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Immunobiology 217 (2012) 235– 243

Contents lists available at ScienceDirect

Immunobiology

j ourna l homepage: www.elsev ier .de / imbio

s complement a culprit in infection-induced forms of haemolytic uraemicyndrome?

ally Johnsona,∗, Aoife Watersb

Department of Paediatric Nephrology, Great North Children’s Hospital, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Queen Victoria Road, Newcastle Upon Tyne, NE1 4LP,nited KingdomInstitute of Child Health, 30 Guilford Street, University College London, WC1N 1EH, United Kingdom

r t i c l e i n f o

rticle history:eceived 14 May 2011eceived in revised form 30 June 2011ccepted 18 July 2011

a b s t r a c t

Haemolytic uraemic syndrome (HUS) accounts for the most common cause of childhood acute renal fail-ure. Characterized by the classical triad of a microangiopathic haemolytic anaemia, thrombocytopaeniaand acute renal failure, HUS occurs as a result of Shiga-toxin producing microbes in 90% of cases. Theremaining 10% of cases represent a heterogeneous subgroup in which inherited and acquired forms ofcomplement dysregulation have been described in up to 60%. Emerging evidence suggests that microbes

eywords:omplement dysregulationndotheliumaemolytic uraemic syndromehiga toxintreptococcus pneumoniae

associated with HUS exhibit interaction with the complement system. With the advent of improvedgenetic diagnosis, it is likely that certain cases of infection-induced HUS may be attributed to underlyingdefects in complement components. This review summarises the interplay between complement andinfection in the pathogenesis of HUS.

© 2011 Elsevier GmbH. All rights reserved.

hrombotic microangiopathy

ntroduction

Haemolytic uraemic syndrome (HUS) is characterised byicroangiopathic haemolytic anaemia, thrombocytopaenia and

cute renal failure. Renal histopathology reveals thromboticicroangiopathy (TMA), characterised by occlusive thrombi in

lomerular capillaries, small arterioles and arteries, detachmentf endothelial cells (ECs) from the glomerular basement mem-

rane, mesangiolysis and widening of the subendothelial spacey electron-lucent material (Fig. 1). EC injury is the key initiat-

ng event in the pathogenesis of TMA, leading to EC dysfunction,

Abbreviations: HUS, haemolytic uraemic syndrome; TMA, thrombotic microan-iopathy; ECs, endothelial cells; AP, alternative pathway; CP, classical pathway;AC, membrane attack complex; CFH, complement factor H; SCRs, short con-

ensus repeats; CFI, complement factor I; DAF, decay accelerating factor; MCP,embrane-bound cofactor protein; aHUS, atypical HUS; THBD, thrombomod-

lin; EHEC, enterohaemorrhagic Escherichia coli; GABS, Group A beta-hemolytictreptococcus; HIV, Human Immunodeficiency Virus; Stx, Shiga toxin; Stx-HUS,higa toxin-induced haemolytic uraemic syndrome; PMNs, polymorphonucleareukocytes; Gb3cer, globotriaosylceramide; pHUS, pneumococcal HUS; T, Thomsen-riedenreich antigen; GEC, glomerular endothelial cells; HAART, highly activentiretroviral therapies; PEX, plasma exchange therapy; VZV, varicella zosterirus; C4BP, C4b-binding protein; TAFIa, thrombin activatable fibrinolysis inhibitor;MEC, human microvascular endothelial cells; HUVEC, human umbilical veinndothelial cells; VEGF, vascular endothelial growth factor.∗ Corresponding author. Tel.: +44 0191 282 1859; fax: +44 0191 282 0077.

E-mail address: sally.johnson@lineone.net (S. Johnson).

