Detailed Biography:

Dr. Chen's laboratory has two major research interests. The first is to delineate molecular genetics of autoantibody production in autoimmune diseases. Specifically, patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) frequently have respectively high titers of high affinity rheumatoid factors (RFs) and anti-DNA antibodies. In contrast, healthy subjects often have low titers of low affinity IgM autoantibodies, termed natural autoantibodies. During the last 15 years, our study of RFs in RA patients has suggested strongly that IgG RFs in rheumatoid synovia arise from natural autoantibodies in an antigen-driven response fashion and are clonally related in an individual patient. It is well established that self-reactive B cells in a normal immune system are either deleted by apoptosis or functionally inactivated (anergy). However, some self-reactive B cells are not tolerized in autoimmune MRL-lpr/lpr mice, which has a defective Fas-mediated apoptosis pathway. Generally, under selection pressure, a variant cell with a survival advantage can expand in a clonal manner. Therefore, we hypothesize that some disease specific autoantibody-secreting B cells in RA and SLE may escape tolerance regulation because of: (1) loss-of-function mutations in apoptosis-related genes; or (2) gain-of-function mutations in apoptosis suppressor genes (such as Bcl-2) at the clonal B cell level, resulting in tolerance-resistant variants. To test these hypotheses, our strategy is to first obtain monoclonal autoantibody-secreting cell lines from patients and scrutinize these cell lines to identify potential tolerance defects. We will then verify that the identified defects are also present in subpopulations of un-transformed autoreactive B cells obtained from the respective patients. The second is to delineate pathogenesis of the antiphospholipid syndrome (APS). Recurrent thrombosis, fetal loss, thrombocytopenia and neurological pathology occur in some patients with SLE. Such patients often have serum antiphospholipid antibodies (APA), including anticardiolipin antibodies (ACA) detected by enzyme-linked immunosorbent assay (ELISA) and/or the lupus anticoagulant (LAC) detected by in vitro blood clotting tests. The hemostatic complications are therefore referred to as the APS. When coagulation abnormalities of APS occur without SLE, it is referred to as primary APS. Although APA is strongly associated with thrombosis, the role of APA in causing thrombosis remains unclear. Considering that many patients with APA do not manifest the APS, he hypothesize that only certain APA in APS patients are thrombogenic, and that such APA may have certain "unique" binding and functional properties. The putative thrombogenic APA is likely to be necessary but not sufficient for causing thrombosis, as APS patients do not suffer thrombosis all the time. Our study will examine these hypotheses. Specifically, we will (1) generate monoclonal IgG APA from APS patients with high titers of serum APA and recurrent thrombosis, and characterize the binding specificity and affinities of the monoclonal APA; (2) determine the functional properties of monospecific APA by in vitro blood clotting assays and an in vivo thrombosis model in mice (to be done by our collaborators in another institution); and (3) study the mechanisms by which thrombogenic and anticoagulant APA exert their effects. The results will help to define various subsets of APA in APS patients with recurrent thrombosis, and to advance our understanding about the role of APA in thrombosis associated with APS. If some thrombogenic APA are found, their immunological characteristics, and structural and genetic basis will be revealed.