V. Michael Holers
MD
Head, Division of Rheumatology
University of Colorado Health Sciences Center

Medical School:  Washington University Medical School, St. Louis, Missouri

Postgraduate training:

1978-1979

Internship - Internal Medicine Barnes Hospital, St. Louis MO

1979-1981

Residency - Internal Medicine Barnes Hospital, St. Louis MO

1981-1983

Clinical Fellowship in Rheumatology - University of Colorado School of Medicine, Denver, CO

1983-1985

Research Associate - Howard Hughes Medical Institute, St. Louis, MO

1983-1985

Research Fellowship in Rheumatology - Washington University School of Medicine

 

When arrived at UCHSC: 1993

Past and current professional positions:

2000-Present Head, Division of Rheumatology - University of Colorado Health Sciences Center
1998-Present Professor of Immunology - University of Colorado Health Sciences Center
1997-Present Professor of Medicine - University of Colorado Health Sciences Center
1993-Present Smyth Professor of Rheumatology - University of Colorado Health Sciences Center
1994-1998  Professor of Immunology - University of Colorado Health Sciences Center
1993-1997  Associate Professor of Medicine (with tenure) - University of Colorado Health Sciences Center
1992-1993  Associate Professor of Medicine (with tenure) - Washington University School of Medicine
1987-1993 Member - Division of Biology and Biomedical Sciences, Washington University School of Medicine
1987-1993 Assistant Professor of Pathology - Washington University School of Medicine
1986-1993  Assistant Investigator - Howard Hughes Medical Institute
1986-1992 Assistant Professor of Medicine - Washington University School of Medicine
1985-1986 Instructor in Medicine - Washington University School of Medicine

 

National commitments, positions:

1992- Present American College of Rheumatology Abstract Selection Subcommittees
1997  Subcommittee Chairman, American College of Rheumatology National Meeting Abstract Selection Committee
1995-1998 Member, Committee on Research, American College of Rheumatology
1997-1998  ACR National Research Conference Planning Committee, American College of Rheumatology
1998  ACR Basic Research Conference Co-Organizer
1995, 1998  Co-Chair, Complement Symposium, AAI Meeting
1998-2000 National Arthritis Foundation Publications Committee
1998-2000  International Complement Workshop Organizing Committee
1999 Co-Chair, ACR Basic Research Conference
1999-2002 Chair, Committee on Research, American College of  Rheumatology
1999-2002 Member, Board of Directors, American College of  Rheumatology Research and Education Foundation
2000-2002 Arthritis Foundation Fellows Research Conference Planning Committee
2000-2001 Blue Ribbon Panel on Research, National Arthritis Foundation
2000  Founding Member and Secretary, International Complement Society
1996-2000 Member, Allergy and Immunology (ALY) Study Section, Center for Scientific Review, NIH
2000 

Pfizer Postdoctoral Fellowship Academic Advisory Board
2002-2004 Member, Board of Directors, American College of Rheumatology
2003-2006 Program Committee Block Chair, American Immunologists
2003-2004 Chair, Task Force on Research Funding, American College of Rheumatology
2003-Present Steering Committee, NIH/NIAMS SLE Biomarkers Consortium
2004-Present Member, Board of Directors American College of Rheumatology Research and Education Foundation
2004-Present Chair, Scientific Advisory Council, American Rheumatology Research and Education Foundation
2005-2006 Chair, Rheumatoid Arthritis Initiative Taks Force, American College of Rheumatology Research and Education Foundation

Awards and Honors received:

1974 Phi Beta Kappa
1985 American Rheumatism Association Senior Fellowship Award
1988-1991 Hulda Irene Duggan Investigator, Arthritis Foundation
1993  Member, American Society for Clinical Investigation
1997 Robert Wood Johnson Award, Arthritis Foundation
1997 Schwartz-Weinstein Research Award, Arthritis Foundation Rocky Mountain Chapter
1998 Harmon Foundation Research Award, Arthritis Foundation Rocky Mountain Chapter
1999 Volunteer Leadership Award, National Arthritis Foundation
2000 Member, American Association of Physicians
2002 Member, Henry Kunkel Society
2003 Pfizer Visiting Professor, Medical University of South Carolina
2004 Inventro of the Year, University of Colorado Health Sciences Center

 

Description about research interests and/or clinical trial interests:

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:

  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.
  2. 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.
  3. 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.

