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Vaccine 26S (2008) I3–I8

Contents lists available at ScienceDirect

Vaccine

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nherited complement deficiencies and bacterial infections

rancesco Tedesco ∗

epartment of Life Sciences, University of Trieste, via Fleming 22, 34127 Trieste, Italy

r t i c l e i n f o

eywords:omplement

nherited deficienciesiagnosis and vaccination

a b s t r a c t

A wide variety of bacteria are recognized by the complement system through the early components thattrigger the three pathways of complement activation, leading to the release of biologically active productsinvolved in opsonization, recruitment of phagocytes and bacterial killing. Deficiencies of complement

components and regulators provide a model to understand the in vivo role of complement as a defensesystem against bacterial infections. An increased susceptibility to these types of infections is frequentlyseen in individuals with C2, C3, late component, properdin and factor I deficiencies. The identificationof these deficiencies is essential for the adoption of preventive measures aimed to reduce the risk ofbacterial infections. Vaccination represents the treatment of choice to protect these subjects, althoughfurther studies on a large number of C-deficient individuals are needed to prove the protective effect of

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. Introduction

Selective deficiencies of complement (C) components andegulators have been reported in man and animals and representxperiments of nature that provide an ideal tool to assess the inivo role of the complement system. There has been some debaten the past among immunologists on the actual importance of C asdefense system based on the observation that C deficiency maye associated with an apparently healthy life. However, this viewoes not reconcile with the extraordinary evolutionary processhat has led the C system to evolve from a simplified version withnly a few proteins already detected in invertebrates [1] to theighly complex organization achieved in man, with more than 30roteins between components and regulators, and three activationathways [2]. In vitro findings have shown that such a complexystem contributes to host defense against foreign intruders andodifies self-exhibiting multiple functions including opsoniza-

ion, enhancement of phagocytosis, promotion of inflammation,irect lytic effect and regulation of specific response [3]. Animals

ith spontaneous C deficiencies have been used in the past to

valuate the role of C in a wide variety of biological systems in vivo4,5]. However, these animals are available in limited numbersnd the deficiency is restricted to a few system components andegulators. A major advance in elucidating the importance of the

∗ Tel.: +39 040 558 4037; fax: +39 040 558 4023.E-mail address: tedesco@units.it.

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ndividual components and regulators has been made with theeneration of animals depleted of these proteins by homologousecombination knockout gene methodology. C-knockout animalsre now extensively used to establish models of pathological con-itions that resemble human diseases thought to be C-mediated.he advantage of animals generated by gene deletions over thoseith spontaneous C-deficiencies is that appropriate syngeneic

ontrols are readily available. However, though extremely useful,he animal models do not entirely reproduce human diseases thatre often influenced by environmental and genetic factors. Over theast 4 decades, the identification of a large number of individuals

ith C component and regulator deficiencies has contributedubstantially to our understanding of the protective role playedy C in vivo [6,7]. These subjects have mostly been recruitedmong patients with severe bacterial infections and autoimmuneiseases, which are the major clinical manifestations associatedith C deficiencies. This of course may represent an ascertainment

ias because C system function is not screened routinely in patientsith other diseases. However, there is now ample evidence indi-

ating that other pathological conditions can be encountered inatients with C inhibitor and regulator deficiencies, includingereditary angioedema, paroxysmal nocturnal hemoglobinuria,typical hemolytic uremic syndrome, membranoproliferativelomerulonephritis type II and age-related macular degeneration8–10].

This review examines the association of C deficiencies withnfectious diseases vis-à-vis the mechanisms involved in theusceptibility of C-deficient patients to bacterial infections, theiagnostic approach to identify these patients and the measureso prevent the infections.

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. C as a defense system against bacteria

Although C may help to neutralize viruses during the extra-ellular phase of their life cycle, of all infectious agents, bacteriare the preferential target of C system activation products. It isorth remembering that bacteriolysis was the first biological activ-

ty attributed to the C system [11]. To fulfill its protective functionsgainst bacteria, C often cooperates with other humoral and cellu-ar components of both innate and acquired immune systems, butt can also be self-sufficient in that it can both recognize and neu-ralize infectious agents [12,13]. It is not unusual for C to providehe first line of defense against bacteria in the absence of antibodiest extravascular sites, which represent the main portal of entry oficroorganisms and contain a fully organized system synthesized

y macrophages and other cell types [14–16]. The system is able todapt to local needs by increasing the level of locally synthesizedcomponents in response to bacterial products (such as LPS) and

ro-inflammatory cytokines [17]. A major problem encountered byin controlling bacterial infections is represented by the multiple

vasion strategies developed by pathogens to neutralize C attack.The protective function of C starts with the recognition of

icroorganisms by three different molecules, C1q, MBL and C3b,hich, once bound, trigger the activation of the classical, lectin

nd alternative pathways, respectively. This eventually leads to theelease of biologically active products that participate in differentays to the clearance of pathogens. The availability of three differ-

nt molecules to initiate C activation allows the system to recognizelarge variety of bacterial targets using the same effectors for

heir neutralization. C1q may bind to bacteria through antibody-ependent and independent mechanisms [12,18]. Critical factors

n antibody-mediated C1q binding are the class of antibodies andheir distribution on the bacterial surface. The ability to activate Cs restricted to IgM, IgG1 and IgG3 and, in the case of IgG, activa-ion only occurs at a high density of antibody molecules bound toacteria, favoring the assembly of doublet IgG [12].

