Idiotypic network interactions, autoimmunity and the pathogenesis of AIDS

The functional disruption of the immune system in acquired immunodeficiency syndrome (AIDS) is incompletely understood. Many clinical features are common to AIDS and Systemic lupus erythematosus (SLE), and it is plausible that autoimmunity is involved in the pathogenesis of AIDS. The immune response directed against human immunodeficiency virus (HIV) and concomitant anti-idiotypic response may cross-react with host cell antigens and result in the depletion of certain T cell populations. A model of AIDS pathogenesis has emerged from a version of idiotypic network theory with sharply defined molecular and cellular mechanisms. In this model, the network is postulated to be able to select clones that have variable (V) regions that are complementary to MHC molecules and clones that have V regions that are images of MHC molecules. A central part of the regulatory T cell repertoire consists of anti-class II MHC helper T cells and class II MHC-image suppressor T cells. The interactions between these two T cell populations are expected to be mutually stabilizing. The model includes a role for allogeneic stimuli as cofactors. The immune response to allogeneic lymphocytes includes a MHC-image response, which is directed against the idiotypes on the foreign receptors that recognize self. The immune response to the MHC-mimicking portions of HIV includes an anti-MHC-image response. MHC-image and anti-MHC-image responses are directed against each other (by definition), and may synergize with each other in such a way to lead to the eventual collapse of the normally self-stabilizing immune system network. In this thesis, several findings that can be understood in the context of that model are described. These findings would otherwise have not been expected. Alloimmune mice make antibodies that bind gpl20 and p24 of HIV, and autoimmune MRL-lpr/lpr and MRL ̶+/+ mice spontaneously make anti-gpl20 antibodies. Anti-gpl20 antibodies are interpreted as being anti-MHC-image since gpl20 is considered to be an image of class II MHC antigens (based on its complementary to the CD4 antigen of T lymphocytes). MHC-image antibodies are typically produced during alloimmunization, and MRL mice were found to spontaneously make MHC-image antibodies. MHC-image antibodies can be detected by the inhibition of alloantibody (and complement) mediated cytotoxicity, and by enzyme-linked immunosorbant assay (ELISA) with polyclonal antisera and monoclonal antibodies. Injection of young MRL-lpr/lpr mice with low doses of gpl20 or p24 of HIV suppressed the production of autoantibodies and enhanced the survival of these mice. These results support the idea that MHC-image and anti-MHC-image antibodies may be involved in the pathogenesis of lupus in these mice. The presence of both MHC-image and anti-MHC-image antibodies in alloimmunity suggests that synergy between immune responses to allogeneic cells and HIV is important in some groups that are at risk for AIDS.Science, Faculty ofMicrobiology and Immunology, Department ofGraduat