John P. Atkinson, M.D.

Acting Chief, Division of Rheumatology
Samuel B. Grant Professor of Clinical Medicine
Department of Medicine
Department of Molecular MicrobiologyLaboratory: 10022 and 10024 Clinical Sciences Research Building
Office: 10025 Clinical Sciences Research Building

Office Phone: 314-362-8391
Fax: 314-362-1366
Lab Phone: 314-362-8392
e-mail: jatkinso@im.wustl.edu

Research

The purpose of the complement system is to defend the host against microbes. It is part of the immune system with a capacity to recognize foreignness (alternative pathway) as well as a very potent effector arm for antibody (classical pathway). Complement facilitates the inflammatory response via the production of small peptides that are proinflammatory and larger fragments that become firmly attached to a target and promote phagocytosis and lysis. Deficiency of complement components leads to infections and autoimmunity.

A wide variety of human diseases, such as many forms of arthritis and glomerulonephritis, are mediated by autoantibodies and immune complexes. Most immune complexes consist of antigen (foreign or auto), antibody and complement components. Complement is a critical factor in the formation, processing, transportation, and tissue localization of these complexes. A long-term goal of this laboratory is to understand how immune complexes are handled by the complement system, especially as it relates to autoimmune syndromes like systemic lupus erythematosus.

Over the past decade, the laboratory has focused on the identification and characterization of membrane glycoproteins that regulate complement activation and process immune complexes. A multigene family of receptor and regulatory proteins was discovered which are related functionally (ligands are complement components attached to targets), genetically (structural genes are located in a tight cluster on the long arm of chromosome one), and structurally (largely composed of a tandem array of cysteine-rich repeating protein modules). These studies have provided insights into the evolution of the complement system and especially its interaction with microorganisms. Recently, these same complement regulatory proteins have been shown to be "receptors" for viruses (EB, measles) and bacteria (streptococci, neisseria, coliforms). Manipulation of the complement regulatory and receptor proteins has important implications for tumor cell destruction, xenotransplantation, reproductive immunology, and host-parasite interactions. Derivatives of these regulatory proteins are now in clinical trials as inhibitors of complement activation in autoimmune diseases and ischemia-reperfusion injury.

Selected References

  1. Kemper, C., Chan, A.C., Green, J.M., Brett, K.A., Murphy, K.M., and Atkinson, J.P.:  Activation of human CD4+ cells with CD3 and CD46 induces a T-regulatory cell 1 phenotype.  Nature 421:388-392, 2003.
  2. Riley-Vargus, R.C., Lanzendorf, S., and Atkinson, J.P.: Targeted and restricted complement activation on acrosome-reacted spermatozoa. J. Clin. Invest. 115:1241-1249, 2005 (cover).
  3. Gill, D.B., Spitzer, D., Koomey, M., Heuser, J.E., and Atkinson, J.P.:  Release of host-derived membrane vesicles following pilus-mediated adhesion of Neisseria gonorrhoeae. Cellular Microbiology  7:1672-1683, 2005 (cover).
  4.  Spitzer, D., Wu, X., Ma, X., Xu, L., Ponder, P., and Atkinson, J.P.: Cutting Edge. Treatment of complement regulatory protein deficiency by retroviral in vivo gene therapy. J. Immunol. 177:4953-4956, 2006.
  5. Chung, K.M., Liszewski, M.K., Nybakken, G., Davis, A.E., Townsend, R.R., Fremont, D.H., Atkinson, J.P., and Diamond, M.S.: West Nile virus non-structural protein NS1 inhibits complement activation by binding the regulatory protein factor H. Proc. Natl. Acad. Sci. 103:19111-19116, 2006.
  6. Richards, A., van den Maagdenberg, A., Jen, J,C., Kavanagh, D., Bertram, P., Spitzer, D., Liszewski, M.K., Barilla-LaBarca, M-L., Terwindt, G.M., Kasai, Y., McLellan, M., Grand, M.G., Vanmolkot, K.R.J., de Vries, B., Wan, J., Kane, M.J., Mamsa, H., Schafer, R., Stam, A.H., Haan, J., de Jong, P.T.V.M., Stroimans, C.W., van Schooneveld, M.J., Oosterhuis, J.A., Gschwendter, A., Dichgans, M., Kotschet, K.E., Hodgkinson, S., Hardy, T.A., Delatycki, M.B., Hajj-Ali, R.A., Kothari, P.H., Nelson, S.F., Frants, R.R., Baloh, R.W., Ferrari, M.D., Atkinson, J.P.:  C-terminal truncations in human 3’-5’ DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy. Nature Genetics. 39:1068-1070, 2007.
  7. Fang, C.J., Fremeaux-Bacchi, V., Liszewski, M.K., Pianetti, G., Noris, M., Goodship, T.H.J., and Atkinson, J.P.:  Membrane cofactor protein mutations in atypical hemolytic uremic syndrome (aHUS), fatal Stx-HUS, C3 glomerulonephritis and the HELLP syndrome. Blood. 111:624-632. 2007.
  8. Liszewski, M.K., Bertram, P., Leung, M., Hauhart, R., Zhang, L., and Atkinson, J.P.: Smallpox inhibitor of complement enzymes (SPICE): Regulation of complement activation on cells and mechanism of its cellular attachment. J. Immunol. In press. 2008.
  9. Wu, X., Spitzer, D., Mao, D., Peng, S.L., Molina, H., and Atkinson, J.P.: Membrane protein Crry maintains homeostasis of the complement system. J. Immunol. In press. 2008.
  10. Snow, M., Chen, M., Guo, J., Atkinson, J., and Stanley, S.L.: Short report: Differences in complement-mediated killing of Entamoeba histolytica between men and women – an explanation for the increased susceptibility of men to invasive amebiasis? Am. J. Trop. Med. Hyg. 78:922-923, 2008.

Selected Review Articles

  1. Liszewski, M.K., Kemper, C., Price, J., and Atkinson, J.P.:  Emerging roles and new functions of CD46.  Springer Seminars in Immunopathology. 27:345-358, 2005.
  2. Kemper, C., and Atkinson, J.P.: T-cell regulation: with complements from innate immunity. Nature Reviews Immunology 7:9-18, 2007.
  3. Atkinson, J.P., and Goodship, T.H.J.: Complement factor H and the hemolytic uremic syndrome. J. Exp. Med. 204:1245-1248, 2007.
  4. Kavanagh, D., Richards, A., and Atkinson, J.P.:  Complement regulatory genes and hemolytic uremic syndrome. Ann. Rev. Med. 59:293-309, 2008.
  5. Richards, A., Kavanagh, D., and Atkinson, J.P.: Inherited complement regulatory protein deficiency predisposes to human disease in acute injury and chronic inflammatory states. Adv. Immunol. 96:141-177, 2007.
  6. Kavanagh, D., Spitzer, D., Kothari, P.H., Shaikh, A., Liszewski, M.K., Richards, A., and Atkinson, J.P.: New roles for the major 3¢-5¢exonuclease TREX1 in human disease. Cell Cycle In press. 2008.
Department of Pathology and Immunology
Campus Box 8118
660 South Euclid Ave.
St. Louis, MO 63110
 
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