C1q can also bind directly to bacteria through several moleculartructures including LPS [19], porins [20], and capsular polysac-harides [21]. The ability of bacteria to interact with C1q is alsonfluenced by their surface properties, since rough strains are morefficient than smooth strains in activating C [21].

MBL is another recognition molecule that binds to mannose,-acetyl glucosamine residues and fucose on the surface of bac-

eria and activates the C system through the lectin pathway [22].he latter shares with the classical pathway the formation of the3 convertase C4b2a leading to the activation and deposition of3. Selander and colleagues [23] have provided evidence for thexistence of a bypass mechanism of activation of C3 in the MBL-ediated lectin pathway without the involvement of C2. MBL iscritical molecule involved in first-line host defense and binds

o a wide range of bacteria. Data obtained by Townsend et al.24] suggest that anaerobic bacteria, in particular bacteroides andlostridium that are commonly implicated in clinical disease, bind

ittle or no MBL.Ficolins are members of the collectin family of proteins which

re able to recognize pathogen-associated molecular patterns onicrobial surfaces and trigger the lectin pathway [25–27]. Three

ypes of ficolins have been identified, two of which, L- and H-ficolin,re present in plasma, while M-ficolin is expressed in peripherallood leukocytes and is stored in the secretory granules of the

eukocytes. Like MBL and other collectins, ficolins are able to bind

o a number of gram-positive and gram-negative bacteria by rec-gnizing carbohydrates, and in particular N-acetylglucosamine, onathogens through the carbohydrate-recognition domain.

C3b is the third recognition molecule that binds to microbes andriggers the alternative pathway. Surface properties of the bacteria

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ontrol the binding of C3b and its inactivation by C regulators, pre-luding in this way C activation. An example is represented by theough strain of E. coli J53 that, unlike the smooth strain O111B4,s able to activate the alternative pathway [28,29]. Expression ofialic acid on the bacterial surface may help to prevent alternativeathway activation, as is the case of group B meningococci thatre coated by a sialic acid-enriched capsule [30,31]. It should beentioned that the alternative pathway is often an amplification

athway and may be initiated by C3b deposited on the bacterialurface as a result of C activation through the classical or the lectinathways.

Whatever the mechanism of C activation, if a sufficient num-er of C3b molecules binds to bacteria and is kept in an activetate, the C sequence proceeds to the assembly of the membranettack complex (MAC) C5b-9. This complex can be bactericidal forram-negative bacteria, but has no lytic effect on gram-positiveacteria. There has been some discussion on the strategy used byAC inserted into the outer membrane to reach the inner mem-

rane of the bacteria, since the two membranes are separated byperiplasmic space. One proposed mechanism is that the com-

lex inserts into the outer membrane allowing the penetration ofysozyme that is eventually responsible for bacterial death [32].lternatively, the complex may insert into areas of the outer mem-rane that physically adhere to the inner membrane. There is alsovidence that the killing effect of MAC is associated with alteredacterial metabolism [33].

C contributes to bacterial clearance by promoting phagocyto-is as a result of the interaction of bound C3b and C3bi with thereceptors CD35 and CD11/CD18b expressed on phagocytes. Two

ignals are required for the engulfment of bacteria bearing C3b and3bi by phagocytic cells. The most efficient second signal is repre-ented by bound IgG, but LPS, cytokines and other factors may alsoelp C3b and C3bi to enhance phagocytosis of bacteria.

Most pathogenic microorganisms, and in particular those thatirculate in the blood stream, develop a wide range of strategieso elude host immune defense, including evasion of C activationnd/or C attack. Pathogens may inhibit C activation by acquiring Control proteins from the host [34] or by expressing molecules thatimic mammalian C regulatory proteins [35]. Moreover, microor-

anisms can prevent access of cytolytic MAC to the outer membranend block its destructive effect by producing thick walls of pep-idoglycan or capsules or by expressing other outer membraneonstituents that form a protective shield against C attack. Theelease of LPS from the cell surface or the expression of LPS withong side chains on the outer membrane may favor the activationf C at some distance from the outer membrane of bacteria, whichecome less vulnerable to C attack [36].

. Frequency of C deficiencies

Screening of the general population for C deficiency in Westernountries and Japan has shown that this is a rare condition withn estimated frequency of approximately 0.03%. The most frequents MBL deficiency with approximately one-third of the Caucasianopulation possessing genotypes that confer low levels of this pro-ein and about 5% with very low level, since no absolute level of

BL deficiency has been defined [22]. The deficiency results fromoint mutations within exon 1 of MBL-2 gene at codons 52, 54 and7, while point mutations in the promoter region at position −550nd −221 result in lower MBL level. Despite the high frequency

f MBL deficiency, the majority of individuals with this defect areealthy [37]. Less common is C2 deficiency that has a prevalence ofbout 5 every 100,000 persons in Western Countries based on thevaluation of the frequency of heterozygous carriers in the generalopulation [38]. A special case is C9 deficiency, which is relatively

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ommon in Japan reaching an incidence of 0.095% [39], and is easilyetected in blood donors.

