Anti–Factor H Autoantibodies Associated with Atypical Hemolytic Uremic Syndrome

Abstract

Several studies have demonstrated genetic predisposition in non-shigatoxin-associated hemolytic uremic syndrome (HUS), involving regulatory proteins of the complement alternative pathway: Factor H (FH) and membrane co-factor protein (CD46). Regarding the observations of thrombotic thrombocytopenic purpura patients, in whom a von Willebrand factor protease (ADAMST-13) deficiency may be inherited or acquired secondary to IgG antibodies, it was speculated that HUS might occur in a context of an autoimmune disease with the development of anti-FH antibodies leading to an acquired FH deficiency. The presence of FH autoantibodies was investigated by an ELISA method using coated purified human FH in a series of 48 children who presented with atypical HUS and were recruited from French university hospitals. Anti-FH IgG antibodies were detected in the plasma of three children who presented with recurrent HUS. The anti-FH specificity was conserved by the Fab2 fraction. The plasma FH activity was found to be decreased, whereas plasma FH antigenic levels and FH gene analysis were normal, indicating that the presence of anti-FH antibodies led to an acquired functional FH deficiency. This report supports for the first time that HUS may occur in a context of an autoimmune disease with the development of anti-FHspecific antibody leading to an acquired FH deficiency. This new mechanism of functional FH deficiency may lead to the design of new approaches of diagnosis and treatment with a particular interest in plasma exchanges or immunosuppressive therapies.

The Central Role of the Alternative Complement Pathway in Human Disease

“…Three separate groups simultaneously reported that a tyrosine-histidine polymorphism at aa 402 of factor H is associated with the development of AMD (71)(72)(73). This polymorphism is located in the binding region for heparin (74) and C-reactive protein (75), the same region of factor H of a mutation identified in a patient with MPGN (55). The retinal lesions of AMD, called drusen, contain deposited components of the membrane attack complex (MAC), as well as serum amyloid P (76), and are structurally similar to those seen in patients with type II MPGN (77).…”

Complement Inhibitor Eculizumab in Atypical Hemolytic Uremic Syndrome

“…Patients who have aHUS with combined mutations have been reported (4). Approximately 10% of children with aHUS have an acquired functional CFH deficiency caused by anti-CFH autoantibodies, frequently associated with absent CFHR1/ CFHR3 (11)(12)(13). In mutation carriers, aHUS penetrance is approximately 50%, suggesting that other genetic or environmental modifiers are needed for disease expression (3).…”

“…In anti-CFH autoantibody-positive patients, add-on immunosuppression may be reasonable (11). In CFH mutation carriers, liver-kidney transplantations have occasionally been performed (17).…”

Complement Factor H–Related Protein 1 Deficiency and Factor H Antibodies in Pediatric Patients with Atypical Hemolytic Uremic Syndrome

“…Antibodies against CFH have been reported in patients with aHUS (25)(26)(27). These antibodies were shown to induce functional CFH deficiency (25)(26)(27)(28) by binding to its C-terminal region and thereby reducing its regulatory function.…”

“…These antibodies were shown to induce functional CFH deficiency (25)(26)(27)(28) by binding to its C-terminal region and thereby reducing its regulatory function. CFHR1 was shown to neutralize CFH antibodies in patients with aHUS (28).…”