Disturbed sialic acid recognition on endothelial cells and platelets in complement attack causes atypical hemolytic uremic syndrome

Abstract

Key Points• Sialic acids are critical for factor H-mediated complement regulation on endothelial cells, erythrocytes, and platelets. • Impaired ability of factor H mutants to simultaneously bind sialic acid and C3b on cells explains their association with aHUS.Uncontrolled activation of the complement system against endothelial and blood cells is central to the pathogenesis of atypical hemolytic uremic syndrome (aHUS). aHUS patients frequently carry mutations in the inhibitory complement regulator factor H (FH). Mutations cluster in domains [19][20], which are critical for recognizing self surfaces. On endothelial cells, binding of FH is generally attributed to heparan sulfate. This theory, however, is questioned by the puzzling observation that some aHUSassociated mutations markedly enhance FH binding to heparin and endothelial cells. In this article, we show that, instead of disturbed heparin interactions, the impaired ability of C-terminal mutant FH molecules to recognize sialic acid in the context of surface-bound C3b explains their pathogenicity. By using recombinant FH19-20 as a competitor for FH and measuring erythrocyte lysis and deposition of complement C3b and C5b-9 on endothelial cells and platelets, we now show that several aHUS-associated mutations, which have been predicted to impair FH19-20 binding to sialic acid, prevent FH19-20 from antagonizing FH function on cells. When sialic acid was removed, the wild-type FH19-20 also lost its ability to interfere with FH function on cells. These results indicate that sialic acid is critical for FH-mediated complement regulation on erythrocytes, endothelial cells, and platelets. The inability of C-terminal mutant FH molecules to simultaneously bind sialic acid and C3b on cells provides a unifying explanation for their association with aHUS. Proper formation of FH-sialic acid-C3b complexes on surfaces exposed to plasma is essential for preventing cell damage and thrombogenesis characteristic of aHUS.

HUS and atypical HUS

“…Most of these mutations lead to impaired regulation of alternative pathway activation. Some disturb recognition of C3b by factor H, 56,60 factor I, 61 or CD46 62 ; some disturb recognition of self-cell surface molecules, such as sialic acid or glycosaminoglycans, by factor H. 55,59 Some mutations in C3 or factor B prolong the C3 convertase half-life or prevent its elimination. 63,64 The frequencies of mutations observed in aHUS are shown in Table 1.…”

“…We observed that sialic acid in in vitro assays is the main ligand for factor H on red cells and also on platelets and endothelial cells. 59 Pneumococci 23 and influenza A virus, 24 most often seen in secondary HUS associated with infections, possess very active neuraminidases specialized in removing sialic For personal use only. on May 10, 2018. by guest www.bloodjournal.org From acid from self cell surfaces.…”

“…88 Accordingly, in aHUS, simultaneous or even earlier damage of these cells compared with that of endothelial cells is possible although not proven. 59 Platelets and coagulation in the pathogenesis of HUS Platelets in the pathogenesis of aHUS Complement-mediated platelet activation has gained much less attention in aHUS than hemolysis or endothelial cell damage. Platelets may, however, be involved, either primarily or secondarily, in pathogenesis of this disease because thrombocytopenia is a typical feature of TMAs, 89 and the thrombi in capillaries and arterioles contain platelets 90 in addition to red cells.…”

“…20 We have recently shown that protection of platelets from complement attack by factor H requires sialic acids on the cell membrane in vitro. 59 Therefore, impaired alternative pathway regulation is a logical explanation for thrombocytopenia and could also contribute to formation of platelet-rich microvascular thrombi. 72,73 Links between complement, coagulation, and platelets in HUS The common conclusion from the numerous studies linking complement and coagulation is that complement activation leads to initiation or enhancement of coagulation.…”

Sweeteners for factor H

“…n REFERENCES In this issue of Blood, Hyvärinen et al 1 show that mutant forms of complement factor H, which are commonly associated with atypical hemolytic uremic syndrome (aHUS), have impairments in binding to sialic acid on C3b-coated erythrocytes, platelets, and endothelial cells. The findings have implications in our understanding of the mechanisms underlying aHUS and the design of therapies for complement-mediated syndromes, infections, and cancer.…”