The relatively low frequency of C deficiencies makes the eval-ation of their association with bacterial infections in the generalopulation rather difficult. An alternative approach would be tonalyse the frequency and the type of infections in individuals withnown C deficiencies that have been identified in increasing num-er in several laboratories. The major limitation of this approach ishat recruitment of patients may suffer from a selection bias since Cnalysis is performed almost exclusively on patients with autoim-une and infectious diseases. With this caveat in mind, a picture

s emerging that identifies bacterial infections as one of the mainlinical manifestations associated with deficiency of some C com-onents and regulators. Data obtained from a large survey of the

iterature [6,7] suggest that a large number of individuals with Component and regulator deficiencies develop bacterial infections,hough with a different frequency, with the exception of patientsith C1-inhibitor, CD46, CD55 and CD59 deficiencies. However, the

ncidence of bacterial infections is relatively low in patients lack-ng the early components, who usually suffer from autoimmuneiseases, and become substantial in patients with C2 deficiency,rimary and secondary defects of C3 and also in individuals with

ate C component deficiencies (LCCD).

. Clinical presentation

Examination of the cause of infections in patients with C defi-iencies reveals a marked prevalence of bacteria as causativegents and only a trivial contribution of viruses and fungi. A moreetailed analysis of the strains of bacteria responsible for the

nfections shows that the infectious agents causing the disease inatients with deficiencies of the early components are heteroge-eous (Table 1). The incidence of infections is low in patients with1q, C1r, C1s, and C4 deficiencies that are instead more frequentlyssociated with SLE and SLE-like disease (Fig. 1). Conversely, theseiseases occur less frequently in C2 deficient individuals, who areften healthy but on the whole more susceptible to bacterial infec-ions. Jönsson and colleagues have recently surveyed a group of 402 deficient Swedish patients and reported data indicating that 57%f them experienced invasive infections represented mainly by sep-icemia and meningitis caused by Streptococcus pneumoniae [40].n a case-control study carried out by Roy et al. [41] on patients

ith pneumococcal disease and a control group of healthy sub-ects, MBL deficiency was found to be significantly associated withneumococcal infections.

Streptococcus pneumoniae and Neisseria are the most frequentauses of infections in patients with primary and secondary C3eficiency, although H. influenzae has also been found to be respon-ible for infections in these patients, though less frequently. Unlike

able 1trains of bacteria responsible for infections in patients with inherited C deficiencies.

eficient components Strains of bacteria Frequency %

1, C4, C2 Neisseria 6S. pneumonite 17H. influenzae 3S. aureus 2

3, H, I Neisseria 28S. pneumonite 28H. influenzae 4S. aureus 0

5, C6, C7, C8 Neisseria 66S. pneumonite 1H. influenzae 0S. aureus 0

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ig. 1. Frequency of infections (open columns), autoimmune diseases (blackolumns) and combination of the two clinical conditions (grey columns) in patientsith inherited C deficiencies.

2 and MBL deficient subjects, very few C3 deficient patients areealthy and the great majority suffers from repeated infections,utoimmune diseases, or both. This can be explained by the impor-ant role played by C3 in promoting phagocytosis and bactericidalctivity as well as in the regulation of the immune response.

A special situation is encountered in patients with properdineficiency and LCCD, who are highly susceptible to Neisserial infec-ions caused mainly by Neisseria meningitidis (Fig. 2). This is not dueo bias in the selection of patients because screening of C activity inatients undergoing infection by a variety of bacteria did not revealsignificant increase of properdin deficiency or LCCD associatedith infections caused by bacteria other than meningococci. The

isk of contracting meningococcal disease in properdin deficientatients has been estimated to be 250 higher than that of the gen-ral population [42] and is 5–10,000 higher in patients with LCCD43].

Meningococcal disease has often a fulminant course in prop-rdin deficient patients, while it is characterized by frequentelapses and recurrences of infection in LCCD patients. In bothroups of deficient patients, the infection tends to occur for therst time in adolescence whereas the age of the first episode inhe general population is about 2–3 years. In addition, the diseases frequently caused by uncommon meningococcal serogroups, inarticular groups Y and W-135, and to a lesser extent X [7,42]. The

ontribution of common serotypes that more frequently infect theeneral population. Patients with LCCD and meningococcal dis-

ig. 2. Frequency of Neisserial infections in patients with inherited C deficiencies.

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ase identified in an Italian survey were all found to be infectedy serogroup C N. meningitidis [44]. Platonov et al. [45] made aimilar observation showing that among 30 Russian LCCD patientsith meningococcal disease, the common serogroups (A, B, and) caused infection in 15 out of 18 patients in whom the Neisseriaeningitidis serogroups were identified.

