PATHOGENESIS OF AUTOIMMUNE THROMBOCYTOPENIA

描述

DESCRIPTION (Adapted from applicant's abstract) Idiopathic Thrombocytopenia (ITP) is an autoimmune disorder characterized by production of antiplatelet antibodies and consequent immune-mediated platelet destruction. The initial stimulus for the autoantibody response in ITP is not known, even though it is one of the most common autoimmune diseases affecting both adults and children. ITP may occur as an isolated phenomenon or in association with many conditions, for example: acquired or congenital immune dysregulation, pregnancy, viral infection like HIV or EBV, or systemic lupus erythematosus (SLE). The dominance of antiplatelet autoantibodies in such a wide variety of immune diseases suggests that there may be an alternative mechanisms to antiplatelet production as compared to other autoimmune diseases. In this grant, the applicants present a model for ITP and hypothesize that the platelet itself may act to short circuit the process of antigen specific immunoglobulin production allowing the emergence of autoantibodies which are normally restricted by a network of anti-idiotypic T and B cell clones. Ordinarily, somatic mutation and antigen selection in the B lymphocyte proceed under the strict supervision and symmetrical evolution of idiotype specific T cell clones. In their model, the platelet, mimicking a T cell, could promote polyclonal expansion of previously restricted clones without the concomitant involvement of regulatory T cells or macrophages. To test this hypothesis, the applicants will focus their efforts in following areas: SPECIFIC AIM #1: To determine the effect of ligation of CD40, membrane lg (mig) receptor, and FcRyIII on IL-1alpha and IL-1beta gene expression and production in B cells and dendritic cell/macrophages. SPECIFIC AIM #2: To determine the effect of polyclonal expansion and epitope shifts, they will use limited oligonucleotide substitutions (within the immunoglobin framework or CDR3 region) to measure changes in antigen binding using a uniquely engineered baculovirus protein expression system. Their long term goal is to identify the dysregulation which drives the production of platelet autoantibody. They believe that interruption of this process will return the immune system to a more restricted process of B cell immunoglobulin production allowing T cell regulation to further limit the emergence of autoreactive clones. (End of Abstract)