Representative Publications:

  1. Xu, C., Mao, D., Holers, V. M., Palanca, B., Cheng, A., and Molina, H. 2000. A critical role for the murine complement regulator Crry in fetomaternal tolerance. Science 287:498-501.
  2. Marchbank, K. J., Watson, C. C., Ritsema, D. F., and Holers, V. M. 2000. Expression of complement receptor 2 (CR2/CD21) in Cr2-/- mice restores humoral immune function.    J. Immunol. 165:2354-2361.
  3. Kaya, Z, Afanasyeva, M., Wang, Y., Dohman, K. M., Schlichting, J., Tretter,  T., Fairweather, D., Holers, V. M., and Rose, N. R. 2001. Contribution of the innate immune system to autoimmune myocarditis: a role for complement.  Nature Immunol. 2:739-745.
  4. Szakonyi, G., Guthridge, J. M., Li, D., Young, K., Holers, V. M., and Chen, X. S. 2001. Structure of complement receptor 2 in complex with its C3d ligand.  Science 292:1725-1728.
  5. Guthridge, J. M., Young, K., Gipson, M. G., Sarrias, M.-R., Szakonyi, G., Chen, X. S., Malaspina, A., Donoghue, E., James, J. A., Lambris, J. D., Moir, S. A., Perkins, S. J., and Holers, V. M. 2001. Epitope mapping using the x-ray crystallographic structure of complement receptor type 2 (CR2/CD21): Identification of a highly inhibitory monoclonal antibody that directly recognizes the CR2-C3d interface.  J. Immunol. 167:5758-5766.
  6. Boackle, S. A., Holers, V. M., Chen, X., Szakonyi, G., Karp, D. R., Wakeland, E. K., and Morel, L. 2001. Cr2, a candidate gene in the murine Sle1c lupus susceptibility locus, encodes a dysfunctional protein. Immunity 15:775-785.
  7. 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.
  8. Girardi, G., Berman, J., Redecha, P., Spruce, L., Kraus, D., Hollmann, T., Casali, P., Wetsel, R. A., Lambris, J. D., Holers, V. M., and Salmon, J. E. 2003. Complement C5a receptors and neutrophils, but not activating Fc g receptors, are critical mediators of anti-phospholipid antibody-induced fetal loss. J. Clin. Invest. 112:1644-1654.
  9. 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.
  10. 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.
  11. 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.
  12. Lyubchenko, T., dal Porto, J., Cambier, J.C., and Holers, V.M.  2005.  Co-ligation of the B cell receptor with complement receptor type 2 (CR2/CD21) using its natural ligand C3dg: activation without engagement of an inhibitory signaling pathway.  J. Immunol.  174:3264-3272.
  13. Gilbert, H.E., Eaton, J.T., Hannan, J.P., Holers, V.M., and Perkins, S.J. 2005. Solution structure of the complex between CR2 SCR 1-2 and C3d of human complement: an X-ray scattering and sedimentation modelling study.  J. Mol. Biol. 346:859-873.
  14. 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.
  15. Thurman, J.M., Lucia, M.S., Ljubanovic, D., and Holers, V.M.  2005.  Acute tubular necrosis is characterized by activation of the alternative pathway of complement.  Kidney. Intl.  67:524-530.
  16. Hibbert, R.G., Teriete, P., Grundy, G.J., Holers, V.M., Hannan, J.P., Sutton, B.J., Gould, H.J. and McDonnell, J.M. 2005. The structure of soluble CD23 and its interactions with IgE and CD21. J. Exp. Med 202:751-760.
  17. Birrell, L., Kulik, L., Morgan, B.P., Holers, V.M., and Marchbank, K.J., 2005. B cells from mice prematurely expressing human CR2/CD21 are unresponsive to T-dependent antigens. J. Immunol. 174:6974-6982.
  18. Atkinson, C., Song, H., Lu, B., Qiao, F., Burns, T.A., Holers, V.M., Tsokos, G.C., and Tomlinson, S.  2005. Targeted complement inhibition by C3d recognition ameliorates tissue injury without apparent increase in susceptibility to infection.  J. Clin. Invest. 115:2444-2453.
  19. Kuhn, K.A., Kulik, L., Tomooka, B., Braschler, K.J., Arend, W.P., Robinson, W.H., and Holers, V.M.  2006.  Antibodies to citrulline-modified proteins enhance tissue injury in inflammatory arthritis. J. Clin. Invest. 116:961-973.
