Acta Tropica 76 (2000) 205–221

Review

Autoimmunity and malaria: what are they doing together?

Claudio T. Daniel-Ribeiro *, Graziela ZaniniDepartment of Immunology, Instituto Oswaldo Cruz-Fiocruz, A6. Brasil 4365, Rio de Janeiro CEP 21.045-900 RJ, Brazil

Received 10 January 2000; accepted 12 April 2000

The authors dedicate this publication in honour of the Instituto Oswaldo Cruz, on the occasion of the 1st Centenary of itsfoundation, May 25th, 1900

Abstract

A common feature of autoimmunity is the presence of autoantibodies (AAb). Two types of AAb have beendescribed: the ‘pathogenic’ AAb, associated with autoimmune diseases (AID), and the so-called ‘natural’ AAb. Thelatter are present in all normal individuals and have been postulated to play a major role as a first defensive barrierof the organism. Both the ‘pathogenic’ and the ‘natural’ AAb can be detected at higher frequencies among individualsexposed to viral, bacterial and parasitic infections. The malaria associated AAb do not seem to result from ageneralised polyclonal B-cell activation (PBA), have specificities that may differ according to the degree of clinicalimmunity and do not seem to be pathogenic. Malaria may offer a protective effect against AID, by diminishing itsseverity or by either preventing or retarding its expression. AAb could also participate in the immune protectionagainst malaria, and this could happen in several ways: (i) AAb directed to modified Ag expressed on the red bloodcell (RBC) membrane during parasitisation and (ii) AAb reactive with crypto- or neo-Ag revealed on both normaland infected RBC membranes, by destroying infected, and also normal, erythrocytes; (iii) anti-idiotype AAb specificof the binding site of anti-merozoite Ab, which would mimic the parasite ligand for the RBC receptor, by competingwith parasites and blocking RBC invasion; (iv) AAb cross-reactive with parasite material — such as nuclear orcytoskeleton Ag — having a direct parasiticide activity; (v) the natural AAb network, through its ‘anti-bacterial firstdefense barrier’; and finally (vi) anti-phospholipid (PL) AAb, by neutralizing the pathogenic properties of parasite-derived PL. Finally, in view of currently available knowledge, it is concluded that, since AAb are not alwayspathogenic, the price for an ‘autoimmunity-mediated’ protection in malaria would not necessarily be immunopathol-ogy and clinical autoimmunity, and a protective role of AAb could be exerted with no danger to the host. © 2000Elsevier Science B.V. All rights reserved.

Keywords: Autoimmunity; Autoantibodies (AAb); Autoimmune diseases (AID); Cross-reactions; Immune protection; Malaria;Plasmodium ; Premunition; Vaccination

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* Corresponding author. Fax: +55-21-2801589.E-mail address: ribeiro@ioc.fiocruz.br (C.T. Daniel-Ribeiro).

0001-706X/00/$ - see front matter © 2000 Elsevier Science B.V. All rights reserved.

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1. Introduction

Inspector Gregory asked Holmes if there was anypoint he wished to emphasise. Holmes repliedthat Gregory should direct his attention to ‘thecurious incident of the dog in the night-time’.Gregory replied, ‘the dog did nothing in thenight-time’, Holmes responded ‘that was the cu-rious incident’.

There are two ways of approaching the mean-ing of the term ‘immunopathology’: an immunesystem mediated pathology, or a pathology of theimmune system. Obviously, this can also apply tothe malaria-associated immunopathology, whereboth the participation of immune mechanisms inthe genesis of the multiple organ damage (anemia,cerebral malaria, lung and kidney failures andliver and spleen function impairments…) recordedduring the disease, and the alteration of the im-mune system’s functions (polyclonal B-cell activa-tion (PBA), immunosuppression, increasedapoptosis, autoimmunity…) have been described.

This paper approaches one particular aspect ofthe malaria-associated immune system dysfunc-tion, that is almost systematically observed duringthe course of both natural human and experimen-tal rodent infections: autoimmunity.

