64 Subsequent studies demonstrated that renal injury was prevented in fH knockout mice that were also C5-deficient or when given an inhibitory anti-C5 antibody, suggesting that terminal complement activation contributes to the pathology.59 Interestingly,

when fI KO mice were generated they also showed low plasma C3 levels, indicating complement consumption, but unlike fH knockout mice they did not develop MPGN.81 Furthermore, fH/fI double deficient mice also failed to develop MPGN.81 Because fI converts C3b into iC3b and C3d, these data suggest that the development of MPGN may depend more on the forms of activated C3 generated by the AP. Thrombotic microangiopathies are a group of diseases characterized by thrombocytopenia, microangiopathic haemolytic anaemia, and either impaired renal or neurologic CHIR-99021 datasheet function.82 Thrombotic Fulvestrant molecular weight thrombocytopenic pupura has varying degrees of renal impairment, but many other organs can be affected, particularly the nervous system. Contrastingly, haemolytic uraemic syndrome (HUS) is another disease in this category, but symptoms are largely restricted

to the kidney. There are two types of HUS, distinguished by the presence or absence of diarrhoea caused by Shiga toxin-producing bacteria.82 Diarrhoea-positive, or D+ HUS, is the most common form of HUS and can usually be cured with antibiotics and symptomatic treatment.82 On the other hand, diarrhoea-negative HUS, often referred to as atypical HUS (aHUS), only makes up 5–10% of HUS cases but has a much poorer prognosis.83 Approximately 50% of aHUS patients progress to end-stage renal failure and at least 25% of cases are fatal.84 It is still unclear what triggers aHUS episodes although it is believed to be initiated by endothelial Aprepitant cell injury caused by

infection or other exogenous injury.35 While mutations in procoagulant proteins such as thrombomodulin have been found in some aHUS cases,85 the majority of mutations found in aHUS patients have been with AP complement proteins. A multitude of clinical studies over the last decade have demonstrated that at least half of the familial cases of aHUS are caused by mutations in the complement system that lead to uncontrolled AP activation.25,35,86 While a few cases have reported mutations in C3 or fB that tend to produce aberrant C3bBb convertases more resistant to inactivation,87–89 most mutations affect the function of regulatory proteins fH, fI and MCP.35,90,91 In fact, the genes for these proteins are all located on the same region of chromosome 1 (1q32), called the regulators of complement activation gene cluster,92,93 making the latter a ‘hot’ chromosomal spot for aHUS-related mutations. A few cases of dysfunctional C4bp have also been reported,94 but interestingly DAF, another regulators of complement activation gene, has not been linked to any aHUS patients to date.