Despite the high frequency of relapses and recurrences, a dis-inct feature of meningococcal disease in LCCD patients is the low

ortality rate, which has been explained with the mild coursef the disease in these patients. Septic complications includingurpura, disseminated intravascular coagulation, shock and braindema are more frequently observed in C-sufficient than in LCCDatients [45,46], suggesting that MAC contributes directly throughascular and pro-coagulant effects, or indirectly through induc-ng meningococci to release endotoxins known to exert similarffects. The plasma concentration of SC5b-9 (terminal complementomplex) in patients with meningococcal disease was found byrandtzaeg et al. [47] to strongly correlate with the level of endo-oxin, and both SC5b-9 and endotoxin levels were inversely relatedo patients’ survival. Lehner et al. [48] provided further supporto this concept, reporting the case of a C6 deficient patient whoeveloped shock and a detectable level of endotoxin followingransfusion with fresh frozen plasma to treat severe complicationsf meningococcal disease.

An important biological effect of sublytic MAC is to promotenflammation through the stimulation of several cell types involvedn this process, including phagocytes and endothelial cells.

Phagocytes stimulated by sublytic MAC may promote inflam-ation by producing reactive oxygen metabolites [49,50] and also

roinflammatory cytokines [50].Endothelial cells lining the microvascular vessels are often

xposed and activated by MAC that can be formed both in the cir-ulation and in the extravascular fluid as a result of C activation51,52]. Insertion of sublytic MAC in the membrane of endothelialells has been shown to induce the expression of P-selectin [53],o enhance TNF-dependent surface appearance of E-selectin andCAM-1 [54], and to stimulate the release of chemokines [55] andlatelet-activating factor [56]. Sublytic MAC may also have a pro-oagulant effect through various mechanisms, including releasef von Willebrand Factor [53], shedding of membrane vesicles orxposure of membrane phospholipids that promote the assemblyf prothrombinase [57] and surface expression of tissue factor [58].ost of these effects are not a direct consequence of the action

f C on the endothelial cells (EC), but are a secondary responsehat requires, as an intermediate step, the release of Interleukin 1lpha (IL-1�), an early product of the EC response to C activation.onversely, MAC seems to exert a direct effect on the release ofhe vasoconstrictor agent tromboxane A2 [59] and the vasodilatorrostaglandin I2 by EC [60]. The terminal C complex can also bindo endothelial cells in a cytolytically inactive form, and stimulatesells to express adhesion molecules and tissue factor procoagu-ant activity [61]. In addition, the inactive complex has been showno induce secretion of IL-8 and MCP-1 and to cause migration ofolymorphonuclear leukocytes through a monolayer of endothelialells both in vitro and in vivo [62].

. Diagnosis of C deficiencies

Given the high frequency of infections caused by encapsulated

acteria in individuals with deficiency of some C components andegulators, an issue that is still open to discussion is whether allatients with infectious diseases should be screened for C deficien-ies considering that these defects are rather uncommon. There iso doubt that the evaluation of C activity through the assessment

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f the three pathways of C activation may help to identify addi-ional patients with these deficiencies and their relatives who maye at risk of infection, and to establish an appropriate preventionhrough vaccination. Unfortunately, the standard tests available in

ost centralized laboratories are restricted to the immunochemicalvaluation of C4 and C3, while hemolytic assays are only performedn a few laboratories. With the development of novel immunoenzy-

atic assays to measure the activity of the classical, alternative andectin C pathways as a result of a concerted European action [63], thecreening assays are now easily available to all routine laboratories.urther work to identify the missing or dysfunctional C componentsr regulators and the molecular basis of the defect remains the taskf specialized laboratories, which are also in charge of performingamily counseling.

It is now generally agreed that patients undergoing repeatedpisodes of meningococcal disease should be studied for C systemunction, particularly when the first episode occurs in the mid-teeneriod. Whether C should be analyzed in patients with sporadicpisodes of the disease is still a matter of debate. Screening ofatients with meningococcal disease for C deficiency has revealedlear difference in the prevalence of LCCD among patients with spo-adic disease in different geographic area. Rasmussen et al. [64]xamined 47 patients with sporadic infections and failed to detectabnormalities. On the other hand, Zimran et al. [65] in Israel

eported an incidence of 7% in their study group, suggesting thathe different ethnic background of the patients may account forhese contrasting results. Further evidence supporting this conclu-ion was provided by the results of a collaborative survey performedome years ago in Italy [44], showing the occurrence of LCCD in 8% ofatients with sporadic episodes of meningitis. These data suggesthat the incidence of these deficiencies is relatively high in peo-le living in the Mediterranean area who should be considered atisk for meningococcal disease caused by common meningococcalerogroups.

. Management of infections in C deficient patients

Vaccination is highly recommended in patients with C defi-iency to avoid the risk of severe bacterial infections. Individualsacking the early C components, in particular C2 and C3, shoulde protected against infections caused by encapsulated pyogenicacteria using conjugated H. influenzae, pneumococcal and tetrava-

ent meningococcal vaccines. One of the problems that one mayncounter in these patients is that the antibody response is lower,ased on the observation that the IgG2 and IgG4 level is reduced

n individuals with classical pathway and C3 deficiencies [66].owever, despite the findings that the antibodies directed againstolysaccharides mostly belong to IgG2 subclass, no evidence waseported by Alper et al. [67] for a correlation between IgG sub-lass concentration and susceptibility to infections in C2 deficientatients. The overall aim was to promote activation of the alterna-ive pathway that has been shown to be triggered by IgA and IgG2ntibodies [68] or even to proceed through the classical pathwayypassing C2 [69].

