Autoantibodies to T-Cell Receptors

It is well documented that humans (1) and experimental animals (2) can produce autoantibodies directed against autologous immunoglobulins in infections and in autoimmune diseases; most notably, rheumatoid arthritis, in which the rheumatoid factors (Rfs) are autoantibodies, usually but not always of the IgM isotype, that bind to conformational determinants on the Fc fragments of autologous γ chains (3,4). In addition, autoantibodies directed against the Fab fragments of human immunoglobulins occur frequently in individuals infected with HIV (5,6). Both types of autoantibodies may be regulatory in initial disease emergence, but may become involved in disease pathogenesis at later stages. Using comprehensive peptide synthesis methods (7) to map epitopes of T-cell receptor (TCR) β chains (8-11), we found that purified polyclonal human IgG immunoglobulin (IVIG) contains low levels of autoantibodies directed against Vβ epitopes in CDR1, FR3, and a loop in the constant domain. The latter can be expected to be glycosylated in the cell-expressed TCR (Fig. 1). Further studies showed the existence of autoantibodies directed against recombinant single chain TCRs containing the complete Vα and Vβ domains (11–13) and the shared peptide-epitope specificities of these antibodies and those reactive with the T-cell expressed TCR (11–13). The titers and isotypes of these autoantibodies vary with normal physiological conditions such as aging (9,10) and pregnancy (14), with allograft transplantation (15), with autoimmune diseases (9-11) and with retroviral infections in humans (16,17) and in mice (18–22). Monoclonal human (23–25) and murine (26,27) autoantibodies to TCR Vβ CDR1 epitopes have been generated to analyze the binding specificities and possible functions of these molecules. Moreover, the tendency of humans and mice to respond to retroviral infections by generating autoantibodies with similar specificities has allowed the development of a peptide-based immunotherapy for retrovirally induced immunodeficiency in mice (19–22), with implications for human AIDS (28).