John P. Atkinson, M.D.

RESEARCH INTEREST

The complement system defends the host against microbes. It is an integral part of innate and adaptive immunity and a particularly potent effector arm of the humoral immune system. This ancient host defense system facilitates inflammatory and immune responses via small peptides that activate cells and larger fragments that become firmly attached to the target. The latter in turn promote immune adherence, phagocytosis, antigen processing and cell lysis.

Many human diseases are mediated by autoantibodies and the deposition in tissues of immune complexes. Most immune complexes consist of an antigen (foreign or auto), antibody and complement. Complement cascade participates in the formation, processing, transportation, and tissue localization of antigen-antibody complexes coated with its opsonic fragments.

Over the past decade this laboratory has focused on characterizing membrane glycoproteins that regulate complement activation and serve as receptors for complement-coated antigens. A multigene family of receptor and regulatory proteins was identified. We are studying their structure-function relationships, cell signalling capabilities, reason for expression in unusual niches and human diseases resulting from their partial or complete deficiency. A second major area of investigation centers on microbial interactions with these proteins. Multiple pathogens, including viruses (measles, pox, adeno and others), bacteria (Neisseria, Streptococcus, E. coli) and parasites (malaria), abuse these complement inhibitors by employing them as a receptor or as a virulence factor to protect themselves from complement attack.

Complement regulatory proteins are in clinical trials as therapeutic agents, both in the form of infused recombinant proteins and as expressed in transgenic animals for xenotransplantation. Our laboratory has been involved in producing these transgenic animals, in developing targeted therapy employing antibody (single chain)/complement regulatory protein fusion constructs, and in gene therapy in which a targeted inhibitor is expressed by hepatocytes. Recently, heterozygous mutations in three complement regulators responsible for the control of the alternative pathway, Factor H, MCP and Factor I, have been identified in approximately 50% of patients (mostly children) with atypical hemolytic uremic syndrome. The molecular and biochemical analysis of these mutations has become a major focus of investigation. This discovery has implications for the etiology, pathogenesis and treatment, especially relative to transplantation, of the thrombotic microangiopathies. The overall goal of these efforts is to devise means to treat human disease in which complement activation causes tissue damage by increasing regulatory activity at the site of injury.

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