Anne Nicholson-Weller, MD
Our laboratory is interested in the normal regulation of the human complement system, and how inflammation is modified through complement activation. The complement system is an integral part of innate immunity, and as such, complement participates in immune surveillance for pathogens and augments the adaptive immune system. Ongoing research projects include understanding how the receptor for C1q on neutrophils, which has just been identified in our laboratory as CD35, is able to mediate the phagocytosis of C1q-opsonized particles and transport C1q-opsonized immune complexes. The reciprocal binding sites on C1q and on the receptor are being mapped by a combination of protein chemistry and molecular biological approaches. The yeast 2-hybrid system is being used to identify the signaling partners of CD35, and define what components of the cytoskeleton hook up with the cytoplasmic tail of CD35. Opsonophagocytosis by complement-complement receptors is known to allow ingestion of microbes without stimulating the production of superoxide by the phagocyte. We are studying how this occurs and might promote the intracellular survival of C1q-binding pathogens, such as Neisseria gonorrhea and Cryptococcus neoformans. We are also the studying signaling pathways used by human neutrophils in response to immobilized C1q. This pathway does not involve CD35, but does lead to the activation of beta-2 integrins, and subsequently to the release of superoxide. This work is being done in collaboration with Dr. Lloyd B. Klickstein, MD, PhD of the Brigham and Women's Hospital.
A second project involves the response of human PMN to a complex of complement C5, C6, and C7, which is known as hemolytically inactive C5b67 (iC5b67). iC5b67 is not able to insert into the plasma membrane of cells, but it signals to PMN from the outside of the cell, presumably through a receptor. iC5b67 can inhibit superoxide production by C5a and FMLP stimulated PMN, and thus it has antagonist effects, which we hypothesize are involved in the resolution of inflammation.