  20. Taube, C., Thurman, J.M., Joetham, A., Takeda, K., Miyahara, N., Dakhama, A., Carroll, M.C., Giclas, P.C., Holers, V.M., and Gelfand, E.W. 2006. Factor B of the alternative pathway is critical to development of airway hyperresponsiveness. Proc. Natl. Acad. Sci. 103:8084-8089.
  21. Gilbert, H.E., Aslam, M., Guthridge, J.M., Holers, V.M., and Perkins, S.J.  2006.  Extended flexible linker structures in the complement chimaeric conjugate CR2-Ig by scattering, analytical ultracentrifugation and constrained modelling: Implications for function and therapy.  J.  Mol. Biol. 356:397-412.
  22. Thurman, J.M., Royer, P.A., Ljubanovic, D., Dursun, B., Lenderink, A.M., Edelstein, C.L., and Holers, V.M.  2006.  Treatment with an inhibitory monoclonal antibody to mouse factor B protects mice from induction of apoptosis and renal ischemia/reperfusion injury.  J. Am. Soc. Nephrol. 17:707-715.
  23. Thurman, J.M., Ljubanovic, D., Royer, P.A., Kraus, D.M., Molina, H., Barry, N.P., Proctor, G., Levi, M., and Holers, V.M.  2006.  Altered renal tubular expression of the complement inhibitor Crry permits complement activation after ischemia/reperfusion.  J. Clin. Invest. 116:357-368.
  24. Leinhase, I., Schmidt, O.I., Thurman, J.M., Rozanski, M., Scheffler, A., John, T., Smith, W.R., Holers, V.M., and Stahel, P.F.  2006.  Pharmacological complement inhibition at the C3 convertase level induces neuroprotective intracerebral gene expression and decreases neurological impairment after traumatic brain injury.  Exp. Neurol. 199:454-463.
  25. Leinhase, I., Holers, V.M., Thurman, J.M., Harhausen, D., Schmidt, O.I., Pietzcker, M., Taha, M.E., Rittirsch, D., Huber-Lang, M., Smith, W.R., Ward, P.A., and Stahel, P.F.  2006.  Reduced neuronal cell death after experimental brain injury in mice lacking a functional alternative pathway of complement activation.  BMC Neurosci. 7:55.
  26. 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.
  27. 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.
  28. 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.
  29. 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.
  30. 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.
  31. 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.
  32. 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.
  33. 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.
  34. Majka, D.S., Deane, K.D., Parrish, L.A., Baron, A.E., Walker, C.W., Rubertone, M.V., Gilliland, W.R., Norris, J.M., and Holers, V.M.  2007.  The duration of pre-clinical rheumatoid arthritis-related autoantibody positivity increases in subjects with older age at time of disease diagnosis. (submitted).
  35. Moir, S., Kulik, L., Ho, J., Malaspina, A., Donoghue, E.T., Miller, N.J., Chun, T.-W., Fauci, A.S., and Holers, V.M.  2007.  Essential role for CD21 in the establishment of an extracellular HIV reservoir in lymphoid tissues. J. Immunol. (in press).
  36. Thurman, J.M., Lenderink, A.M., Royer, P.A., Coleman, K.E., Zhou, J., Lambris, J.D., Nemenoff, R.A., Quigg, R.J., and Holers, V.M.  2007.  C3a is required for the production of CXC chemokines by tubular epithelial cells after renal ischemia/reperfusion.  J. Immunol. 178:1819-1828.
  37. Lyubchenko, T., Dal Porto, J., Holers, V.M., and Cambier, J.C.  2007. C3d-linked antigens break B cell anergy. J. Immunol. (in press).
  38. Young, K.A., Chen, X.S., Holers, V.M., and Hannan, J.P.  2007.  Isolating the Epstein-Barr virus (EBV) gp350/220 binding site on complement receptor type 2 (CR2/CD21). (submitted).
  39. Song, H., Qiao, F., Atkinson, C., Holers, V.M., and Tomlinson, S.  2007.  A complement C3 inhibitor specifically targeted to sites of complement activation effectively ameliorates collagen-induced arthritis. (submitted).
  40. 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).