The role of heparan sulfate as determining pathogenic factor in complement factor H-associated diseases

•Factor H mutations cause the renal diseases aHUS, DDD and the ocular disease AMD.•Mutations cluster in domains that recognize host cells by binding heparan sulfate.•Recent studies suggest that interactions with HS significantly affect FH activity.•Factor H-binding HS domains are differentially expressed in eyes and kidneys.•Disturbed recognition of HS could explain the tissue-specific disease phenotypes.

Complement factor H (FH) systemically inhibits excessive complement activation in the microenvironment of host cells, but for instance not on microbes. This self-recognition is mediated by two binding sites that recognize distinctly sulfated heparan sulfate (HS) domains. The interaction with HS not only concentrates FH on host cells, but directly affects its activity, evoking novel models of conformational activation. Genetic aberrations in the HS-binding domains systemically disturb the protective function of FH, yet the resulting loss of complement control affects mainly ocular and renal tissues. Recent results suggest that the specific expression of HS domains in these tissues restricts the interaction of HS to a single binding site within FH. This lack of redundancy could predispose eyes and kidneys to complement-mediated damage, making HS a central determinant for FH-associated diseases.