171-2985/$ – see front matter © 2011 Elsevier GmbH. All rights reserved.oi:10.1016/j.imbio.2011.07.022

apoptosis and necrosis with exposure of the subendothelial matrix(Bauwens et al. 2011). Activation of platelets, leukocytes and thecoagulation cascade contribute to intravascular microthrombosis(Ruggenenti et al. 2001). A number of triggers for EC injury havebeen identified in HUS. Most cases follow infection with Shiga toxinproducing enteric pathogens (Lynn et al. 2005). Others present fol-lowing pneumococcal infection (Waters et al. 2007). The majorityof remaining patients have an inherited defect of complement reg-ulation. In this review we will summarise the role of complement inthe pathogenesis of HUS, before considering the molecular mecha-nisms employed by microbial pathogens in the pathogenesis of HUSand whether these may involve the complement system. Finally, wewill examine the role of infection in triggering HUS in geneticallysusceptible individuals.

Overview of alternative complement pathway

Complement proteins provide an important host defense mech-anism by recognizing and eliminating microbial pathogens duringinfection (Zipfel et al. 2007). Activation of C3, a key comple-ment effector, occurs by three major pathways: the alternativepathway (AP), the classical pathway (CP) and the lectin path-ways (Fig. 2). The AP is initiated by the spontaneous hydrolysis of

plasma C3 to generate C3b, triggering formation of a C3-convertase,C3bBb. Subsequent formation of the lytic membrane attack com-plex (MAC) occurs with binding of C3b to C3bBb which generatesa C5-convertase that cleaves C5 (Zipfel and Skerka 2009).

236 S. Johnson, A. Waters / Immunobiology 217 (2012) 235– 243

Fig. 1. Renal histopathological features of thrombotic microangiopathy. A renal biopsy demonstrating features of acute thrombotic microangiopathy (TMA) with segmentalv ntric

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asculitic changes and fibrin thrombi within the glomerular capillary loops. Conceompartment was normal.

Continuous activation of circulatory C3 is regulated by severalroteins which act both in the fluid phase and at the cell membraneFig. 2). Of these, complement factor H (CFH), a plasma glycopro-ein consisting of 20 short consensus repeats (SCRs), plays a majorole in the inactivation of C3bBb. CFH binds to complement factor ICFI), which cleaves C3b to iC3b (co-factor activity) (Pangburn et al.977). CFH also inhibits the formation of C3bBb and promotes theissociation of C3bBb (decay-accelerating activity). Binding of CFHy its C-terminus to cell surface polyanions increases its affinity forurface-bound C3b. Other regulatory proteins include five struc-urally related proteins to CFH (CFHR1–5) which share different

egrees of identity with CFH (Zipfel and Skerka 2009). Membrane-ound complement regulators including complement receptors 1nd 2, decay accelerating factor (DAF), membrane-bound cofactor

ig. 2. Activation and regulation of Complement. Activation of C3 occurs by the alternativehis results in formation of a C3 convertase enzyme (producing C3a and C3b) and subseomplement activation occurs by three major mechanisms. (i) co-factor activity (for the CFctivity (dissociation of the C3 convertase) by CFH, MCP and DAF, and (iii) inhibition of MBL, Mannose binding lectin; DAF, Decay accelerating factor; MCP, Membrane cofactor p

actor D; CFH, complement factor H; CFI, complement factor I.

intimal thickening was noted in adjacent afferent arterioles. The tubulointerstitial

protein (MCP; CD46), protectin (CD59) and complement receptorof the immunoglobulin superfamily (CRIg) regulate complement bya variety of mechanisms (Fig. 2).

