Complement in Typical Hemolytic Uremic Syndrome

ABSTRACT

Hemolytic uremic syndrome (HUS) is a severe disease characterized by the clinical triad of hemolytic anemia, thrombocytopenia, and acute renal failure. HUS exists in two forms: the atypical diarrhea-negative HUS, which is often associated with complement disorders, and the more frequent diarrheal-associated typical HUS, which is caused by infections with enterohemorrhagic Escherichia coli. The virulence factors of the latter have been studied well, and Shiga toxin (Stx)2 is reported to represent the most important one. In contrast, risk factors on the host side have not been intensively studied until recently: Complement activation products have been detected in the serum and plasma of HUS patients, and an in vitro study could show that Stx2 not only damages the kidney directly but also indirectly via complement, in two ways. First, it activates complement, and second, it delays the functions of its control protein factor H on the cell surface, both known to damage the kidney.

KEYWORDS

Hemolytic uremic syndrome - Shiga toxin - complement

REFERENCES

• 1 Karch H, Tarr P I, Bielaszewska M. Enterohaemorrhagic Escherichia coli in human medicine.  Int J Med Microbiol. 2005;  295(6–7) 405-418
• 2 Kavanagh D, Richards A, Atkinson J. Complement regulatory genes and hemolytic uremic syndromes.  Annu Rev Med. 2008;  59 293-309
• 3 Orth D, Grif K, Khan A B, Naim A, Dierich M P, Würzner R. The Shiga toxin genotype rather than the amount of Shiga toxin or the cytotoxicity of Shiga toxin in vitro correlates with the appearance of the hemolytic uremic syndrome.  Diagn Microbiol Infect Dis. 2007;  59(3) 235-242
• 4 te Loo D M, Monnens L A, van Der Velden T J et al. Binding and transfer of verocytotoxin by polymorphonuclear leukocytes in hemolytic uremic syndrome.  Blood. 2000;  95(11) 3396-3402
• 5 Orth D, Grif K, Zimmerhackl L B, Würzner R. Prevention and treatment of enterohemorrhagic Escherichia coli infections in humans.  Expert Rev Anti Infect Ther. 2008;  6(1) 101-108
• 6 Loirat C, Noris M, Frémeaux-Bacchi V. Complement and the atypical hemolytic uremic syndrome in children.  Pediatr Nephrol. 2008;  23(11) 1957-1972
• 7 Caprioli J, Remuzzi G. Complement hyperactivation may cause atypical haemolytic uraemic syndrome—gain-of-function mutations in factor B.  Nephrol Dial Transplant. 2007;  22(9) 2452-2454
• 8 Frémeaux-Bacchi V, Miller E C, Liszewski M K et al. Mutations in complement C3 predispose to development of atypical hemolytic uremic syndrome.  Blood. 2008;  112(13) 4948-4952
• 9 Speth C, Würzner R, Stoiber H, Dierich M P. Complement. In: Paul WE Fundamental Immunology. Philadelphia, PA; Lippincott-Raven 2008: 1047-1078
• 10 Würzner R. Evasion of pathogens by avoiding recognition or eradication by complement, in part via molecular mimicry.  Mol Immunol. 1999 36(4–5) 249-260
• 11 Orth D, Khan A B, Naim A et al. Shiga toxin activates complement and binds factor H: evidence for an active role of complement in hemolytic uremic syndrome.  J Immunol. 2009;  182(10) 6394-6400
• 12 Monnens L, Molenaar J, Lambert P H, Proesmans W, van Munster P. The complement system in hemolytic-uremic syndrome in childhood.  Clin Nephrol. 1980;  13(4) 168-171
• 13 Thurman J M, Marians R, Emlen W et al. Alternative pathway of complement in children with diarrhea-associated hemolytic uremic syndrome.  Clin J Am Soc Nephrol. 2009;  4(12) 1920-1924
• 14 Markiewski M M, Lambris J D. The role of complement in inflammatory diseases from behind the scenes into the spotlight.  Am J Pathol. 2007;  171(3) 715-727
• 15 van Setten P A, van Hinsbergh V W, van den Heuvel L P et al. Monocyte chemoattractant protein-1 and interleukin-8 levels in urine and serum of patents with hemolytic uremic syndrome.  Pediatr Res. 1998;  43(6) 759-767
• 16 Lathem W W, Grys T E, Witowski S E et al. StcE, a metalloprotease secreted by Escherichia coli O157:H7, specifically cleaves C1 esterase inhibitor.  Mol Microbiol. 2002;  45(2) 277-288
• 17 Grys T E, Walters L L, Welch R A. Characterization of the StcE protease activity of Escherichia coli O157:H7.  J Bacteriol. 2006;  188(13) 4646-4653
• 18 Lathem W W, Bergsbaken T, Welch R A. Potentiation of C1 esterase inhibitor by StcE, a metalloprotease secreted by Escherichia coli O157:H7.  J Exp Med. 2004;  199(8) 1077-1087
• 19 Giannakis E, Jokiranta T S, Male D A et al. A common site within factor H SCR 7 responsible for binding heparin, C-reactive protein and streptococcal M protein.  Eur J Immunol. 2003;  33(4) 962-969
• 20 Sánchez-Corral P, Pérez-Caballero D, Huarte O et al. Structural and functional characterization of factor H mutations associated with atypical hemolytic uremic syndrome.  Am J Hum Genet. 2002;  71(6) 1285-1295
• 21 Martinez-Barricarte R, Pianetti G, Gautard R European Working Party on the Genetics of HUS et al. The complement factor H R1210C mutation is associated with atypical hemolytic uremic syndrome.  J Am Soc Nephrol. 2008;  19(3) 639-646
• 22 Paixão-Cavalcante D, Botto M, Cook H T, Pickering M C. Shiga toxin-2 results in renal tubular injury but not thrombotic microangiopathy in heterozygous factor H-deficient mice.  Clin Exp Immunol. 2009;  155(2) 339-347
• 23 Ikeda K, Nagasawa K, Horiuchi T, Tsuru T, Nishizaka H, Niho Y. C5a induces tissue factor activity on endothelial cells.  Thromb Haemost. 1997;  77(2) 394-398
• 24 Wojta J, Huber K, Valent P. New aspects in thrombotic research: complement induced switch in mast cells from a profibrinolytic to a prothrombotic phenotype.  Pathophysiol Haemost Thromb. 2003;  33(5-6) 438-441