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.