Inherited defects of complement regulation

Complement dysregulation in aHUS was first observed almostfifteen years ago (Warwicker et al. 1998). Mutations have sincebeen identified in genes encoding both complement regulators(CFH, CFI, CFHR 1/3 and CFHR 1/4A and MCP) (Bienaime et al. 2010;

Caprioli et al. 2001, 2003, 2006; Chan et al. 2009; Couzi et al.2008; Cruzado et al. 2009; Dragon-Durey et al. 2004, 2009; Esparza-Gordillo et al. 2006; Fremeaux-Bacchi et al. 2004, 2006; Heinen et al.2009; Kavanagh et al. 2005, 2008; Manuelian et al. 2003; Moore

pathway, classical pathway or lectin (MBL) pathways following a variety of triggers.quent generation of C5a and the membrane attack complex (MAC). Regulation ofI-mediated cleavage of C3b) exhibited by CFH, MCP and CR1 (ii) decay-acceleratingAC by CD59. Ag, antigen; Ab, antibody; MASP, Manose associated serine protease;rotein; CR1 complement receptor-1; CFB, complement factor B; CFD, complement

S. Johnson, A. Waters / Immunobi

Table 1Summary of clinical outcome in patients with aHUS.

Genetic defect Frequency Long-term outcome

CFH 20–30% Rate of death or ESRD: 70–80%CFI 4–10% Rate of death or ESRD: 60–80%CFHR1 & 3 with CFH

autoantibodies6% Rate of death or ESRD: 30–40%

MCP 10–15% Rate of ESRD or death <20%CFB 1–2% Rate of death or ESRD: 70%C3 5–10% Rate of death or ESRD: 60%

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THBD 5% Rate of death or ESRD: 60%

SRD, End Stage Renal Disease.

t al. 2010; Noris et al. 2003; Perez-Caballero et al. 2001; Ponce-astro et al. 2008; Richards et al. 2003; Sellier-Leclerc et al. 2007;enables et al. 2006) and complement activators (complement

actor B, CFB, and C3) (Fremeaux-Bacchi et al. 2008; Goicoecheae Jorge et al. 2007; Roumenina et al. 2009) (Table 1). Mutations

n thrombomodulin (THBD), encoding anticoagulant glycoproteinhich regulates C3b inactivation by CFI were recently identified in

further 6–10% of aHUS cases (Delvaeye et al. 2009). When con-idering a correlation between genotype and clinical phenotype,utations in the C-terminal domain of CFH (within SCR20) are

ssociated with more severe disease. Patients with CFH or THBDutations have been reported to have the earliest onset and high-

st mortality while mutations in membrane-cofactor protein (MCP)end to have a much better outcome (Caprioli et al. 2006; Noris et al.010; Sellier-Leclerc et al. 2007). For a more detailed overview ofhe genetic aetiology of aHUS, the reader is referred to several excel-ent reviews on this topic (Kavanagh and Goodship 2010; Loiratt al. 2008; Noris and Remuzzi 2009).

cquired defects of complement regulation

6–10% of aHUS cases are associated with CFH autoantibodieshich block the C-terminal recognition domain of CFH (Dragon-urey et al. 2005; Jozsi et al. 2007). In most patients these developn a background of CFHR1 and/or CFHR3 deficiency (Jozsi et al.008). A number of patients have clear evidence of infection atnset, including varicella, Escherichia coli 0157, norovirus and upperespiratory tract infection (Dragon-Durey et al. 2011). In addition,ntense abdominal pain, diarrhoea and vomiting are common pre-enting features.

ecent advances in treatment of aHUS

aHUS associated with complement dysregulation has a highorbidity and mortality with progression to end-stage renal dis-

ase occurring in 50% of cases and disease recurrence in up to0% of renal allograft recipients (Caprioli et al. 2006; Sellier-Leclerct al. 2007). Guidelines have recently been proposed for the initialanagement of aHUS (Ariceta et al. 2009), comprising aggres-

ive plasma therapy with the rationale to replace deficient plasmaactors and/or remove mutant complement regulators or auto-ntibodies.

