ReviewWhere next with atypical hemolytic uremic syndrome?
Introduction
Hemolytic uremic syndrome (HUS) is a systemic disease characterized by damage to endothelial cells and erythrocytes, thrombocytopenia, microthrombosis and kidney failure. In many cases the alternative pathway of complement is activated (Ruggenenti et al., 2001). The majority of human HUS cases are associated with a gastrointestinal infection with enterohemorrhagic E. coli such as the serotype O157:H7 and sometimes these cases are seen as epidemics (so called “typical” HUS). In approximately 10% of the HUS cases there is no evidence of an E. coli infection. These cases are found sporadically or in a familial pattern, follow a more aggressive course than the typical HUS cases, and respond poorly to medical treatment. Based on these differences this group has been named atypical HUS (aHUS, OMIM 235400) or diarrhoea-negative HUS (D-HUS). HUS is part of the disease cluster called thrombotic microangiopathies (TMA) and classification of these diseases is discussed later in this review.
During the last few years it has become evident that aHUS is strongly associated with mutations in proteins needed either for activation or regulation of the alternative pathway of complement. The complement system is part of innate immunity that consists of a set of plasma and membrane-bound proteins that protect the body against invading organisms. In addition, the complement system is involved in removal of debris from plasma and tissues, and enhancement of cell-mediated immune responses. Complement is activated through three cascade-like activation pathways. Activation of the classical and lectin pathways requires binding of antibody or a pattern recognition molecule to the target. By contrast, the alternative pathway (AP) is initiated spontaneously in plasma at a low level and if left uncontrolled leads to attack against all the particles, membranes, and cells which are plasma-exposed but not specifically protected from it (Fearon and Austen, 1977). The published aHUS associated mutations of complement genes represent proteins involved in activation or regulation of the alternative pathway, namely complement factor H (CFH), factor I (CFI), membrane cofactor protein (MCP, CD46), C3 and factor B (CFB). Therefore, we first introduce the alternative pathway activation and regulation followed by a description of the mutations so far described in these molecules.
The key molecule in AP activation is C3. It is spontaneously hydrolyzed in plasma at a low rate leading to covalent deposition of a low amount of C3b molecules onto practically all surfaces in contact with plasma (Pangburn et al., 1981). CFB binds to C3b and this complex acts as a substrate for a protease factor D (CFD) that releases Ba fragments and generates an active C3-convertase of AP, C3bBb. This complex has a relatively short half-life but is stabilized by plasma protein properdin (CFP). In the presence or absence of CFP, the C3bBb complex cleaves more C3 to C3b and this leads to the so-called amplification cascade and efficient deposition of C3b onto the target surface (Fig. 1).
The aim of AP activation is to label and attack harmful invaders or debris. That is why, in the absence of regulators, activation proceeds via an amplification cascade and leads to effective opsonization of the foreign structures with C3b together with simultaneous formation of complement membrane attack complexes leading to cell lysis. It is essential that activity is down-regulated on self cells and other tissue surfaces while efficient activation is permitted on foreign targets. Activation also needs to be controlled in the fluid-phase of plasma since activation on any surface also leads to generation of fluid-phase C3b (Fig. 1).
Both plasma proteins and membrane-bound proteins are involved in regulation of the alternative pathway. CFH and CFI are the key plasma regulators of the alternative pathway of complement. If one of them is missing, or totally dysfunctional, AP activation in plasma is vigorous and leads to secondary deficiency of active complement via over-consumption of C3 and some other complement components. CFI is able to permanently inactivate C3b by proteolysis but needs a cofactor. CFH is such a cofactor and is composed of 20 short consensus repeat domains (SCRs or complement control protein units, CCPs) each consisting of approximately 60 amino acids. CFH regulates AP activation by competing with CFB in binding to C3b, by acting as a cofactor for CFI leading to proteolytic inactivation of C3b, and by enhancing dissociation of the C3bBb complex (Farries et al., 1990, Weiler et al., 1976, Whaley and Ruddy, 1976). In addition to its regulatory activity in plasma CFH is practically the only regulator that is involved in down-regulating AP activation on host structures that lack other membrane-bound regulators such as basement membranes in kidney glomeruli (Meri et al., 1992, Zipfel et al., 2006); CFH also contributes to protection of cellular surfaces as discussed later.
The membrane-bound regulators of the alternative pathway include MCP, decay-accelerating factor (DAF, CD55), and complement receptor 1 (CR1, CD35). In the same way as CFH, MCP acts as a cofactor for CFI, but it only protects those cells on which it is expressed. DAF enhances dissociation of the C3bBb complex similarly to CFH but again, only on expressing cells. CR1 has both cofactor and decay-accelerating activities. Functional sites of all of these molecules are composed of SCR domains.
