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The basic and translational research focus of my laboratory is on two areas. The first is the roles of complement receptors and membrane regulatory proteins in the immune response, with a special emphasis on B lymphocytes and autoimmune diseases. The second is the role of autoantibodies and the evolution of autoimmunity in RA from the pre-symptomatic autoantibody-positive period through the onset of clinically active disease.

With regard to the first area, complement is a complex system of serum proteins which, upon activation, covalently bind targets (bacteria, viruses, immune complexes, cell membranes) and marks them as foreign. These covalently attached complement fragments bind high affinity receptors on lymphocytes and FDCs. The interaction of complement with B cell receptors results in substantial enhancement of humoral immunity. In addition to this role, excessive activation of complement is centrally involved in the tissue damage that occurs in many inflammatory diseases involving organs such as the kidney. My laboratory has developed human and mouse models in which to study these complement related biologic processes. With regard to the second area, we now know that autoimmune diseases such as RA, SLE and Type 1 Diabetes Mellitus begin years before clinical signs and symptoms are apparent. That is because these individuals manifest highly predictive autoantibodies in their serum. This observation suggests that we must extend our study of the genetic epidemiology of autoimmune diseases such as RA into this important period, and that additional therapeutic and/or prevention strategies should be considered for individuals in this at-risk but asymptomatic period. It is also relevant to determine how individuals transition from this autoantibody-positive, at-risk period to clinically active disease. My research group has established several ongoing studies in RA that are related to these questions.

Specific areas of emphasis include:

Roles of complement receptor type 2 (CR2, CD21) in B lymphocyte development and activation. Using both human and mouse CR2 as a model, we are analyzing the ways by which CR2 regulates B lymphocyte responses to antigens bound by complement. The specific mechanisms by which CR2 and other complement receptors act to modify B lymphocyte responses are incompletely understood, though we have shown that CR2 deficient mice have a markedly impaired humoral immune response. We are now studying the signaling responses of these receptor deficient B lymphocytes. We have also recently created human CR2 transgenic mice as a way to study structure-function relationships and the effects of over-expression of receptors on B cell development and tolerance. Finally, we are determining the three dimensional structure of the CR2 ligand binding sites for its three ligands (C3d, Epstein-Barr virus and CD23) using NMR, x-ray crystallographic and other structural techniques.
Analysis of the role of complement during the development of SLE, RA and other autoimmune and inflammatory diseases. A recent interest is on the role of specific complement activation pathways (classical, alternative and lectin) in the initiation of injury. In murine studies we are using complement receptor knockouts and complement inhibitors we developed to determine how the alteration of these systems affects self tolerance and tissue injury. A major finding has been to determine that the alternative pathway and its amplification loop are absolutely essential to generate pathologic complement activation fragments in antibody-dependent and –independent disease models and to develop new generations of inhibitors to take advantage of that observation. In patients, we have led a therapeutic trial of a complement inhibitor in patients with SLE and active glomerular disease and continue to be focused on learning how complement inhibition can positively affect patients with various human diseases.

In addition to the above areas of emphasis, a study of pre-disease autoimmunity in patients at risk for the development of RA has also been initiated in collaboration with Dr. Jill Norris of the Department of Preventive Medicine and other members of the Division of Rheumatology. By using unique human populations at risk for developing RA, we are determining what RA-associated autoantibodies and other biomarkers are present that could predict the development of clinical disease. In addition, we have developed an animal model of the pathogenic role of a newly described autoantibody system directed to citrullinated antigens, commonly called anti-CCP antibodies. These studies have clearly shown that these autoantibodies are pathogenic and are opening up additional therapeutic targets and opportunities.