Recent data from animal studies and clinical trials confirm theentrality of complement C5 in the pathogenesis of aHUS and her-ld the introduction of novel therapies. In a mouse model of aHUSecondary to Cfh C-terminal mutation, TMA does not develop inhe absence of C5 (de Jorge et al. 2011). In two landmark clini-al trials, eculizumab (a monoclonal antibody that blocks cleavagef C5) was administered to two groups of patients with aHUS.

lasma therapy was safely withdrawn in 20 patients dependentn chronic plasma therapy, with no relapses (Muus et al. 2010).n 17 patients who experienced TMA exacerbation despite plasmaherapy, eculizumab led to a sustained resolution of haemoylsis

ology 217 (2012) 235– 243 237

and thrombocytopenia within the first week (Legendre et al. 2010).Remarkably, five out of seven dialysis patients became dialysis-free.This exciting data suggests that early eculizumab therapy rapidlystops TMA and restores renal function.

Role of complement in EC homeostasis and activation

It is important to consider how complement dysregulation leadsto TMA. All three complement pathways have been implicatedin EC activation (Heinen et al. 2007; Megyeri et al. 2009; Zhanget al. 2007). The products of the terminal complement pathway(C5a and C5b–9) have direct effects on ECs. Human umbilical veinendothelial cells (HUVEC) stimulated with C5a show progressiveincreases in gene expression for cell adhesion molecules (e.g. E-selectin, ICAM-1, VCAM-1), cytokines and chemokines (ENA-78,GRO, IL-1�, IL-6, IL-8, MCP-1, RANTES) in addition to angiogenicgrowth factors (PIGF, VEGFC) (Albrecht et al. 2004; Brunn et al.2006; Fosbrink et al. 2006; Skeie et al. 2010). C5a also promotesmigration, proliferation and angiogenesis in HMEC (Kurihara et al.,2010). C5b–9 can cause cell death by lysis, however in sub-lyticdoses can activate signaling pathways involved in cell cycle regu-lation and survival (Niculescu and Rus 2001). For example, C5b–9stimulation of aortic ECs induces EC proliferation and migration viaphosphatidylinositol 3-kinase signaling (Fosbrink et al. 2006).

Recent studies have shown a critical role for DAF in down-regulating the response to vascular injury, mediated via C3aand C5a (Sakuma et al., 2010). Following vascular injury, leuko-cyte recruitment, cellular proliferation and neointimal thickeningwere enhanced in Daf−/− mice versus wild-type controls, whiledeficiency of either the C3a or the C5a receptor reversed thesefindings. Interestingly, treatment of ECs with VEGF (vascularendothelial growth factor) upregulates DAF expression and reducescomplement-mediated EC lysis (Mason et al. 2004). ECs mayrequire autocrine VEGF secretion (Lee et al. 2007) and inhibitionof VEGF has recently been implicated in the pathogenesis of TMA(Eremina et al. 2008; Sison et al. 2010). Therefore, it is plausiblethat EC injury by a range of injurious agents, leads to reducedautocrine VEGF production, secondary DAF deficiency and furthercomplement-mediated EC injury. In support of this, serum deficientfor ADAMTS-13 (an enzyme which cleaves von Willebrand Fac-tor and is deficient in Thrombotic Thrombocytopenic Purpura, alsocharacterized by TMA) leads to C3 and C5b–9 deposition on humanmicrovascular endothelial cells (HMEC), promoting EC cytotoxicity(Ruiz-Torres et al. 2005). If this proves to be true, therapeutic com-plement inhibition may be effective in treating TMA from a varietyof causes.

Infection-induced HUS

Bacteria commonly associated with HUS include enterohaem-orrhagic E. coli (EHEC), Shigella dysenteriae and Streptococcuspneumoniae. Other bacteria less frequently associated includeGroup A beta-hemolytic streptococcus (GABS), Bordetella Pertus-sis, Coxiella burnetii and Fusobacterium necrophorum. There arealso reports of HUS in the context of viral illnesses illness(Constantinescu et al. 2004). Viruses that have been associated withthe development of HUS include Influenza A (Asaka et al. 2000;Watanabe 2001) (including H1N1) (Bento et al. 2010; Caltik et al.2011; Golubovic et al. 2011; Printza et al. 2011; Trachtman et al.2011), Human Immunodeficiency Virus (HIV) (Benjamin et al. 2009;Gomes et al. 2009; Hartel et al. 2007), Dengue fever (Wiersinga et al.

