IMMUNOLOGICAL & GENETIC STUDIES OF THROMBOCYTOPENIAS

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Most patients with chronic idiopathic thrombocytopenic purpura (ITP) produce IgG anti-platelet antibodies, which have been shown to be directly responsible for the enhanced platelet destruction. Based on the disease onset, ITP can be divided into "acute" and "chronic" ITP. The latter often has a gradual onset with no preceding infection, suggesting an autoimmune mechanism. As such, chronic ITP is also called "autoimmune thrombocytopenia". While several platelet antigens recognized by the disease-specific autoantibodies have been well characterized, little is known about the culprit antibodies, in terms of their structures and genetic elements, as well as their induction and regulation. Therefore, the goals of this proposal are to characterize the expressed Ig variable region (V) genes that encode the pathogenic anti-platelet antibodies, identify their germline counterparts, determine the role of somatic mutations in the production of pathogenic autoantibodies, and assess the polymorphisms of the autoantibody-related Ig V genes and their possible linkage to the induction and clinical features (such as severity, duration and responses to various treatment) of the diseases. Specifically, we plan to: 1) generate monoclonal anti-platelet hybridomas from patients with autoimmune thrombocytopenia, and determine the immunological properties of the secreted antibodies; 2) clone and sequence the expressed Ig V genes in the aforementioned hybridomas; 3) identify and characterize the germline origins of the anti-platelet antibodies; and 4) study the polymorphisms of the selected Ig V genes, including anti- platelet antibody-associated V genes and physiologically important Ig V genes, in patients and normal controls matched for ethnic origins. These studies will reveal the Ig V gene usage by anti-platelet antibodies in patients. Do the disease-specific autoantibodies employ a special set of V genes? If so, are they similar to those used by the "physiological" autoantibodies in normal immune system and expressed preferentially during early ontogenic development? The answers will help us understand the induction and regulation of anti-platelet antibodies, as well as the basis of the effectiveness of intravenous Ig treatment in patients with autoimmune thrombocytopenia. In addition, the proposed polymorphism studies may reveal the role of certain V genes in this autoimmune disorder.