Candidate T cell epitopes of the human La/SSB autoantigen
Davies, M.L., Taylor, E.J., Gordon, C., Young, S.P., Welsh, K., Bunce, M., Wordsworth, B.P., Davidson, B. and Bowman, S.J. (2002) Candidate T cell epitopes of the human La/SSB autoantigen. Arthritis & Rheumatism, 46 (1). pp. 209-214.
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To identify T cell epitopes of the human La autoantigen involved in the generation of anti-Ro/La autoantibodies.
Molecular techniques were used for HLA typing of 219 white patients with systemic lupus erythematosus and 125 white patients with primary Sjögren's syndrome. Anti-Ro/La antibody levels were measured by enzyme-linked immunosorbent assay. Peripheral blood mononuclear cell responses to an overlapping series of synthetic 15-mer peptides spanning the entire La sequence were examined in pools or individually in conventional 7-day proliferation assays.
HLA typing confirmed that the HLA-DR3/DQ2 haplotype is closely associated with the occurrence of anti-Ro/La antibodies, and that the frequency of HLA-DR1 and DR4 haplotypes is reduced among antibody-positive patients. We identified 3 regions of the La sequence likely to contain T cell epitopes and 1 peptide, La 49–63, that generated a low-level but clear-cut T cell proliferative response. The HLA restrictions of these responses mirrored the HLA association data from the cohort study. Among individuals who were HLA-DR3 positive, there was no difference between patients and controls in the proliferative response to the La 49–63 peptide.
Our data suggest that these are naive T cell responses, and that the identification of T cell epitopes involved in the generation of anti-Ro/La autoantibodies should focus on alternative candidate antigens.
Between 30% and 40% of patients with systemic lupus erythematosus (SLE) and 70–80% of patients with primary Sjögren's syndrome (primary SS) have anti-52-kd/60-kd Ro/SSA and or/anti-La/SSB antibodies (1). These antibodies are class switched and somatically hypermutated, implying a T cell-dependent process. Furthermore, 80–90% of patients with these antibodies possess the HLA-DR3/DQ2 major histocompatibility complex haplotype (1), suggesting that T cells responding to peptides presented by these HLA molecules are involved in the generation of these autoantibodies.
The most likely T cell antigens are those targeted by the autoantibodies or closely linked “carrier” proteins (2). Helsloot and Sturgess (3) previously identified a precursor frequency of La-specific T cells of 1:103,000 to 1:230,000 in peripheral blood of patients with primary SS and 1:77,000 to 1:115,000 in controls. This finding suggests that these cells escape thymic deletion, but their low frequency implies a naïve T cell response. Halse et al (4), using an ELISpot assay, found similar results. T cells specific for 52-kd Ro have been identified in the salivary glands of Japanese patients with primary SS, although their frequency and activation phenotype are unknown (5).
A major shift in our approach followed the discovery that Ro and La are found in cell-surface “blebs” of cells undergoing programmed death (apoptosis) (6), thus explaining how these intracellular proteins become exposed to the immune system. The cleavage or posttranslational modification of these proteins during apoptosis (7, 8) could generate antigenic neoepitopes and explain why in vitro studies of native proteins did not identify a primed T cell response. Since La (8), but not Ro, is cleaved during apoptosis, it is the more likely candidate in which to identify such neoepitopes.
In order to bypass any requirement for specific processing that may have prevented the identification of responses to whole Ro/La protein, we generated a peptide series encompassing the entire La molecule. The present study was undertaken to address the hypothesis that HLA-DR3-restricted T cell responses to La peptide neoepitopes could be identified in patients with SLE and in those with primary SS, thereby playing a part in the subsequent generation of anti-La antibodies.
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|Copyright:||2002 American College of Rheumatology|
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