Elevated surface-bound complement FH alters the function of platelets and monocytes in FHR1/3 null healthy individuals

Abstract Complement factor H (FH) and FH-related proteins (FHRs), structurally similar proteins are involved in the regulation of complement activation. Homozygous deletion of FHR 1 and 3 proteins (FHR1/3−/−) is known as a risk factor for disorders such as aHUS and SLE, characterised by thrombo-inflammatory complications. Interestingly, FHR1/3−/− genotype also exists as polymorphism in healthy population of various ethnicities around the world including 8–10% Indians. In an effort to understand the functional role of this polymorphism, we describe in this study an elevated surface-bound FH on platelets and monocytes, but not other blood cells in FHR1/3 −/− healthy individuals. The FHR1/3−/− platelets displayed diminish ability to form aggregates in response to agonists in vitro . The FHR1/3−/− monocytes displayed elevated secretion of TNFα, IL1β, IL6 and IL10 in response to TLR ligands. However, exogenous FH limits platelet aggregates formation as well as cytokine secretion in monocytes. Therefore, observations together suggest a differential regulation of platelets and monocytes by FH-FHR1/3 axis in healthy individuals. While these findings will need more detailed investigation, it is clear that the connection between FH-FHR axis and thrombo-inflammatory complications is likely to be complex in diseases including aHUS and SLE, and provide interesting new directions for future study.