Clinical Information

Complement factor H (FH) is an important regulator of cell-bound activated C3b, and most importantly of activated C3b in the fluid phase. It is estimated that C3 activation takes place at a rate of 1% to 2%, thus constant activity of FH and other regulators is essential to retain control of complement's alternative pathway. Anti-factor H (AFH) is an autoantibody that interferes with the ability of FH to bind the C3 convertase, therefore allowing unrestricted amplification of C3b in the complement cascade.

Anti-factor H is predominantly seen in children between the ages of 9 and 13 years but can also affect adults. AFH is found in atypical hemolytic uremic syndrome (aHUS) and in C3 glomerulopathies. AHUS is a form of thrombotic microangiopathy, a condition that can cause small blood vessels in the kidneys to become damaged and inflamed as a result of clots forming in the vessels. The clots clog the glomeruli of the kidneys and can cause problems with the kidney' s ability to filter and eliminate waste products. Compared to typical HUS, which is caused by Shiga toxin-producing bacterial infection, aHUS is a diagnosis of exclusion, associated with genetic variants in the complement alternative pathway or acquired autoantibodies that contribute to uncontrolled activation of the complement system. C3 glomerulopathies (C3G) are rare kidney diseases resulting from complement deposition in the kidney (mostly C3 fragments) and causing glomerular damage. C3G may have autoimmune or genetic causes and is attributed mostly to dysfunction of the complement alternative pathway.

Anti-factor H are found in 6% to 10% of patients with aHUS, and the presence or absence of AFH can be a determinant of whether immunosuppressive therapy is warranted versus complement-blocking therapy.(1) Deletion of the CFHR1 gene, with or without other CFHR genes, can result in predisposition to generation of AFH; however, not all individuals with CFHR1 deletion develop AFH, and conversely, some individuals with the autoantibody do not have a CFHR1 deletion.(2) Most commonly, the deletion encompasses both the CFHR1 and CFHR3 genes. The allele frequency of the CFHR3/CFHR1 deletion varies among populations, from 0% in Japanese and South American populations to 54.7% in Nigeria; similarly, the frequency of homozygosity for the deletion ranges from 0% up to 33% in Nigeria.(3) Interestingly, while AFH are much more common in aHUS cohorts from India, accounting for approximately 50% of cases, the population frequency of homozygous CFHR1 deletion is 9.5%, which is not significantly higher than in other populations.(4,5) The mechanism that results in AFH formation in the presence of the deletion remains unknown. Most of the autoantibodies inhibit FH function by binding and blocking the C-terminus, impairing its ability to bind endothelial cell surfaces, sialic acids, and C3b; however, in some individuals, the AFH may recognize other regions, such as the N-terminal SCR1-4.