2006), Epstein Barr Virus (Watanabe et al. 2004), Human HerpesVirus 6 (Matsuda et al. 1999), Hepatitis C (Baid et al. 1999), Cox-sackie A & B (Austin and Ray 1973; Glasgow and Balduzzi 1965),and Parvovirus B-19.

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Complement dysregulation is a clear cause of HUS, and it isherefore plausible that in the context of infection-induced HUS,athogen-mediated complement activation plays a role in EC

njury. Evidence to support this hypothesis is explored below.

higa-toxin induced HUS (Stx-HUS)

Shiga toxin (Stx) producing enteric pathogens such as EHECnd S. dysenteriae account for over 90% of childhood HUS casesLynn et al. 2005). About 10–15% of those infected develop HUS,fter a prodrome of abdominal pain and bloody diarrhoea (Tarrt al. 2005). In general, the majority of cases recover, but chronicenal impairment, hypertension and proteinuria occur (Garg et al.003). Most cases are caused by serotype E. coli O157:H7, however

n recent weeks there has been a large outbreak (3222 cases) of. coli O104:H4 in Northern Germany, with 810 cases of HUS (25%f infected patients, much higher than usual) (Frank et al. 2011).9% of those with HUS were adults, in contrast to the paediatricredominance of HUS with O157. Many patients required intensiveare support and 3.3% of those who developed HUS died.

athogenesis of Stx-induced HUS (Stx-HUS)

The development of Stx-HUS has been attributed to a directffect of Stx on renal cells. In brief, EHEC attach to the luminalut surface and Stx is translocated into host enterocytes, theneleased and transmitted in polymorphonuclear leukocytes (PMNs)o the target microvascular endothelium (Dean and Kenny 2009).tx binds to globotriaosylceramide (Gb3Cer/CD77), expressed onCs within the glomerulus, brain and pancreas (Zoja et al. 1992), isndocytosed and interferes with ribosomal protein synthesis, ulti-ately leading to cell death (Obrig et al. 1987). Stx may also activate

Cs causing a change to a more procoagulant endothelial cell phe-otype (Matussek et al. 2003; Petruzziello et al. 2009; Zoja et al.002).

Stx also impairs protein synthesis in glomerular mesangial cellsVan Setten et al. 1997), and activates human proximal tubular cellsHughes et al. 1998). Elevated levels of interleukin-8 and tumourecrosis factor, and high PMN counts have been described in chil-ren with Stx-HUS, suggesting that the inflammatory response is

mportant in mediating microvascular injury (Monnens et al. 1974;origi et al. 1995).

ole of complement in Stx-HUS

Low plasma C3 levels were noted in some children withiarrhoea-associated HUS over 30 years ago (Cameron and Vick973; Kaplan et al. 1973; Koster et al. 1978; Monnens et al. 1974,980) and were associated with leukocytosis and severe diseaseRobson et al. 1992). In the HUS SYNSORB Pk study (a clinical trialf an adsorbent agent proposed to reduce Stx absorption fromhe intestine), levels of Bb and sC5b–9 (a form of soluble MAC)ere transiently elevated in children with Stx-HUS compared withealthy controls (Thurman et al. 2009).

Addition of Stx to normal human serum leads to AP activa-ion (Orth et al. 2009), but since unbound Stx is not detectable inhe serum of patients with EHEC infection, it is difficult to inter-ret this finding. In the same study, Stx2 (the Stx-subtype mostrequently associated with HUS) exhibited binding to CFH. Stx2inding was mapped to SCRs6–8 and 18–20 of CFH, both key regionsor surface recognition. Interestingly, Stx2 exhibited stronger bind-ng to the 402Y CFH variant than to 402H (the 402H polymorphism

s strongly associated with age-related macular degeneration).FH–Stx2 retained fluid-phase co-factor activity. However Stx2inding appeared to reduce the cell surface co-factor activity of CFH.hether EHEC exerts some of its pathogenic effects through inhibi-

ology 217 (2012) 235– 243

tion of CFH with subsequent EC surface complement dysregulationrequires further investigation. It would be interesting to determinethe Y402H frequencies in cohorts of patients with Stx-HUS, to ascer-tain whether Stx2–CFH interaction is a significant mechanism in thedevelopment of Stx-HUS.

