. A hypothesis was postulated that a shared antigen, such as a stress protein, might account for some of these findings. Indeed, a rabbit antiserum against a 65-kDa heat shock protein of Mycobacterium tuberculosis revealed a corresponding 65-kDa band with all six Streptococcus sanguis strains examined and S. pyogenes but not with S. salivarius. By applying a panel of nine monoclonal antibodies to the mycobacterial 65-kDa heat shock protein, an approximately 65-kDa antigen was identified in the uncommon serotypes of S. sanguis ST3 and H.83 and one with a different Mr was identified in KTH-1 and S. pyogenes. Monoclonal antibodies Y1.2, C1.1, II H9, and ML30, which reacted with these streptococci, recognize residues 11 to 27, 88 to 123, 107 to 122, and 276 to 297 of the 65-kDa heat shock protein, respectively, suggesting that these residues are conserved among some uncommon serotypes of S. sanguis and S. pyogenes. Immunoblot analyses of sera from patients with BS for immunoglobulin A (IgA) and IgG antibodies revealed bands of 65 to 70 kDa with the mycobacterial heat shock protein, S. sanguis strains, and S. pyogenes, although these reactivities were also found to a lesser extent in controls. A 65to 70-kDa band was found more frequently with S. sanguis KTH-2 or KTH-3 and IgA in serum from patients with BS than with serum from controls (P < 0.02). Antibodies in serum were then studied by a radioimmunoassay, and in patients with BS this revealed significantly raised IgA antibodies to the recombinant 65-kDa mycobacterial heat shock protein and to soluble protein extracts of S. sanguis ST3, KTH-1, KTH-2, and KTH-3. Whereas significant anti-65-kDa heat shock protein and anti-S. sanguis ST3 antibodies were also found in sera from patients with rheumatoid arthritis and recurrent oral ulcers, the anti-S. sanguis KTH-1, KTH-2, and KTH-3 antibodies were confined to BS. The results are consistent with the hypothesis that some of the streptococcal antigens are associated with heat shock or stress proteins, which will need to be formally established by isolating heat shock proteins from streptococci.

Oral tolerization with peptide 336–351 linked to cholera toxin B subunit in preventing relapses of uveitis in Behcet's disease

“…For analytical purposes HSP65 was prepared from M. bovis as described elsewhere [28]. The peptide 336-351 and control peptide 136-151 were synthesized in the Hansen's Disease Laboratory (Centre for Disease Control, Atlanta, GA, USA) as described before [7].…”

Peripheral blood T cell expansions in patients with Behcet's disease

“…The observed restricted V and J gene usages in the T cell expansions suggest that they had been caused by conventional antigens. hsp peptides derived from streptococci or HSV have been implicated in the pathogenesis of BD [4,9,17,28]. Each of the manifold manifestations of BD might be induced by different antigens and heterogeneous T cell expansions might thus be in part due to such variability.…”

Excessive expression of Txk, a member of the Tec family of tyrosine kinases, contributes to excessive Th1 cytokine production by T lymphocytes in patients with Behcet's disease

“…Human heat shock protein (HSP) is an unique antigen with a potent immunostimulatory property [17]. HSP is involved in the pathogenesis of autoimmune diseases [18].…”