John P. Atkinson, MD
Difficult to diagnosis and/or manage inflammatory disorders, including autoimmune conditions like SLE.
Over the past decade, my laboratory focuses on the identification and characterization of membrane glycoproteins that regulate complement activation and process immune complexes; recently, mutations in these proteins have been identified in several rare as well as common human diseases.
The primary purpose of the complement system is to defend the host against microbes. It is especially designed to prevent successful bloodstream invasion by bacteria (“the guardian of the intravascular space”). The ancient alternative pathway is also a key player in processing injured and degenerated cells and tissues as well as extracellular debris. A unique feature of this immune system is that it works in seconds. It is a major player in innate immunity as well as a potent effector arm of humoral immunity. Complement system facilitates the host response to infection via the production of small peptides (anaphylatoxins) that are proinflammatory and cell activating and larger fragments (opsonins) that become covalently attached to a target to promote phagocytosis and antigen presentation. The terminal components cause membrane perturbation including lysis of targets. Deficiency of complement components leads to infections (predominantly bacterial) and autoimmunity (commonly SLE). On the other hand, an inadequately regulated complement system leads to undesirable tissue injury secondary to excessive activation at a site of injury. Atypical hemolytic uremic syndrome and age-related macular degeneration are representative examples of a rare and a common disease, respectively, in which predisposing genetic variants have been identified in complement inhibitors leading to an undesirable degree of activation of the alternate pathway.
A wide variety of human diseases, such as many forms of arthritis and glomerulonephritis, are mediated by autoantibodies. Most immune complexes consist of antigen, antibody and complement activation fragments. Complement system 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 autoimmunity.
The laboratory has contributed to 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 a target), 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, especially relative to its interaction with microorganisms. These membrane complement receptors and regulatory proteins have been co-opted to be “receptors” for viruses and bacteria. Also, many pathogens abuse the complement system by synthesizing complement inhibitors or by hijacking the host’s regulators to protect themselves.
Manipulation of the complement system has important therapeutic implications for acute and chronic inflammatory conditions, autoimmunity, tumor cell destruction, xenotransplantation, reproductive immunology and host-parasite interactions. Derivatives of the regulatory proteins are now in clinical trials as inhibitors of complement activation. A monoclonal Ab to C5 is in the marketplace, being FDA approved to treat paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. Additional inhibitors of the alternative pathway are in clinical trials to treat autoimmune disease and acute and chronic inflammatory syndromes.
- Kemper C, Chan AC, Green JM, Brett KA, Murphy KM, Atkinson JP. Activation of human CD4+ cells with CD3 and CD46 induces a T-regulatory cell 1 phenotype. Nature 2003;421:388-92.
- Riley-Vargas RC, Lanzendorf S, Atkinson JP. Targeted and restricted complement activation on acrosome-reacted spermatozoa. J Clin Invest 2005;115:1241-9.
- Gill DB, Spitzer D, Koomey M, Heuser JE, Atkinson JP. Release of host-derived membrane vesicles following pilus-mediated adhesion of Neisseria gonorrhoeae. Cell Microbiol 2005;7:1672-83.
- Spitzer D, Wu X, Ma X, Xu L, Ponder KP, Atkinson JP. Cutting edge: Treatment of complement regulatory protein deficiency by retroviral in vivo gene therapy. J Immunol 2006;177:4953-6.
- Chung KM, Liszewski MK, Nybakken G, et al. West Nile virus nonstructural protein NS1 inhibits complement activation by binding the regulatory protein factor H. Proc Natl Acad Sci USA 2006;103:19111-6.
- Fang CJ, Fremeaux-Bacchi V, Liszewski MK, et al. Membrane cofactor protein mutations in atypical hemolytic uremic syndrome (aHUS), fatal Stx-HUS, C3 glomerulonephritis, and the HELLP syndrome. Blood 2008;111:624-32.
- Liszewski MK, Leung MK, Hauhart R, Fang CJ, Bertram P, Atkinson JP. Smallpox inhibitor of complement enzymes (SPICE): Dissecting functional sites and abrogating activity. J Immunol 2009;183:3150-9.
- Wu X, Spitzer D, Mao D, Peng SL, Molina H, Atkinson JP. Membrane protein Crry maintains homeostasis of the complement system. J Immunol 2008;181:2732-40.
- Avirutnan P, Fuchs A, Hauhart RE, et al. Antagonism of the complement component C4 by flavivirus nonstructural protein NS1. J Exp Med 2010;207:793-806.
- Cardone J, LeFriec G, Vantourout P, et al. Complement regulator CD46 promotes immunoregulation by distinct effects on conventional and unconventional human T cells. Nat Immunol 2010;11:862-71.
- Namjou B, Kothari PH, Kelly JA, et al. Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort. Genes Immun 2011;12:270-9.
- Salmon JE, Heuser C, Triebwasser M, et al. Mutations in complement regulatory proteins predispose to preeclampsia: a genetic analysis of the PROMISSE cohort. PLoS Med 2011;8:e1001013.
- Liszewski MK, Kolev M, Le Friec G, et al. Intracellular complement activation sustains T cell homeostasis and mediates effector differentiation. Immunity 2013;39:1143-57.
- Seddon JM, Yu Y, Miller EC, et al. Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration. Nat Genet 2013;45:1366-70.
- Park HJ, Guariento M, Maciejewski M, et al. Using mutagenesis and structural biology to map the binding site for the Plasmodium falciparum merozoite protein PfRh4 on the human immune adherence receptor. J Biol Chem 2014;289:450-63.
Selected review articles
- Liszewski MK, Kemper C, Price JD, Atkinson JP. Emerging roles and new functions of CD46. Springer Semin Immunopathol 2005;27:345-58.
- Kemper C, Atkinson JP. T-cell regulation: with complements from innate immunity. Nat Rev Immunol 2007;7:9-18.
- Atkinson JP, Goodship TH. Complement factor H and the hemolytic uremic syndrome. J Exp Med 2007;204:1245-8.
- Richards A, Kavanagh D, Atkinson JP. Inherited complement regulatory protein deficiency predisposes to human disease in acute injury and chronic inflammatory states: the examples of vascular damage in atypical hemolytic uremic syndrome and debris accumulation in age-related macular degeneration. Adv Immunol 2007;96:141-77.
- Kavanagh D, Richards A, Atkinson JP. Complement regulatory genes and hemolytic uremic syndromes. Annu Rev Med 2008;59:293-309.
- Fang C, Richards A, Liszewski MK, Kavanagh D, Atkinson JP. Advances in understanding of pathogenesis of aHUS and HELLP. Br J Haematol 2008;143:336-48.
- Kemper C, Atkinson JP, Hourcade DE. Properdin: emerging roles of a pattern-recognition molecule. Annu Rev Immunol 2010;28:131-55.
- Atkinson JP, Yu CY. Genetic susceptibility and class III complement genes. In: Lahita RG, Tsokos GC, Buyon J, Koike T, eds. Systemic Lupus Erythematosus. Fifth ed. London: Elsevier; 2010:21-45.
- Liszewski MK, Atkinson JP. Too much of a good thing at the site of tissue injury: the instructive example of the complement system predisposing to thrombotic microangiopathy. Hematology Am Soc Hematol Educ Program 2011;2011:9-14.
- Ambati J, Atkinson JP, Gelfand BD. Immunology of age-related macular degeneration. Nat Rev Immunol 2013;13:438-51.