In mice exposed to Stx2, heterozygous Cfh deficiency did notincrease host susceptibility to Stx-HUS (Paixao-Cavalcante et al.2009). However, both Cfh ± and wild-type mice developed renaltubular injury, not TMA, highlighting that Gb3Cer expression in themouse kidney is predominantly on renal tubular cells (Fujii et al.2005).

A recent study demonstrated the presence of C3 onplatelet–leukocyte complexes in a patient with Stx-HUS (Stahlet al. 2011), and C3, C9 and MAC deposition on blood cell-derivedmicroparticles, particularly those originating from platelets.Patients also exhibited elevated levels of C3a and terminal com-plement complex in plasma. Stx1 and Stx2 have both been shownto cause complement activation and C3 deposition on HMEC underflow conditions (Morigi et al. 2011).

Further evidence for the role of complement in Stx-HUS comesfrom a recent report describing three children with severe Stx-HUS,including rapidly progressive neurological involvement, who weregiven eculizumab (Lapeyraque et al. 2011). All three children exhib-ited a dramatic improvement in neurological status within 24–48 hof the first infusion (alongside normalisation of haematologicalparameters), and were discharged home with normal neurologicalexamination. Following this report, eculizumab was administeredto over 200 patients with severe disease in the recent German out-break, but outcome data is not available at the time of publication(personal communication, Alexion Pharmaceuticals).

Following EC injury by Stx, these data suggest a role for comple-ment in the promotion of blood and endothelial cell activation withsubsequent release of microparticles, cytokines and procoagulantmediators in Stx-HUS.

S. pneumoniae induced HUS

A distinctive form of HUS occurs as a complication of infectionwith S. pneumoniae (Brandt et al. 2002), referred to as pneumo-coccal HUS (pHUS). Over 200 cases have been described, usually inchildren (Bender et al. 2010; Chen et al. 2011; Waters et al. 2007).pHUS follows pneumococcal infection, most frequently pneumo-nia, with empyema occurring in two-thirds of cases (Waters et al.2007), and less commonly following meningitis (Cabrera et al.1998; Eber et al. 1993; Huang and Lin 1998). The incidence appearsto be increasing (Milford et al. 1990; Waters et al. 2007). pHUScarries higher morbidity and mortality than Stx-HUS (Besbas et al.2006; Brandt et al. 2002; Waters et al. 2007), with death usuallyrelated to the complications of pneumococcal infection.

Pathogenesis of pHUS

pHUS is thought to be mediated by bacterial neuraminidase,which removes sialic acid from cell membranes and has beendetected in the serum of patients with pHUS (de Loos et al. 2002;Eber et al. 1993). Cleavage of sialic acid exposes the Thomsen-Friedenreich (T) antigen (Thomsen 1927), which has been detectedon erythrocytes, platelets and endothelium in pHUS (Klein et al.1977). The majority of individuals possess anti-T IgM (Ramasethuand Luban 2001), which are postulated to bind to T and initiate acascade of events leading to TMA (Brandt et al. 2002; Cabrera et al.1998; Copelovitch and Kaplan 2008). It is not clear whether anti-T

cause pHUS since they are cold reactive, and at 37 ◦C cause nei-ther red-cell agglutination nor complement activation (Crookstonet al. 2000; Klein et al. 1977; Moores et al. 1975; Novak et al. 1983;Seges et al. 1981; Williams et al. 1989). Eber described a 4 month

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ld girl with severe pHUS and T exposure in whom anti-T werendetectable throughout the disease (Eber et al. 1993).

