DOI: 10.1097/PCC.0b013e3181d8e19b

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PMID: 20823737

Issn Print: 1529-7535

Publication Date: 2010/09/01


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Pathophysiology of disinhibition of complement activation*

Michael Eisenhut

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In this issue of Pediatric Critical Care Medicine, the article by Agbeko et al (1) investigates functional polymorphisms in the complement activation cascade in children who had at least one organ failure and who were admitted to a tertiary pediatric intensive care unit. The authors found that homozygosity for the complement factor H Y402H polymorphism CC was associated with a reduction in systemic inflammatory response syndrome, whereas structural variant Mannose Binding Lectin genotypes at positions 52, 54, and 57 and promotor single nucleotide polymorphism variants at positions −221, −550, and +4 were associated with increased risk of systemic inflammatory response syndrome and sepsis. The findings regarding Mannose Binding Lectin polymorphisms confirmed results of previous studies, whereas the protective effect of the complement factor H (CFH) polymorphisms represents a new finding. It was emphasized that vigorous complement activation may offer protection from development of systemic inflammation. The authors mentioned the potential adverse effect of the CFH mutation that increased systemic complement activation may play a role in acute macular degeneration. What the authors did not discuss is the detrimental role reduced CFH activity plays in a potentially life-threatening complication of infection, which is atypical hemolytic-uremic syndrome (aHUS).
CFH has been investigated most extensively in the context of hemolytic-uremic syndrome (HUS) (2). In 1981, investigators found aHUS in two brothers, who had no detectable CFH. Subsequently, in 1998, a group of investigators showed an association between aHUS and the chromosome 1q32 locus, which contains genes for CFH. More than 100 mutations in the CFH gene have now been identified in patients with aHUS with a mutation frequency of 40% to 45% in patients with the familial form. Most of the mutations are heterozygous, which demonstrates that 50% of normal CFH is not sufficient to counteract the dysfunction of the mutated CFH. Penetrance of the disease, however, is about 50% in carriers of a mutation. The majority (67%) of patients with CFH mutation-associated HUS are affected in childhood; manifestations include severe hemolytic anemia, thrombocytopenia, acute renal failure, and in 20%, there is central nervous system or multivisceral involvement (3, 4). The pathophysiology of CFH has been clarified in this context, and it down-regulates alternative-complement pathway activation on structures without other complement regulators, such as the glomerular basement membranes, and contributes to endothelial protection when membrane-bound regulators are present. Normal function is linked to the five exons that encode the most C-terminal part of CFH. This area contains a C3b-binding site and a polyanion-binding site, which are determinants for CFH contact with host endothelial cells and for surface cofactor activity involved in degradation of endothelial-bound C3b.
Disinhibition of the alternative pathway in patients with CFH mutations causes excess C3b formation and deposition on vascular endothelium, leading to increased C5 convertase formation, which initiates the formation of the membrane attack complex. Endothelial injury hereby creates a prothrombotic state through exposure of subendothelial collagen, von Willebrand factor, and fibrinogen. In addition, CFH has defective binding to platelets, allowing C3 and C9 deposition and platelet activation (2). Agbeko and colleagues (1) found systemic inflammatory response syndrome in 24 patients with CFH Y402H CC genotype. It would be important to investigate whether these patients were more likely to suffer complications compatible with features of HUS during their acute illness. Complications previously attributed to septicemia like limb gangrene and skin necrosis, which are particularly common in meningococcal septicemia, as well as thrombocytopenia or renal failure, may be related to excessive complement activation associated with CFH mutations.

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