The studies described in this proposal are designed to broaden our understanding of the genetic and structural basis of antibody specificity and idiotypes, the definition of immunoglobulin variants and the elucidation of the mechanism of amyloid fibril formation. The primary structure of the variable region of light and heavy chains of human monoclonal immunoglobulin M with antibody activity against self antigens and bacterial antigens will be determined in search of insights into the structural-idiotype-antigen specificity relationships and the genetic restrictions that appear to be present in autoantibody synthesis. The occurrence of variable region subgroups and complementarity-determining region antigens in monoclonal autoantibodies with defined specificity and normal immunoglobulins using antisera raised to synthetic framework residues fragments and complementarity determining region peptides will be studied. Our theory is that certain complementarity determining antigens and variable region subgroups are selectively associated with autoantibodies and that in spite of the heterogeneity of some autoantibody responses, the specificities of the binding sites and the idiotypes of autoantibodies are germline- gene encoded. The first clues to the discontinuous nature of gene coding for immunoglobulin chains, heavy chains in particular, emerged from serological and structural studies of Heavy Chain Disease proteins or immunoglobulin variants, which clearly indicated the existence of separate gene segments coding for different domains, a prediction confirmed by analysis of murine and human heavy chain gene structure. Studies of patients with these disorders and the proteins they produce are important in order to describe additional clinical syndromes associated with abnormal Ig synthesis and define their molecular defects. Studies of human AA amyloidosis and murine secondary amyloidosis due to chronic inflammation will be continued in order to confirm our hypothesis that amyloid fibrils are derived by degradation of a soluble precursor; that processing of the amyloid precursor is tissue specific, and that other factors, like amyloid enhancing factor, are involved in amyloidogenesis. This may in turn provide leads as to possible therapeutic approaches for the prevention of amyloid fibril formation and deposition.
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