As properdin-deficient and LCCD individuals are highly sus-eptible to meningococcal disease, vaccination with tetravalenteningococcal vaccine is highly recommended. Properdin-

eficient patients have been shown to mount an antibody responseollowing vaccination sufficient to kill meningocci [70,71].

Data obtained by several groups suggest that LCDD patients

espond reasonably well to tetravalent meningococcal vaccine72–76], and that the antibody response was also associated withn increased bactericidal and opsonophagocytic activity. It is stillnclear why LCCD patients experience recurrent infections despitehe fact that they generate antibodies to outer membrane pro-

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eins [77,78] and to capsular polysaccharide [76] following naturalnfection. One possible explanation is that these antibodies do notustain adequate clearance of meningococci by phagocytes. It islso possible that infected LCCD patients bear an Fc�RIIa recep-or allotype on phagocytic cells that binds IgG2 antibodies poorly79]. There is general agreement that phagocytic killing is a reli-ble indicator of protection against meningococcal disease since theevel of antibodies to capsular polysaccharide in vaccinated patientsoes not always correlate with post-vaccination opsonophagocyticctivity [73,75]. A follow-up study of LCCD patients immunizedith the tetravalent capsular polysaccharide showed that patientsere disease free for 3.5 years after vaccination [75]. A problem

hat needs to be solved in these patients is to find a way to protecthem from infections caused by serogroup B meningococci. A goodandidate is the outer membrane vesicle vaccine containing a neis-erial antigen prepared as a recombinant protein that was recentlyhown by Plested and Granoff [80] to induce a good response inerms of bactericidal as well as opsonophagocytic activity.

Further studies on a large number of LCCD and properdin defi-ient individuals are needed to evaluate the protective effect ofaccination against meningococci and its duration, as well as theest way to monitor this effect in terms of level, specificity, andunction of antibodies produced in response to the vaccine. To thisnd, a registry of C deficient subjects has been organized in therame of a European concerted action which already contains overwo hundreds cases and needs to be implemented.

cknowledgements

The support by the Italian Ministry of Education, University andesearch (PRIN 2007 H9AWXY 003) and by the region of LombardySan Matteo General Hospital) is gratefully acknowledged.

Conflict of interest statement: The author declares no conflict ofnterest with people or organizations that could inappropriatelyave influenced his work.

eferences

[1] Nonaka M. Phylogeny of the complement system. In: Volanakis JE, Frank MM,editors. The human complement system in health and disease. New York: Mar-cel Dekker; 1998. p. 203–15.

[2] Volanakis JE. Overview of the complement system. In: Volanakis JE, Frank MM,editors. The human complement system in health and disease. New York: Mar-cel Dekker; 1998. p. 9–32.

[3] Walport MJ, Complement. First of two parts. N Engl J Med 2001;344(14):1058–66.

[4] Linton S. Animal models of inherited complement deficiency. Mol Biotechnol2001;18(2):135–48.

[5] Rother K. Complement deficiencies in animals: impact on biological functions.In: Rother K, Till GOGMH, editors. The complement system. Berlin: Springer;1998. p. 343–50.

[6] Figueroa JE, Densen P. Infectious diseases associated with complement defi-ciencies. Clin Microbiol Rev 1991;4(3):359–95.

[7] Ross SC, Densen P. Complement deficiency states and infection: epidemiology,pathogenesis and consequences of neisserial and other infections in an immunedeficiency. Medicine (Baltimore) 1984;63(5):243–73.

[8] Davis 3rd AE. The pathophysiology of hereditary angioedema. Clin Immunol2005;114(1):3–9.

[9] Luzzatto L, Gianfaldoni G. Recent advances in biological and clinical aspects ofparoxysmal nocturnal hemoglobinuria. Int J Hematol 2006;84(2):104–12.

10] Zipfel PF, Heinen S, Jozsi M, Skerka C. Complement and diseases: defectivealternative pathway control results in kidney and eye diseases. Mol Immunol2006;43(1–2):97–106.

11] Buchner H. Über die nähere Natur der bakerientötenden Substanzen in Blut-serum. Zentralbl Bakteriol 1889;6:561–5.

12] Hänsch GM. Host defense against infection. Defense against bacteria. In: RotherK, Till GO, Hänsch GM, editors. The complement system. Berlin: Springer; 1998.

13] Petry F, Loos M. Bacteria and complement. In: Volanakis JE, Frank MM, edi-tors. The human complement system in health and disease. New York: MarcelDekker; 1998. p. 375–91.

14] Johnson E, Hetland G. Mononuclear phagocytes have the potential to syn-thesize the complete functional complement system. Scand J Immunol1988;27(5):489–93.