The first link between complement and aHUS came from identification of mutations in the CFH encoding gene CFH. The mutations cause either truncation of CFH or amino acid substitutions mainly within domains 19–20 of CFH (Caprioli et al., 2001, Dragon-Durey et al., 2004, Manuelian et al., 2003, Neumann et al., 2003, Perez-Caballero et al., 2001, Sanchez-Corral et al., 2002, Warwicker et al., 1998). Since aHUS is characterized by endothelial cell damage, microthrombosis, kidney failure, and alternative pathway activation it appeared that protection of endothelial cells and/or kidney glomeruli from complement attack was impaired by malfunction of the carboxy-terminus of CFH. The next complement gene in which mutations were detected in aHUS patients was the MCP gene (Fremeaux-Bacchi et al., 2006, Fremeaux-Bacchi et al., 2007b; Noris et al., 2003, Richards et al., 2003). Lately mutations in genes coding for CFI (Fremeaux-Bacchi et al., 2004, Kavanagh et al., 2005), CFB (Goicoechea de Jorge et al., 2007), and C3 (Fremeaux-Bacchi et al., 2007a) have also been reported and recently deficiency of CFH-related molecules 1 and 3 (CFHR1 and CFHR3) has been found in aHUS (Zipfel et al., 2007). A comprehensive and continuously updated list of published (and unpublished) mutations of CFH, CFI and MCP is found in the aHUS mutation database (www.fh-hus.org) (Saunders et al., 2007).
In this review we concentrate on the current knowledge of complement-associated aHUS, compare this disease with the other types of aHUS on classification level and highlight some new aspects and areas of research into the role of complement in pathogenesis, diagnostics and management of aHUS.
Section snippets
Molecular pathogenesis of complement-related aHUS
The functional consequences of genetic abnormality in complement genes have been studied for a number of mutations by in vitro mutagenesis. The defects can be classified into two types. In Type I, the mutations lead to quantitative deficiency indicating that the mutant protein is either absent from the plasma or is present in lower amounts than normal. In Type II, the mutations lead to functional changes. The mutant protein is present in normal amounts in plasma but one or more of its functions
Should aHUS be divided into distinct subtypes?
The pathological finding of thrombotic microangiopathy (TMA) appears to be common not only to complement associated aHUS and the typical HUS associated with enterohemorrhagic E. coli but to several other clinical disorders. As our understanding of the molecular mechanisms involved in the pathogenesis of HUS increases should we be modifying the diagnostic classification for this disease? Currently hemolytic uremic syndrome is included as a single entity in the World Health Organization
Current diagnostic approaches in aHUS
In the past 10 years we have learned that the introduction of molecular tests into clinical practice provides a tool for diagnosis of susceptibility factors in aHUS. In practice in 2007 we propose a comprehensive screening test based on protein expression levels (either serum levels or surface expression), CFH autoantibody detection and genetic testing of at least three of the known susceptibility genes (CFH, CFI and MCP) as shown in Table 2.
Patients suspected of having aHUS should be initially
Plasma treatment
Some, although not all, patients with aHUS respond to plasma treatment (Caprioli et al., 2006, Lara et al., 1999, Licht et al., 2005). It has been proposed that plasma exchange might be relatively more effective than plasma infusion since it might remove potentially toxic substances from the patient's circulation and exchange was found to have superior efficacy to plasma infusion in one study (Ruggenenti et al., 2001). Moreover there are risks attached to infusion of plasma in patients who are
New scenarios and conclusions
Mutations in most, but not all, of the alternative complement pathway proteins have so far been searched for in aHUS cases. One protein that has not been reported to be mutated in aHUS but, at least theoretically, could cause similar effects to the reported CFH, CFI, C3, or CFB proteins, is properdin. In searching for new aHUS associated mutations – as well as in interpretation of the previously published mutations – it must be considered that screening of mutations or polymorphisms in several
Acknowledgements
Work of TSJ has been financially supported by the Academy of Finland (projects #201506 and #202529), the Helsinki University Central Hospital Funds, The Finnish Cultural foundation and the Sigrid Jusélius Foundation. Work of VF-B is supported by the Délégation Régionale à la Recherche Clinique, Assistance Publique—Hôpitaux de Paris (PHRC AOM 05130). THJG is supported by the Foundation for children with atypical HUS. Work form PFZ is funded by the Deutsche Forschungsgemeinschaft and Kidneeds,
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2016, ImmunobiologyCitation Excerpt :Prior reviews of the topic have largely focused on the role of membrane regulatory proteins (Linton and Morgan, 1999; Liszewski et al., 1996), and thus this topic will not be reviewed. With regard to soluble regulatory proteins, though, factor H (FH)-mediated control of complement activation is increasingly understood to be centrally involved in the pathogenesis of human diseases, especially where mutations or highly informative polymorphisms of FH are associated with diseases such as atypical hemolytic uremic syndrome (aHUS) and membranoproliferative glomerulonephritis type II (MPGN Type II) (Jha et al., 2007; Jokiranta et al., 2007; Kavanaugh et al., 2006). Importantly, FH can function in both the fluid phase and on surfaces, and the major characteristic that controls its surface inhibitory capacity is its relative ability to bind in a tissue-specific manner to glycosaminoglycans (GAG) as well as C3b/C3d molecules that are fixed onto the target surface (reviewed in Zipfel et al., 2002).