Synthetic Autoantigens of Immunoglobulins and T-Cell Receptors: Their Recognition in Aging,Infection,and Autoimmunity

Abstract

Immunoglobulins and their close relatives, the antigen-specific T-cell receptors, are recognition proteins that express structures which readily serve as self-immunogens. Healthy humans can produce antibodies against variable region-defined recognition structures termed idiotypes, as well as against constant region structures, and the levels of these can increase markedly in autoimmune disease; e.g., rheumatoid factors are autoantibodies directed against a conformational determinant of the γ heavy chain. More recent analyses employing synthetic peptide technologies and construction of recombinant T-cell receptors document that autoantibodies directed against both variable and constant region markers of the α/β T-cell receptor occur in healthy individuals. Alterations in levels of antibody, usage of IgM or IgG isotypes, and specificity for particular peptide-defined regions vary with natural physiological processes (aging, pregnancy), with artificial allografting, with retroviral infection, and with the inception and progression of autoimmune disease (e.g., rheumatoid arthritis, systemic lupus erythematosus). Two of the major autoimmunogeneic regions of the Tcr α/β are “constitutive” markers inasmuch as all Individuals tested produce antibodies against these regions. The most frequently observed autoantibodies are against Tcr Vβ CDR1 and Fr3 markers. It is hypothesized that these are normally involved in immunoregulation. Autoantibodies usually are not detected against CDR2 region determinants, or the “private idiotypes” defined by the CDR3 region, or the highly conserved FR4 segment specified by the joining gene segment. However, autoantibodies against the CDR2 of the Tcrα chain occur in some SLE patients, and healthy pregnant women produce antibodies against the common peptide determinant expressed by the joining gene and the beginning of the Cα or Cβ domain. Although the precise role of the naturally occurring autoantibodies in immunoregulation remains to be determined, modification of the course of autoimmune diseases in experimental rodent models (experimental allergic encephalomyelitis) has been successfully carried out by immunization with synthetic peptides corresponding to the CDR2 and Fr3/CDR3 segments, and immunization of humans with synthetic Vβ CDR2 segments may prove helpful in multiple sclerosis.