[

[

S (2008) I3–I8 I7

15] Langeggen H, Pausa M, Johnson E, Casarsa C, Tedesco F. The endothelium is anextrahepatic site of synthesis of the seventh component of the complementsystem. Clin Exp Immunol 2000;121(1):69–76.

16] Morgan BP, Gasque P. Extrahepatic complement biosynthesis: where, when andwhy? Clin Exp Immunol 1997;107(1):1–7.

17] Colten HR, Garnier G. Regulation of complement protein gene expression. In:Volanakis JE, Frank MM, editors. The human complement system in health anddisease. New York: Marcel Dekker; 1998. p. 217–40.

18] Clas F, Loos M. Antibody-independent binding of the first component of com-plement (C1) and its subcomponent C1q to the S and R forms of Salmonellaminnesota. Infect Immun 1981;31(3):1138–44.

19] Loos M, Bitter-Suermann D, Dierich M. Interaction of the first (C1), thesecond (C2) and the fourth (C4) component of complement with differentpreparations of bacterial lipopolysaccharides and with lipid A. J Immunol1974;112(3):935–40.

20] Galdiero F, Tufano MA, Sommese L, Folgore A, Tedesco F. Activation of comple-ment system by porins extracted from Salmonella typhimurium. Infect Immun1984;46(2):559–63.

21] Levy NJ, Kasper DL. Surface-bound capsular polysaccharide of type Ia group BStreptococcus mediates C1 binding and activation of the classic complementpathway. J Immunol 1986;136(11):4157–62.

22] Dommett RM, Klein N, Turner MW. Mannose-binding lectin in innate immu-nity: past, present and future. Tissue Antigens 2006;68(3):193–209.

23] Selander B, Martensson U, Weintraub A, Holmstrom E, Matsushita M, ThielS, et al. Mannan-binding lectin activates C3 and the alternative complementpathway without involvement of C2. J Clin Invest 2006;116(5):1425–34.

24] Townsend R, Read RC, Turner MW, Klein NJ, Jack DL. Differential recognitionof obligate anaerobic bacteria by human mannose-binding lectin. Clin ExpImmunol 2001;124(2):223–8.

25] Matsushita M, Fujita T. The role of ficolins in innate immunity. Immunobiology2002;205(4–5):490–7.

26] Runza VL, Schwaeble W, Mannel DN. Ficolins: novel pattern recognitionmolecules of the innate immune response. Immunobiology 2008;213(3–4):297–306.

27] Thiel S. Complement activating soluble pattern recognition molecules withcollagen-like regions, mannan-binding lectin, ficolins and associated proteins.Mol Immunol 2007;44(16):3875–88.

28] Joiner KA. Studies on the mechanism of bacterial resistance to complement-mediated killing and on the mechanism of action of bactericidal antibody. CurrTop Microbiol Immunol 1985;121:99–133.

29] Rottini GD, Cian F, Tedesco F, de Nicola G, Patriarca P. Effect of antibodies andcomplement on the interaction between Escherichia coli 0111:B4 and polymor-phonuclear leukocytes. Infection 1979;7(4):160–5.

30] Jarvis GA, Vedros NA. Sialic acid of group B Neisseria meningitidis regulatesalternative complement pathway activation. Infect Immun 1987;55(1):174–80.

31] Vogel U, Hammerschmidt S, Frosch M. Sialic acids of both the capsule and thesialylated lipooligosaccharide of Neisseria meningitis serogroup B are prerequi-sites for virulence of meningococci in the infant rat. Med Microbiol Immunol1996;185(2):81–7.

32] Feingold DS, Goldman JN, Kuritz HM. Locus of the action of serum and the roleof lysozyme in the serum bactericidal reaction. J Bacteriol 1968;96(6):2118–26.

33] Kroll HP, Bhakdi S, Taylor PW. Membrane changes induced by exposure ofEscherichia coli to human serum. Infect Immun 1983;42(3):1055–66.

34] Zipfel PF, Wurzner R, Skerka C. Complement evasion of pathogens: commonstrategies are shared by diverse organisms. Mol Immunol 2007;44(16):3850–7.

35] Pausa M, Pellis V, Cinco M, Giulianini PG, Presani G, Perticarari S, et al.Serum-resistant strains of Borrelia burgdorferi evade complement-mediatedkilling by expressing a CD59-like complement inhibitory molecule. J Immunol2003;170(6):3214–22.

36] Joiner KA. Complement evasion by bacteria and parasites. Annu Rev Microbiol1988;42:201–30.

37] Dahl M, Tybjaerg-Hansen A, Schnohr P, Nordestgaard BG. A population-basedstudy of morbidity and mortality in mannose-binding lectin deficiency. J ExpMed 2004;199(10):1391–9.

38] Pickering MC, Botto M, Taylor PR, Lachmann PJ, Walport MJ. Systemiclupus erythematosus, complement deficiency, and apoptosis. Adv Immunol2000;76:227–324.

39] Inai S, Kitamura H, Hiramatsu S, Nagaki K. Deficiency of the ninth componentof complement in man. J Clin Lab Immunol 1979;2(1):85–7.

