Recent work has yielded new insight into how the body eliminates small immune complexes (sic) from the blood. We have long known that pathogenic IC, depositing in organs like kidneys, cause inflammation and disease such as glomerulonephritis and SLE. However, by far the majority of these ic are eliminated harmlessly by the liver, most believe by its macrophages (Kupffer cells, kc). Further, a particular Fc receptor, FcgRII (RIIb), expressed on B cells, macro- phages, and dendritic cells, is known to temper ic-mediated disease. With this background, these investigators present two remarkably novel findings: first, that RIIb on liver sinusoidal endothelium (lsec), not liver kc, eliminate th major fraction of sic from blood, and, second, that three-quarter of the body's RIIb is expressed on the lsec. Based on this information they hypothesize that RIIb on the lsec eliminates sic from blood and protects against SLE and other ic- mediated disease in humans and mice. This hypothesis has four specific predictions, each a specific aim of the proposal.
The first aim affirms the hypothesis by measuring rates of in vivo decay of infused ic in conditional and chimeric knockout mice; and by showing that a wide spectrum of ic are effective in the same in vivo rate-of-decay measurement.
The second aim i solates and purifies scavenger cells from liver and makes use of these in vitro for dissecting the mechanism of RIIb-mediated pinocytosis on lsec.
The third aim i s that clearance is efficient, rapid, recoverable, and robust; a prediction approached by careful kinetic analysis of in vivo de- cay; and confirmed by in vitro studies.
The fourth aim i s that RIIb controls the manifestations of inflammatory ic-mediated disease, a prediction approached using an experimental model of mouse serum sickness in mouse strains in which RIIb has been ablated in select tissues. The outcomes expected are that the lsec and not the kc is the major liver scavenger for sic; that RIIb on the lsec and not on myeloid or B cell is the operant scavenging receptor; that the capacity of the clearance mechanism is robust; that serum sickness can easily be produced in the absence of RIIb; and that lsec RIIb clearance of ic likely contributes to SLE and other ic-mediated dis- ease. The project challenges existing orthodoxy that the kc is the major liver scavenger for immune complexes, suggesting instead that the lsec is the scavenger. As well the project presents a new paradigm whereby RIIb on lsec clears pathogenic ic, thus protecting the host from ic-mediated inflammatory diseases such as SLE.
This project has wide relevance to public health in that it will define the mechanism by which FcgRIIb on liver endothelium removes circulating immune complexes, thereby controlling the manifestation of inflammatory autoimmune diseases such as glomerulonephritis and SLE. Understanding this mechanism should suggest ways of modifying the rate of immune complex elimination and thus both treating and preventing immune complex- mediated inflammatory diseases.
|Mates, Jessica M; Yao, Zhili; Cheplowitz, Alana M et al. (2017) Mouse Liver Sinusoidal Endothelium Eliminates HIV-Like Particles from Blood at a Rate of 100 Million per Minute by a Second-Order Kinetic Process. Front Immunol 8:35|
|Ganesan, Latha P; Mates, Jessica M; Cheplowitz, Alana M et al. (2016) Scavenger receptor B1, the HDL receptor, is expressed abundantly in liver sinusoidal endothelial cells. Sci Rep 6:20646|
|Yao, Zhili; Mates, Jessica M; Cheplowitz, Alana M et al. (2016) Blood-Borne Lipopolysaccharide Is Rapidly Eliminated by Liver Sinusoidal Endothelial Cells via High-Density Lipoprotein. J Immunol 197:2390-9|
|Ganesan, Latha P; Kim, Jonghan; Wu, Yun et al. (2012) Fc?RIIb on liver sinusoidal endothelium clears small immune complexes. J Immunol 189:4981-8|