SYNTHETIC AUTOANTIGENS OF IMMUNOGLOBULINS AND T-CELL RECEPTORS - THEIR RECOGNITION IN AGING, INFECTION, AND AUTOIMMUNITY

Immunoglobulins and their close relatives, the antigen-specific T-cell receptors, are recognition proteins that express structures which rea dily serve as self-immunogens. Healthy humans can produce antibodies a gainst variable region-defined recognition structures termed idiotypes , as well as against constant region structures, and the levels of the se can increase markedly in autoimmune disease; e.g., rheumatoid facto rs are autoantibodies directed against a conformational determinant of the gamma heavy chain. More recent analyses employing synthetic pepti de technologies and construction of recombinant T-cell receptors docum ent that autoantibodies directed against both variable and constant re gion markers of the alpha/beta T-cell receptor occur in healthy indivi duals. Alterations in levels of antibody, usage of IgM or IgG isotypes , and specificity for particular peptide-defined regions vary with nat ural physiological processes (aging, pregnancy), with artificial allog rafting, with retroviral infection, and with the inception and progres sion of autoimmune disease (e.g., rheumatoid arthritis, systemic lupus erythematosus). Two of the major autoimmunogeneic regions of the Tcr alpha/beta are ''constitutive'' markers inasmuch as all individuals te sted produce antibodies against these regions. The most frequently obs erved autoantibodies are against Tcr V beta CDR1 and Fr3 markers. It i s hypothesized that these are normally involved in immunoregulation. A utoantibodies usually are not detected against CDR2 region determinant s, or the ''private idiotypes'' defined by the CDR3 region, or the hig hly conserved FR4 segment specified by the joining gene segment. Howev er, autoantibodies against the CDR2 of the Tcr alpha chain occur in so me SLE patients, and healthy pregnant women produce antibodies against the common peptide determinant expressed by the joining gene and the beginning of the C alpha or C beta domain. Although the precise role o f the naturally occurring autoantibodies in immunoregulation remains t o be determined, modification of the course of autoimmune diseases in experimental rodent models (experimental allergic encephalomyelitis) h as been successfully carried out by immunization with synthetic peptid es corresponding to the CDR2 and Fr3/CDR3 segments, and immunization o f humans with synthetic VP CDR2 segments may prove helpful in multiple sclerosis. Moreover, infusion of intravenous immunoglobulins has been successful in the treatment of many autoimmune diseases, including ex amples where levels of T cells bearing particular V beta gene subsets were elevated. The recent knowledge gained from T-cell receptor struct ural analysis and antigenic modeling holds promise for determining the roles of particular variable domain structures in antigen recognition MHC-restriction and immunoregulation, and in the development of synth etic and recombinant reagents for modulation of autoimmune and infecti ous diseases.