40] Jonsson G, Truedsson L, Sturfelt G, Oxelius VA, Braconier JH, SjoholmAG. Hereditary C2 deficiency in Sweden: frequent occurrence of inva-sive infection, atherosclerosis, and rheumatic disease. Medicine (Baltimore)2005;84(1):23–34.

41] Roy S, Knox K, Segal S, Griffiths D, Moore CE, Welsh KI, et al. MBL geno-type and risk of invasive pneumococcal disease: a case-control study. Lancet2002;359(9317):1569–73.

42] Fijen CA, van den Bogaard R, Schipper M, Mannens M, Schlesinger M, NordinFG, et al. Properdin deficiency: molecular basis and disease association. MolImmunol 1999;36(13–14):863–7.

43] Densen P. Complement deficiencies and infections. In: Volanakis JE, Frank MM,editors. The human complement system in health and disease. New York: Mar-cel Dekker; 1998. p. 409–21.

44] D’Amelio R, Agostoni A, Biselli R, Brai M, Caruso G, Cicardi M, et al. Complementdeficiency and antibody profile in survivors of meningococcal meningitis dueto common serogroups in Italy. Scand J Immunol 1992;35(5):589–95.

I ine 26

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[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

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[

[

[

[

[

[

[

[

[

[

[

[

[79] Fijen CA, Bredius RG, Kuijper EJ, Out TA, De Haas M, De Wit AP, et al. The role

8 F. Tedesco / Vacc

45] Platonov AE, Beloborodov VB, Vershinina IV. Meningococcal disease in patientswith late complement component deficiency: studies in the U.S.S.R. Medicine(Baltimore) 1993;72(6):374–92.

46] Tedesco F, Nurnberger W, Perissutti S. Inherited deficiencies of the terminalcomplement components. Int Rev Immunol 1993;10(1):51–64.

47] Brandtzaeg P, Mollnes TE, Kierulf P. Complement activation and endotoxin lev-els in systemic meningococcal disease. J Infect Dis 1989;160(1):58–65.

48] Lehner PJ, Davies KA, Walport MJ, Cope AP, Wurzner R, Orren A, et al. Meningo-coccal septicaemia in a C6-deficient patient and effects of plasma transfusionon lipopolysaccharide release. Lancet 1992;340(8832):1379–81.

49] Morgan BP, Campbell AK. The recovery of human polymorphonuclear leuco-cytes from sublytic complement attack is mediated by changes in intracellularfree calcium. Biochem J 1985;231(1):205–8.

50] Hänsch GM, Seitz M, Betz M. Effect of the late complement components C5b-9on human monocytes: release of prostanoids, oxygen radicals and of a fac-tor inducing cell proliferation. Int Arch Allergy Appl Immunol 1987;82(3–4):317–20.

51] Saadi S, Platt JL. Immunology of xenotransplantation. Life Sci 1998;62(5):365–87.

52] Tedesco F, Fischetti F, Pausa M, Dobrina A, Sim RB, Daha MR. Complement-endothelial cell interactions: pathophysiological implications. Mol Immunol1999;36(4–5):261–8.

53] Hattori R, Hamilton KK, McEver RP, Sims PJ. Complement proteins C5b-9 inducesecretion of high molecular weight multimers of endothelial von Willebrandfactor and translocation of granule membrane protein GMP-140 to the cellsurface. J Biol Chem 1989;264(15):9053–60.

54] Kilgore KS, Shen JP, Miller BF, Ward PA, Warren JS. Enhancement by the com-plement membrane attack complex of tumor necrosis factor-alpha-inducedendothelial cell expression of E-selectin and ICAM-1. J Immunol 1995;155(3):1434–41.

55] Kilgore KS, Flory CM, Miller BF, Evans VM, Warren JS. The membrane attackcomplex of complement induces interleukin-8 and monocyte chemoattractantprotein-1 secretion from human umbilical vein endothelial cells. Am J Pathol1996;149(3):953–61.

56] Benzaquen LR, Nicholson-Weller A, Halperin JA. Terminal complement proteinsC5b-9 release basic fibroblast growth factor and platelet-derived growth factorfrom endothelial cells. J Exp Med 1994;179(3):985–92.

57] Hamilton KK, Hattori R, Esmon CT, Sims PJ. Complement proteins C5b-9induce vesiculation of the endothelial plasma membrane and expose catalyticsurface for assembly of the prothrombinase enzyme complex. J Biol Chem1990;265(7):3809–14.

58] Saadi S, Holzknecht RA, Patte CP, Stern DM, Platt JL. Complement-mediated reg-ulation of tissue factor activity in endothelium. J Exp Med 1995;182(6):1807–14.

59] Bustos M, Coffman TM, Saadi S, Platt JL. Modulation of eicosanoid metabolismin endothelial cells in a xenograft model. Role of cyclooxygenase-2. J Clin Invest1997;100(5):1150–8.

60] Suttorp N, Seeger W, Zinsky S, Bhakdi S. Complement complex C5b-8 inducesPGI2 formation in cultured endothelial cells. Am J Physiol 1987;253(1 Pt1):C13–21.

