Research Abstract:
The complement system defends the host against microbes, being an integral part of the innate and adaptive immune responses. It serves as recognizing and coating pathogens and mediating the acute inflammatory reaction. In this process, the complement system instructs the adaptive immune system by releasing small peptides that activate cells and by attaching large fragments to a target. The latter serve as opsonins to promote immune adherence and phagocytosis and antigen processing.
Many human diseases are mediated by autoantibodies that form complement activating immune complexes which damage cells and tissues if not properly regulated and disposed of. A more recently recognized function of the complement system is its interaction with altered self such as apoptotic and necrotic cells. Further, debris such as oxidized lipids (atherosclerosis), amyloid proteins (Alzheimer’s), lipofuscin pigments (age-related macular degeneration) and urate crystals (gout) accumulate in man to cause much morbidity and mortality. For example, a polymorphism in the complement inhibitor factor H predispose to age-related macular-degeneration.
To facilitate clinical-pathologic correlations, this laboratory has focused on characterizing a multigene family of receptor and regulatory proteins that inhibit complement activation and serve as receptors for complement-coated antigens. Structure-function relationships, cell signaling, disease associations and microbial interactions are under investigation. Multiple pathogens, including viruses (measles, pox, adeno and flavi), bacteria (Neisseria, Streptococcus, E. coli) and parasites (malaria), abuse these proteins by employing them as a receptor for cellular attachment or as a regulator to protect themselves against complement attack. Complement regulatory proteins are also in clinical trials as therapeutic agents to thwart undesirable complement activation. A recent highlight has been the identification of heterozygous mutations in complement inhibitors that prednisone to several human diseases featuring thrombi in the microvasculature including hemolytic uremic syndrome and preeclampsia.
Selected Publications:
Spitzer D, Wu X, Ma X, Xu L, Ponder P and Atkinson JP. Cutting Edge. Treatment of complement regulatory protein deficiency by retroviral in vivo gene therapy. J. Immunol. 2006 177: 4953-4956.
Richards A, Kavanagh D and Atkinson JP. Inherited complement regulatory protein deficiency predisposes to human disease in acute injury and chronic inflammatory states. Adv. Immunol. 2007 96: 141-177.
Kemper C and Atkinson JP. T-cell regulation: with complements from innate immunity. Nature Reviews Immunology 2007 7: 9-18.
Kavanagh D, Richards A and Atkinson JP. Complement regulatory genes and hemolytic uremic syndrome. Ann. Rev. Med. 2008 59: 293-309.
Moulton EA, Atkinson JP and Buller RML. Surviving mousepox infection requires the complement system. Plos Pathogens 2008 4:1-14.
Last Updated: 08/17/2009 |