Principal Investigators Clark Anderson, MD, Latha Ganesan, PhD, and John Robinson, PhD have acquired a five-year RO1 grant ($1.7 million total) from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) for “ Immune Complex Elimination by Sinusoid Endothelial FcgRIIb: Mechanism and Disease.”
The NIAMS grant will mark Anderson’s 40th year of continuous RO1 grant funding from the National Institutes of Health (NIH). Funding will be used to facilitate the continued investigation of how the liver acts as a garbage dump for the body.
Two types of cells line the liver’s blood vessels: endothelium and macrophages. Endothelium constitutes the boundary of the blood vessels while macrophages rest upon them. Macrophages have formerly been recognized as the main scavengers of harmful immune complexes in the blood; however, these workers have discovered that endothelium is just as important and perhaps more so. While macrophages take up large immune complexes, the fate of the small immune complexes has remained unknown.
Preliminary data show that liver sinusoidal endothelial cells (LSEC) have a prominent function in the liver’s garbage disposal-like functions. LSEC express molecular structures called Fc receptors, which are known to take up antigen-antibody (immune) complexes. This team of researchers has found that a specific Fc receptor, FcgRII (RIIb), is the scavenger of LSEC responsible for taking up small immune complexes that cause diseases like glomerulonephritis and systemic lupus erythematosus.
The grant has four aims, First, to test the hypothesis that RIIb of LSEC eliminates small immune complexes from the blood; second, to isolate and purify scavenger cells from the liver; third, to show that elimination of small immune complexes by RIIb of LSEC is efficient, fast and robust; and finally, to show that RIIb controls the manifestation of immune complex-mediated disease.
Knockout mice will be used to characterize the mechanisms that mediate RIIb scavenger activity. “These mechanisms are the biology of the body,” says Anderson. “We are basic scientists interested in studying how the body works. If we can understand these mechanisms, we can apply these principles to specific diseases.”