Of mice and men: The factor H protein family and complement regulation

• The complement regulator factor H is structurally and functionally highly conserved in mice and men.
• Both mice and men express several factor H-related proteins.
• Humans express five factor H-related proteins while only two factor H-related proteins are found in mice.
• There is no splice variant of factor H reported in mice, whereas humans express the splice variant factor H-like 1.

For decades immunological research has relied, with variable success, on mouse models to investigate diseases and possible therapeutic interventions. With the approval of the first therapeutic antibody targeting complement, called eculizumab, as therapy in paroxysmal nocturnal hemoglobinuria (PNH) and more recently atypical hemolytic uremic syndrome (aHUS), the viability of targeting the complement system was demonstrated. The potent, endogenous complement regulators have become of increasing interest as templates for designing and developing new therapeutics. Recently, complement inhibitors based on (parts of) the human complement regulator factor H (FH) are being examined for therapeutic intervention in inflammatory conditions. The first step to evaluate the potency of a new drug is often testing it in a mouse model for the target disease. However, translating results to human conditions requires a good understanding of similarities and, more importantly, differences between the human and mouse complement system and particularly regulation. This review will provide a comprehensive overview of the complement regulator FH and its closely related proteins and current views on their role in mice and men.