ole of complement in pHUS

Cell membrane polyanions, including sialic acid, are crucial forhe regulation of complement activity on cell surfaces. Cells whichctivate the AP in human serum have few sialic acid residuesDurocher et al. 1975) whereas non-activators (e.g. sheep ery-hrocytes) are rich in sialic acids. Neuraminidase converts sheeprythrocytes into AP activators via removal of sialic acid andeduced CFH binding to the cell surface (Fearon 1978; Pangburnt al. 2000), but neuraminidase does not convert human erythro-ytes into AP activators (Pangburn et al. 2000).

Neuraminidase-treated human glomerular endothelial cellsGEC) show deposition of cell surface C3b and MAC after incubationith human serum, but a paradoxical increase in cell surface CFH

Johnson et al. 2009). Some mutant CFH proteins show enhancedinding to GEC, despite reduced cell surface co-factor activityLehtinen et al. 2009). It is tempting to hypothesise that the alter-tion of cell surface polyanions by neuraminidase interrupts therucial trimolecular interaction of CFH, C3b and polyanions, lead-ng to a functional CFH defect on the cell surface. In essence, ancquired form of CFH dysfunction.

Low C3 and C4 levels have been described in the acute phasef pHUS (Johnson et al. 2009). Further studies should examine evi-ence of AP activation in pHUS and clarify the role (if any) of anti-T

n acquired endothelial cell surface complement dysregulation.

roup A beta-hemolytic Streptococcus (GABS) induced HUS

HUS may follow infection with GABS (Bollaert et al. 1989; Izumit al. 2005; Shepherd et al. 2003; Yildiz et al. 2004). Transientypocomplementaemia was noted in one case (Shepherd et al.003). GABS M1 and Fba proteins bind CFH, and this interactionith the complement system may be implicated in pathogenesis.

. pertussis-induced HUS

HUS has been reported following infection with B. pertussisBerner et al. 2002; Chaturvedi et al. 2010; Pela et al. 2006). Aeonate with a possible underlying CFH defect (reduced mobilityn western blot) developed HUS six weeks following B. pertussisnfection (Berner et al. 2002). Two further infants developed non-elapsing HUS following B. pertussis infection without evidence ofnderlying complement defect (Chaturvedi et al. 2010; Pela et al.006). B. pertussis binds the CP regulators C4b-binding proteinnd C1-inhibitor in order to escape complement-mediated killingBerggard et al. 2001). It has recently been shown that B. pertus-is also binds to SCRs19–20 of CFH (Amdahl et al. 2011), thereforeay alter CFH surface complement regulation and contribute to

evelopment of TMA.

. necrophorum bacteremia-induced HUS

F. necrophorum is a Gram-negative anaerobic bacillus that haseen reported in a 19 year old female presenting with non-familialUS (Chand et al. 2001). Hypocomplementaemia was not observed.. necrophorum produces exotoxins that include a lipase that dam-

ges cell membranes, a leukocidin and haemolysin (Duerden 1994;an et al. 1996). Whether any of these factors play a role in theathogenesis of the TMA is speculative and true underlying mech-nisms are unknown.

ology 217 (2012) 235– 243 239

Viral-induced HUS

Influenza AHUS may follow infection with Influenza A (Asaka et al. 2000;

Huang et al. 1998; Watanabe 2001), and a number of cases werereported during the 2009 H1N1 pandemic (Bento et al. 2010; Caltiket al. 2011; Golubovic et al. 2011; Printza et al. 2011; Trachtmanet al. 2011). In H1N1 infected individuals, serum concentrationsof C3a, C4a and C5a were high (Ohta et al. 2011) and C5 protectsagainst H5N1 influenza pathogenesis (Boon et al. 2010), suggestingthat complement plays a major role in regulating the virulence ofinfluenza viruses (Caltik et al. 2011). Influenza A is a neuraminidaseproducing organism but presence or absence of T-activation ininfluenza-induced HUS has not been reported. However, adminis-tration of plasma in one case exacerbated haemolysis, as previouslyreported in pHUS (Cochran et al. 2004). Influenza-induced HUS maybe mediated by neuraminidase in a similar way to pHUS, raising thepossibility of acquired complement dysregulation.

