HUMAN ORGAN-SPECIFIC AUTOIMMUNE-DISEASE - MOLECULAR-CLONING AND EXPRESSION OF AN AUTOANTIBODY GENE REPERTOIRE FOR A MAJOR AUTOANTIGEN REVEALS AN ANTIGENIC IMMUNODOMINANT REGION AND RESTRICTED IMMUNOGLOBULIN GENE USAGE IN THE TARGET ORGAN

The most common organ-specific autoimmune disease in humans involves t he thyroid. Autoantibodies against thyroid peroxidase (TPO) are presen t in the sera of virtually all patients with active disease. We report the molecular cloning of the genes for 30 high-affinity, IgG-class hu man autoantibodies to TPO from thyroid-infiltrating B cells. Analysis of the putative germline genes used for the TPO human autoantibodies s uggests the use of only five different H and L chain combinations invo lving four H chains and three L chains. In addition, the same combinat ion of H and L chains was found in multiple patients. The F(ab) protei ns expressed by these genes define two major, closely associated domai ns (A and B) in an immunodominant region on TPO. These A and B domains contain the binding sites of approximately 80% of IgG-class TPO autoa ntibodies in the sera of patients with autoimmune thyroid disease. The present information permits analysis, not previously possible, of the relationship between autoantibody H and L chain genes and the antigen ic domains on an autoantigen. Our data, obtained using target organ-de rived autoantibodies, indicate that there is restriction in H and L ch ain usage in relation to the interaction with specific antigenic domai ns in human, organ-specific autoimmune disease.