This research intends to investigate at the immunochemical, genetic, structural and functional level the variable (V) region of self-reactive antibodies bearing a defined idiotype proven to be immunoregulatory. It is based on the hypothesis that self recognition and autoimmunity are physiological events in the immune system -- autoimmune network -- and V regions of some self-reactive antibodies are pivotal immunoregulatory elements. This study will utilize, as a model system, a putative germline idiotype (Id62) borne independently on the heavy and light chains of murine monoclonal autoantibodies from either adult or neonatal mice. Two major issues will be addressed. The genetic relatedness and the structural correlate for a number of adult and neonatal Id62-positive autoantibodies. The functional impact such V regions may have on ontogenic development and reactivity of a defined autoimmune network.
The specific aims to this research are as follows: 1) Detection and Immunochemical Analysis of Id62-Positive Antibodies within a large pool of hybridoma self-reactive antibodies. 2) Molecular Genetic Analysis of all Id62-positive V regions and selection by specific VH gene probing of putative Id62-positive antibodies. 3) Amino Acid Sequence Analysis of V regions identified and retained through the preceding two approaches and comparisons with prototype sequence. 4) Functional studies of the autoimmune network based on perturbation of the neonatal repertoire by Id62 or anti-ID62 antibodies. 5) Functional studies of the autoimmune network based on immunization of adult mice with Id62 or anti-Id62 antibodies, including anti-single chain or anti-peptide antibodies. It is hoped that the approach will help considerably to elucidate the contribution that inheritable genetic elements and functional network interactions may have on the ability of the immune system to respond to self components. Undoubtedly, new light will be shed onto the fundamental laws of regulation of autoimmunity and invaluable new knowledge will be generated in understanding autoimmune diseases in general. Ultimately, this study may constitute the basis for rational therapeutic approaches to immunologically-mediated disease process.
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