John P. Atkinson, MD

Internal Medicine
Molecular Microbiology

Immunology Program
Molecular Microbiology and Microbial Pathogenesis Program
Human and Statistical Genetics Program

  • 314-362-8391

  • 314-362-8392

  • 314-362-1366

  • 10025 Clinical Sciences Research Building


  • immunology, inflammation, autoimmunity, complement system, innate immunity

  • Complement activation and regulation in innate and adaptive immunity

Research Abstract:

Complement is an ancient host defense system. It that also is an integral player in both innate and adaptive immunity. The complement system guards the intravascular space from bacterial and viral infections. Most striking is that it works in seconds, being particularly noted for serving as a first responder to an invasion of the circulation. By releasing small peptides to activate local proinflammatory cell responses and by attaching large opsonic fragments to a target, complement provides protection against pathogens and instructs (nature’s adjuvant) the adaptive immune response. The cell-bound activation fragments promote immune adherence, phagocytosis and cell lysis. It facilitates antigen processing and presentation and lymphocyte responsiveness.

Several decades ago this laboratory identified a multigene family of receptor and regulatory proteins that inhibit complement activation and serve as receptors for complement-opsonized antigens. Structure-function relationships, cell signaling, microbial interactions and disease associations of these complement inhibitors and receptors continue to be a primary focus of the laboratory’s efforts. Many pathogens, including multiple viruses (measles, pox, adeno and flavi), bacteria (neisseria, streptococci, coliforms) and parasites (malaria), abuse the complement system by 1) employing as a receptor for cellular attachment, 2) hijacking a host regulator to protect against complement attack or 3) synthesizing a homologous inhibitory replicate. A focus of the laboratory had been to characterize the poxviral mimics of complement regulators and to define interactions with flaviviruses (dengue and West Nile).

Many human diseases feature autoantibodies that form complement-fixing immune complexes such as in systemic lupus erythematosus. Since the Complement system is activated by the autoantibody to a host antigen, it commonly is responsible for much of the ensuing cell/tissue damage. A related, more recently recognized function of the complement system is the safe clearance of “altered self” including host antigens in extracellular debris such as produced by apoptotic and necrotic cells. During the aging process, oxidized lipids (atherosclerosis), amyloid proteins (Alzheimer’s Disease), lipofuscin pigments (age-related macular degeneration - AMD) and urate crystals (gout) accumulate and cause substantial morbidity and mortality. The complement system facilitates the handling of this so-called cellular “garbage”. As an example of this and an exciting and emerging paradigmarea of complement research is represented by common and rare variants in the complement inhibitors factor H and factor I. These account for approximately 50% of the genetic risk of AMD, the most common cause of blindness in the developed world.

A second genetic highlight the past decade has been the identification of heterozygous mutations in complement inhibitors that predispose to human diseases in which thrombi develop in the microvasculature (for example, atypical hemolytic uremic syndrome). Along this line, we are employing next- generation targeted gene sequencing technology to identify disease-causing mutations associated with the complement system in thrombomicroangiopathies, C3 glomerulopathies, and the pregnancy-related disorder, preeclampsia. Although a therapeutic agent that blocks C5 is now FDA approved to treat several diseases featuring excessive complement activation, it is also the costliest drug in the world (~ $600,000/year). Additional agents are under study and will soon be entering the market place.

Lastly, work over the past five years driven by our laboratory has led to the discovery of an intracellular complement system to autoactivate cells and to influence metabolic pathways. . Much of the initial was carried out in human peripheral blood CD4+ T cells but multiple cell types can synthesize complement components and, remarkably, or take up and process blood C3. These emerging areas may ultimately lead to the development of new complement-based therapeutic targets.

