Diversity in antigen recognition by Mycobacterium tuberculosis‐reactive T cell clones from the synovial fluid of rheumatoid arthritis patients

Abstract

In a previous study we have shown that synovial fluid mononuclear cells from many rheumatoid arthritis (RA) patients exhibit an enhanced response to M. tuberculosis antigens as compared to peripheral blood mononuclear cells. The 65-kDa heat-shock protein of M. tuberculosis was shown not to play an important role in this response, therefore other mycobacterial proteins must be involved. In this study we have investigated the possibility that synovial fluid T cells from RA patients predominantly recognize a limited number of M. tuberculosis antigens, as a result of a lesion-specific activation of only those M. tuberculosis-reactive T cells that have cross-reacted with joint-related autoantigens. From the synovial fluid of four RA patients M. tuberculosis-reactive T cell clones were isolated and analyzed for their phenotype, HLA-DR restriction and proliferation to immunoblot fractions containing sodium dodecyl sulfate-polyacrylamide gel-separated M. tuberculosis proteins of known molecular weight range. The overall M. tuberculosis immunoblot recognition pattern of the clones was strikingly heterogeneous. Within a panel of 15 clones 12 different antigenic specificities could be distinguished. In other words, we did not observe a dominant recognition of a few M. tuberculosis antigens by synovial fluid T cells. This argues against the hypothesis that the elevated synovial T cell reactivity against M. tuberculosis is a reflection of an in vivo expansion of a limited number of different types of M. tuberculosis-reactive T cells as a result of a cross-reaction with putative joint autoantigens.

Human T cells recognize mycobacterial heat shock proteins in the context of multiple HLA-DR molecules: studies with healthy subjects vaccinated with Mycobacterium bovis BCG and Mycobacterium leprae

“…PBMC from M. lepraevaccinated subjects responded strongly to both M. leprae and BCG, whereas the response of PBMC from BCGvaccinated subjects to M. leprae was weak. Human T cells have been shown to recognize mycobacterial antigens primarily in the context of HLA-DR molecules (3,14,27,34,35,37). However, the difference in response between the two vaccinated groups could not be due to a difference in the expression of HLA-DR molecules because PBMC from most of the BCG-vaccinated subjects carried the same HLA-DR haplotypes as PBMC from the M. leprae-vaccinated subjects ( Table 1).…”

“…Human CD4+ T cells recognize foreign antigens in association with HLA class II molecules, and it has been demonstrated that mycobacterial antigens are recognized by human T cells primarily in the context of HLA-DR molecules (3,14,27,34,35,37). To be useful as specific diagnostic reagents or vaccines, mycobacterial HSP should be recognized in the context of most HLA-DR molecules.…”

Reactivity Patterns of Synovial T‐Cell Lines Derived from a Patient with Rheumatoid Arthritis. I. Reactions with Defined Antigens and Auto‐Antigens Suggest the Existence of Multireactive T‐Cell Clones

“…In the past, attempts to define synovial T-cell specificity have concentrated on stimulating bulk cultures with various antigens [6][7][8][9]. Occasionally analyses were performed at the clonal level in limiting dilution cultures [10] or with clones established by antigen selection [9,[11][12][13][14]. Two antigens inducing arthritis in animal models have attracted most attention: collagen type II (CII) and heat-shock proteins (hsp) of mycobacteria [3,15].…”

“…The hsp60 of Mycobacterium tuberculosis and of M. bovis are identical and 50% homologous to the mitochondrial human hsp60 [16]. However, only few attempts to establish Tcell clones from RA patients reactive with CII or mycobacterial hsp60 and restricted to DR4 were successful [11,14,17,18]. On the other hand, several groups including our own showed that certain subpopulations of T cells characterized by their T-cell receptor (TCR) Va-or Vb-gene usage were enriched in the joint as compared to the peripheral blood [2,[19][20][21][22].…”