Serum autoantibodies are a characteristic of patients with systemic lupus erythematosus. Some of these bind to the ribonucleoprotein complexes Ro/SSA and La/SSB. Strong associations between the presence of these autoantibodies and particular HLA class II molecules have been described. The biological function of these HLA molecules suggests that specific T cell receptors may recognize Ro/SSA-HLA and La/SSB-HLA complexes and play a critical in the perpetuation of these autoimmune responses. Polymorphisms of the T cell receptor beta genes have been identified by the principal investigator which act as genotypic markers for the subset of lupus patients which produce anti=Ro/SSA autoantibodies, and which are strongly associated with HLA genetic markers. In this study, the molecular characteristics of these T cell receptor genes will be elucidated. Variable genes which code for Ro/SSA-specific T cell receptors will be isolated by subtractive DNA techniques and sequenced. The germline sequences of diversifying and joining genes will also be determined and compared between patients with and without the anti-Ro/SSA antibody. T cells selected for the recognition of the Ro/SSA molecule will be cloned, and cDNA of their T cell receptor transcripts produced. Nucleotide sequencing of these molecules will determine if the genes identified above are expressed as functional T cell receptors in Ro/SSA-responsive cells. The genes identified in these experiments will be used as nucleotide probes to study the familial response to Ro/SSA and the role that similar T cell receptors may play in the anti-Ro/SSA immune response in Sjogren's syndrome patients. These studies will enhance our basic knowledge of T cell receptors and their role in autoimmunity. They will be useful in understanding multigenic interaction in the immune response, and may be of use in the future in designing immunomodulatory regimens in lupus patients.
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