61] Tedesco F, Pausa M, Nardon E, Introna M, Mantovani A, Dobrina A. The cytolyt-ically inactive terminal complement complex activates endothelial cells toexpress adhesion molecules and tissue factor procoagulant activity. J Exp Med1997;185(9):1619–27.

62] Dobrina A, Pausa M, Fischetti F, Bulla R, Vecile E, Ferrero E, et al. Cytolytically

inactive terminal complement complex causes transendothelial migration ofpolymorphonuclear leukocytes in vitro and in vivo. Blood 2002;99(1):185–92.

63] Seelen MA, Roos A, Wieslander J, Mollnes TE, Sjoholm AG, Wurzner R, et al.Functional analysis of the classical, alternative, and MBL pathways of the com-plement system: standardization and validation of a simple ELISA. J ImmunolMethods 2005;296(1–2):187–98.

[

S (2008) I3–I8

64] Rasmussen JM, Brandslund I, Teisner B, Isager H, Svehag SE, Maarup L, et al.Screening for complement deficiencies in unselected patients with meningitis.Clin Exp Immunol 1987;68(2):437–45.

65] Zimran A, Rudensky B, Kramer MR, Tedesco F, Ehrenfeld M, Raz R, et al.Hereditary complement deficiency in survivors of meningococcal disease:high prevalence of C7/C8 deficiency in Sephardic (Moroccan) Jews. Q J Med1987;63(240):349–58.

66] Bird P, Lachmann PJ. The regulation of IgG subclass production in man: lowserum IgG4 in inherited deficiencies of the classical pathway of C3 activation.Eur J Immunol 1988;18(8):1217–22.

67] Alper CA, Xu J, Cosmopoulos K, Dolinski B, Stein R, Uko G, et al. Immunoglobulindeficiencies and susceptibility to infection among homozygotes and heterozy-gotes for C2 deficiency. J Clin Immunol 2003;23(4):297–305.

68] Selander B, Kayhty H, Wedege E, Holmstrom E, Truedsson L, Soderstrom C,et al. Vaccination responses to capsular polysaccharides of Neisseria meningi-tidis and Haemophilus influenzae type b in two C2-deficient sisters: alternativepathway-mediated bacterial killing and evidence for a novel type of blockingIgG. J Clin Immunol 2000;20(2):138–49.

69] Knutzen Steuer KL, Sloan LB, Oglesby TJ, Farries TC, Nickells MW, Densen P, etal. Lysis of sensitized sheep erythrocytes in human sera deficient in the secondcomponent of complement. J Immunol 1989;143(7):2256–61.

70] Densen P, Weiler JM, Griffiss JM, Hoffmann LG. Familial properdin deficiencyand fatal meningococcemia. Correction of the bactericidal defect by vaccina-tion. N Engl J Med 1987;316(15):922–6.

71] Soderstrom C, Braconier JH, Danielsson D, Sjoholm AG. Bactericidal activityfor Neisseria meningitidis in properdin-deficient sera. J Infect Dis 1987;156(1):107–12.

72] Andreoni J, Kayhty H, Densen P. Vaccination and the role of capsularpolysaccharide antibody in prevention of recurrent meningococcal disease inlate complement component-deficient individuals. J Infect Dis 1993;168(1):227–31.

73] Schlesinger M, Greenberg R, Levy J, Kayhty H, Levy R. Killing of meningococciby neutrophils: effect of vaccination on patients with complement deficiency.J Infect Dis 1994;170(2):449–53.

74] Platonov AE, Beloborodov VB, Pavlova LI, Vershinina IV, Kayhty H. Vaccination ofpatients deficient in a late complement component with tetravalent meningo-coccal capsular polysaccharide vaccine. Clin Exp Immunol 1995;100(1):32–9.

75] Fijen CA, Kuijper EJ, Drogari-Apiranthitou M, Van Leeuwen Y, Daha MR, DankertJ. Protection against meningococcal serogroup ACYW disease in complement-deficient individuals vaccinated with the tetravalent meningococcal capsularpolysaccharide vaccine. Clin Exp Immunol 1998;114(3):362–9.

76] Biselli R, Casapollo I, D’Amelio R, Salvato S, Matricardi PM, Brai M. Antibodyresponse to meningococcal polysaccharides A and C in patients with comple-ment defects. Scand J Immunol 1993;37(6):644–50.

77] Orren A, Warren RE, Potter PC, Jones AM, Lachmann PJ, Poolman JT. Anti-bodies to meningococcal class 1 outer membrane proteins in South Africancomplement-deficient and complement-sufficient subjects. Infect Immun1992;60(11):4510–6.

78] Potter PC, Frasch CE, van der Sande WJ, Cooper RC, Patel Y, Orren A. Pro-phylaxis against Neisseria meningitidis infections and antibody responses inpatients with deficiency of the sixth component of complement. J Infect Dis1990;161(5):932–7.

of Fcgamma receptor polymorphisms and C3 in the immune defence againstNeisseria meningitidis in complement-deficient individuals. Clin Exp Immunol2000;120(2):338–45.

80] Plested JS, Granoff DM. Vaccine-induced opsonophagocytic immunity to Neis-seria meningitidis group B. Clin Vac Immunol 2008;15(5):799–804.