Selected Publications:

1. Liszewski, M.K., Java, A., Schramm, E.C., and Atkinson, J.P. (2017) Complement dysregulation and disease: Insights from contemporary genetics. Annual Rev. Pathol. 12:25-52.
2. Lyzogubov, V.V., Bora, P.S., Wu, X., Horn, L.E., de Roque, R., Rudolf, X.V., Atkinson, J.P., and Bora, N.S. (2016) The complement regulatory protein CD46 deficient mouse spontaneously develops dry-type age-related macular degeneration-like phenotype. Am. J. Path. 186(8):2088-2103.
3. Kavanagh, D., Yu, Y. Schramm, E.C., Triebwasser, M., Raychaudhuri, S., Daly, M.J., Atkinson, J.P., and Seddon, J.M. (2015) Rare genetic variants in the CFI gene are associated with advanced age-related macular degeneration and commonly result in reduced serum factor I levels. Human Molecular Genetics 24(13):3861-70. PMCID: PMC4459386.
4. Schramm, E., Roumenina, L.T., Rybkine, T., Chauvet, S., Vierira-Martins, P., Hue, C., Maga, T., Valoti, E., Wilson, V., Jokiranta, S., Smith, R.J.H., Noris, M., Goodship, T., Atkinson J.P., and Fremeaux-Bacchi, V. (2015) Mapping interactions between complement C3 and regulators using mutations in atypical hemolytic uremic syndrome. Blood. 125:2359-2369, PMCID: PMC4392009.
5. Schramm, E.C., Clark, S.J., Triebwasser, M.P., Raychaudhuri, S., Seddon, J.M., Atkinson, J.P.: Genetic variants in the complement system predisposing to age-related macular degeneration: A review. (2014) Mol. Immunol. Oct; 61(2): 118-125.
6. Park, H.J., Guariento, M., Maciejewski, M., Hauhart, R., Tham, W.-H., Cowman, A.F., Schmidt, C.Q., Mertens, H.D.T., Liszewski, M.K., Hourcade, D.E., Barlow, P.N., and Atkinson, J.P. (2014) 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. 289:450-463. PMCID: PMC3879568
7. Liszewski, M.K., Kolev, M., LeFriec, G., Leung, M., Bertram, P.G., Fara, A., Subias, M., Pickering, M.C., Drouet, C., Meri, S., Arstila, T.P., Pekkerinen, P.T., Ma, M., Cope, A., Reinheckel, T., Rodriguez de Cordoba, S., Afzali, B., Atkinson, J.P., and Kemper, C.K. (2013) Intracellular complement activation sustains T cell homeostasis and mediates effector differentiation. Immunity 39:1143-1157. PMCID: PMC3865363.
8. Seddon, J.M., Yu, Y., Miller, E.C., Reynolds, R., Tan, P.L., Gowrisankar, S., Goldstein, J.I., Triebwasser, M., Anderson, H.E., Zerbib, J., Kavanagh, D., Souied, E., Katsanis, N., Daly M.J., Atkinson, J., and Raychaudhuri, S. (2013) Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration. Nat. Genet. 45(11): 1366-70. PMCID: PMC3902040.
9. Avirutnan, P., Fuchs, A., Hauhart, R.E., Somnuke, P., Youn, S., Diamond, M.S., and Atkinson, J.P. (2010) Antagonism of the complement component C4 by flavivirus non-structural protein NS1. J. Exp. Med. 207:793-806.
10. Moulton, E.A., Atkinson, J.P., and Buller, R.M.L. (2008) Surviving mousepox infection requires the complement system. PLoS Pathogens 4:1-14.
11. Fremeaux-Bacchi, V., Miller, E., Liszewski, M.K., Strain, L., Blouin, J., Brown, A.L., Moghal, N., Kaplan, B.S., Weiss, R.A., Lhotta, K., Kapur, G., Mattoo, T., Nivet, H., Wong, W., Gie, S., de Ligny, B.H., Fischbach, M., Gupta, R., Hauhart, R., Meunier, V., Loirat, C., Dragon-Durey, M.-A., Fridman, W.H., Janssen, B.J.C., Goodship, T.H.J., and Atkinson, J.P. (2008) Mutations in complement C3 predispose to development of atypical hemolytic uremic syndrome. Blood. 112:4948-4952. PMCID: PMC2597601.
12. Kemper, C., and Atkinson, J.P. (2007) T-cell regulation: with complements from innate immunity. Nat. Rev. Immunol. 7:9-18.

Last Updated: 8/10/2018 8:13:19 AM

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