V. Michael Holers, M.D. Professor Integrated Department of Immunology M.D. (1978), Washington University School of Medicine Campus Box B115 School of Medicine, Room 4665 S/M Rheumatology - Rheumatology Division Ph: 303-315-7592 Michael.Holers@UCHSC.edu

Research Interests:

The focus of my laboratory is on the roles of complement receptors and membrane regulatory proteins in the immune response, with special emphases on B lymphocytes and autoimmune diseases. 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. Specific areas of emphasis include:
1. 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. These studies, as well as analyses of novel ligands, are allowing us to understand the molecular details of important receptor-ligand interactions as well as design new inhibitors and receptor-ligand mimics.

2. Analysis of the role of complement during the development of autoimmune diseases in murine models and human patients. In murine studies we are using complement receptor knockouts and a complement inhibitor we described called Crry to determine how the alteration of these systems affects self tolerance, inflammation and tissue injury. We are also using transgenic and recombinant protein expression techniques to learn how complement inhibition can lead to beneficial therapeutic effects. In patients, we have begun a therapeutic trial of a complement inhibitor in patients with systemic lupus erythematosus and active glomerular disease and as part of these studies are learning how complement inhibition alters the human immune response.

3. Studies of the evolution of autoimmunity in patients with rheumatoid arthritis. A new area of interest is the study of individuals at risk for the development of this disease. Using humans and a newly established model of arthritis-related autoimmunity, we are increasing our understanding of how autoimmune diseases develop in patients and how we might be able to prevent this process.

Selected Publications

Holers, V. M., Girardi, G., Mo, L., Guthridge, J. M., Molina, H., Pierangeli, S. S., Espinola, R., Xiaowei, L. E., Mao, D., Vialpando, C. G., and Salmon, J. E. 2002. Complement C3 activation is required for anti-phospholipid antibody-induced fetal loss. J. Exp. Med. 195: 211-220.

Fleming, S. D., Shea-Donohue, T., Guthridge, J. M., Kulik, L., Waldschmidt, T. J., Gipson, M. G., Tsokos, G. C., and Holers, V. M. 2002. Mice deficient in complement receptors 1 and 2 lack a tissue injury-inducing subset of the natural antibody repertoire. J. Immunol. 169: 2126-2133.

Marchbank, K. J., Kulik, L, Gipson, M. G., Morgan, B. P., and Holers, V. M. 2002. Expression of human complement receptor 2 (CR2, CD21) in mice during early B cell development results in a reduction in mature B cells and hypgammaglobulinemia. J. Immunol. 169:3526-3535.

Thurman, J. M., Ljubanovic, D., Edelstein, C. L., Gilkeson, G. S, and Holers, V. M. 2003. Lack of a functional alternative complement pathway ameliorates ischemic renal failure in mice. J. Immunol. 170: 1517-1523.

Majka, D. S., and Holers, V. M. 2003. Can we accurately predict the development of rheumatoid arthritis in the preclinical phase? Arth. Rheum. 48:2701-2705

Mikuls, T.R., O’Dell, J.R., Stoner, J.A., Parrish, L.A., Arend, W.P., Norris, J.M., and Holers, V.M. 2004. The association of rheumatoid arthritis treatment response and disease duration with declines in serum levels of IgM rheumatoid factor and anti-CCP antibody. Arth. Rheum. 50:3776-3782.

Hannan, J.P., Young, K.A., Guthridge, J.M., Asokan, R., Szakonyi, G., Chen, X.S., and Holers, V.M. 2005. Mutational analysis of the complement receptor type 2 (CR2/CD21)–C3d interaction reveals a putative charged SCR1 binding site for C3d. J. Mol. Biol. 346:845-858.

Kuhn, K.A., Kulik, L., Braschler, K.J., Arend, W.P., and Holers, V.M. 2006. Antibodies to citrulline-modified proteins enhance tissue injury in inflammatory arthritis. J. Clin. Invest. 54(9):3057-9.

Thurman, J.T., Ljubanovic, D., Royer, P.A., Kraus, D.M., Molina, H., Barry, N.P., Proctor, G., Levi, M., and Holers, V.M. 2006. Renal tubular expression o fhte complement inhibitor Crry permits complement activation after ischemia/reperfusion. J. Clin. Invest. 116(2):357-68.