Systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD) are characterized by the presence of autoantibodies against small nuclear ribonucleoprotein (SnRNP). In these diseases autoantibodies mediate host cell injury. The investigator proposes that B-cell autoantibody production is under the control of T-cell help in these diseases. This is supported by studies in animal models of SLE, in which depletion of CD4+ T-cells has therapeutic benefit, and recently autoantibody production to the RNP antigens has been found to have HLA DR4 and DR2 associations, implying control by T-cells restricted to these MHC alleles. The investigator proposes to analyze the hypothesis that Sn RNP reactive T-cells provide help for anti-Sm RNP autoantibody producing B-cells and that these T-cells play a role in the immunopathogenesis of SLE and MCTD. Therefore, in Aim I, the investigator will determine if Sm reactive human T-cell clones can provide help to anti-Sm autoantibody production and determine the cytokines produced by such Sm reactive T-cells.
In Aim II, the investigator will characterize the TCR Va and Vb gene segment usage and CDR3 sequences of human T-cell clones specific for the B and D polypeptides of Sm antigens.
In Aim III, the T-cell epitopes of the B and D polypeptides will be mapped using overlapping peptides, and, finally, in aim IV, the MHC restriction of the T-cell clones will be determined using transfections of a variety of HLA MHC class II alleles, notably those encoding HLR DR2.
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