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V. Michael Holers, Professor and Division Head

M.D. (1978) Washington University School of Medicine



Integrated Department of Immunology

Campus Box B115
Barbara Davis Center, Room 3102-E

Ph: 303-724-7605

Michael.Holers@UCDenver.edu

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.

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.

Mikuls, T.R., Holers, V.M., Parrish, L.A., Alarcon, G.S., Conn, D.L., Gilkeson, G., Smith, E.A., Kamen, D.L., Jonas, B.L., Callahan, L., Howard, G., Moreland, L.W., and Bridges, Jr., S.L. 2006. Diagnostic utility of anti-cyclic citrullinated peptide (CCP) antibody and rheumatoid factor (RF) in African Americans with early onset rheumatoid arthritis: results from the CLEAR registry. Arth. Rheum. 154:3057-3059.

Banda, N.K., Thurman, J.M., Kraus, D.M., Wood, A., Carroll, M.C., Arend, W.P., and Holers, V.M. 2006. Alternative complement pathway activation is essential for inflammation and joint destruction in the passive transfer model of collagen-induced arthritis. J. Immunol. 177:1904-1912.

Asokan, R., Hua, J., Young, K.A., Gould, H.J., Hannan, J.P., Kraus, D.M., Szakonyi, G., Grundy, G.J., Chen, X.S., Crow, M.K., and Holers, V.M. 2006. Characterization of human complement receptor type 2 (CR2/CD21) as a receptor for interferon-alpha: a potential role in systemic lupus erythematosus. J. Immunol. 177:383-394.

Gilbert, H.E., Asokan, R., Holers, V.M., and Perkins, S.J. 2006. The 15 SCR flexible extracellular domains of human complement receptor type 2 can mediate multiple ligand and antigen interactions. J. Mol. Biol. 362:1132-1147.

Szakonyi, G., Klein, M., Hannan, J.P., Young, K.A., Ma, R., Holers, V.M., and Chen, X. 2006. Structure of the major envelope glycoprotein gp350 of Epstein-Barr virus. Nature Struc. and Molec. Biol. 13:996-1001.

Bhatia, S.S., Majka, D.S., Kittelson, J.M., Parrish, L.A., Ferucci, E.D., Deane, K.D., Arend, W.P., Rewers, M., Holers, V.M., and Norris, J.M. 2006. Rheumatoid factor seropositivity is inversely associated with oral contraceptive use in women without rheumatoid arthritis. Ann. Rheum. Dis. 66:267-269.

Girardi, G., Yarilin, D., Thurman, J.M., Holers, V.M., and Salmon, J.E. 2006. Complement activation induces dysregulation of angiogenic factors and causes fetal rejection and growth restriction. J. Exp. Med. 203:2165-2175.

Young, K.A., Parrish, L., Zerbe, G. Rewers, M., Deane, K.D., Holers, V.M., and Norris, J.M. 2007. Perinatal and early childhood risk factors associated with rheumatoid factor positivity in a healthy pediatric population. Ann. Rheum. Dis. 66:179-183.

Banda, N.K., Takahashi, K. Wood, A.K., Holers, V.M., and Arend, W.P. 2007. Initiation and amplification of complement by the alternative pathway in immune complex-induced arthritis in mice. J. Immun. (in press).