Parvovirus B19-induced HUS

Parvovirus B19 infection has been infrequently associated withHUS (Hartel et al. 2007; Seward et al. 1999). A 34 year old maledeveloped HUS three weeks following presentation with a rashand abdominal pain. Transient hypocomplementaemia was docu-mented and IgM antibodies against parvovirus B19 were detected.The patient recovered fully with supportive management only. Thepresence of hypocomplementaemia indicates a putative role forcomplement in development of TMA.

HIV-associated HUS

TMA has been reported as a manifestation of HIV infection(Fine et al. 2008; Gomes et al. 2009; Ross et al. 2009; Soler-Garciaet al. 2009). The prevalence of TMA appears much reduced inpatients treated with highly active antiretroviral therapies (HAART)(Gervasoni et al. 2002). TMA may result from a direct interactionbetween HIV virions and the renal EC (Huang et al. 2001). Otheraetiologies which have been postulated include development ofanti-ADAMTS13 IgG antibodies (seen in Thrombotic Thrombocy-topenic Purpura) (Hart et al. 2011). Remission of TMA has beenachieved with prompt initiation of HAART in addition to PEX (Hartet al. 2011). A role for complement has not yet been proposed inHIV-associated HUS.

Varicella-associated HUS

HUS may follow infection with varicella zoster virus (VZV)infection (Kwon et al. 2009; Sharman and Goodwin 1980). Onepatient had an underlying MCP mutation, and interestingly, anotherpatient was shown to have anti-CFH antibodies (Kwon et al. 2009).Infection with VZV is known to induce anti-protein S and anti-phospholipid antibodies (Larakeb et al. 2009) and in a similar way,VZV may trigger autoimmunity in patients with a genetic suscep-tibility linked to CFHR1/CFHR3 deletion. Perhaps there is a degreeof cross-reactivity between VZV antigen and CFH protein, but thepresence of CFHR1 and/or 3 protects from anti-CFH antibody for-mation.

The interplay of complement and infection in thedevelopment of HUS

The last case highlights the interplay between genetic sus-ceptibility and a triggering infection in the pathogenesis of HUS.The majority of the case reports above pre-date the discovery ofcomplement dysregulation in HUS, and therefore do not include

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nformation about complement genomics or auto-antibodies. Someatients may have had an underlying genetic susceptibility becausef a complement gene mutation, and the infection provided therigger to express disease. In support of this, the majority of patientsith aHUS due to such mutations have an apparent infective

riggering event (upper respiratory tract infection, fever, flu-likellnesses, gastroenteritis and other infections) at or shortly beforeisease onset (Dragon-Durey et al. 2011). In others, these infec-ions may have triggered the production of anti-CFH antibodiessuch as the VZV report), or in fact auto-antibodies to other com-lement proteins. In some cases, complement dysregulation mayave developed in an as yet unknown pathogen-specific manner. Inrder to understand the relationship between such infections andUS, it is vital that in the future such patients undergo complementene analysis and auto-antibody screening.

onclusion

Recent evidence points to a complex interaction between bothnfectious diseases and the complement system in the pathogen-sis of HUS. Infections are a common trigger for disease onset orelapse in those with genetic complement defects, microbes mayxert some of their pathogenic effects via interaction with comple-ent, and infections may trigger the formation of anti-complement

ntibodies.For the first time, therapeutic complement inhibition shows the

otential to rapidly reverse acute HUS in those with complementysregulation. If complement truly is a culprit in infection-inducedUS, such treatments might offer benefit in severe cases, but fur-

her studies would need to investigate the safety of complementnhibition in the context of infection.

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