The dialogue reproduced in the beginning ofthis paper was extracted from the ‘Silver Blaze’ byConan Doyle (the creator of the Sherlock Holmescharacter) and can be considered as an analogy ofthe situation of tolerance to ‘self’ components(autoantigens — AAg) described — togetherwith the concept of ‘Horror autotoxicus ’ — in thebeginning of the century (Ehrlich and Morgen-roth, 1900). In such a comparison, the immunesystem would be the dog, the whole organismwould be the house where the crime was commit-ted, and the criminal — considered familiar bythe dog — would represent a pathogen withantigenic characteristics very similar to those ofthe host (the house). The aim of such a literaryexample is to remind the reader that the immunesystem, usually, does not produce an immuneresponse against ‘self’ components — unless themechanisms of such tolerance are broken — and,

therefore, does not attack exogenous agents(pathogenic or not) that resemble AAg.

Since the classic discovery made by Ivan Roitttogether with Deborah Doniach that the anti-thy-roglobulin autoantibodies (AAb) were associatedwith Hashimoto’s thyroiditis (Roitt et al., 1956),several papers have been published leading scien-tists and medical doctors to believe that autoim-munity appears as a result of an immune systemfailure and is associated — in a causative manner— to autoimmune diseases (AID). Other exam-ples of association between AAb and AID wouldinclude anti-red blood cell (RBC) antibodies (Ab)and autoimmune hemolytic anemia, Ab to acetyl-choline receptors and Myasthenia gra6is, the anti-IgG rheumatoid factors, and antiDNA AAb andsystemic lupus erythematosus (SLE) (Bach, 1993).

However, with the advent of sensitive technol-ogy for the detection of AAb, it became evidentthat Ab reactive with self-components were de-tected at low levels in the serum of normal indi-viduals, at frequencies that increased with age(Roitt, 1988).

In addition, besides the ‘pathogenic’ AAb, oneother type of autoimmune (AI) Ab (or of cellularAI responses), which may be ‘more physiological’,has been described by the team of Avrameas atthe Pasteur Institute of Paris (Dighiero et al.,1982; Guilbert et al., 1982) and comprises theso-called ‘natural’ AAb. These AAb, present in allnormal individuals independently of age, are char-acterised by such a degree of polyreactivity thatthey can be completely absorbed, regardless oftheir basic reactivity, by successive affinity purifi-cation on immunoadsorbent with only three anti-gens (Ag): DNA, trinitrophenylate (TNP) andactin (Dighiero, personal communication). AsDighiero (1997), one could consider that although‘self-reactive’, the natural AAb (as well as the‘pathogenic’ ones) are not ‘self-specific’, since,most often, they recognise AAg for which nopolymorphism has been demonstrated, and thatare present not only in all individuals of the samespecies, but also in several other species. For thisreason, it has been reasonably postulated that thenatural AAb could play a major role as a firstdefensive barrier of the organism.

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Finally, it also became evident that as much asthe ‘pathogenic’ AAb of different specificities —mainly, but not exclusively, those considered asnon-organ-specific AAb, such as anti-nuclear,anti-muscle or anti-phospholipid (PL) Ab — thenatural AAb can also be detected at higher fre-quencies among individuals exposed to viral, bac-terial and parasitic diseases, including malaria (forreview, refer to Abu-Shakra and Schoenfeld, 1991and Coutinho et al., 1995).

The present paper critically reviews data avail-able in the literature relating to different possi-bilties of interrelationships between malaria andautoimmunity: autoimmunity causing or con-tributing to the malaria associated pathology;AAb appearing as a consequence of malaria infec-tion; and malaria preventing the development ofAAb and of AID. Emphasis is given in the analy-sis and discussion of a fourth unconventional andpreviously poorly discussed possibility, i.e. au-toimmunity participating in the immune protec-tion against malaria infection and/or disease.

2. Pathogenic autoantibodies in malaria, doessuch a thing exist?

Data implicating the participation of AI pro-cesses in the genesis of clinical manifestations orcomplications of human malaria are mostly re-lated to anemia — a common feature of Plas-modium falciparum severe malaria — and thePlasmodium malariae associated nephritis. Otherexamples are rare and would include the demon-stration of an immune-mediated platelet destruc-tion leading to thrombocytopenia (Sorensen et al.,1984).

An exhaustive review of the literature on themalaria anemia pathogenesis is outside the scopeof this work. Nevertheless, some informationmust be given to help the non-specialist reader tounderstand why AAb against RBC have beenclassically evoked to explain anemia in a diseasecaused by an intra-cellular parasite, which infectsand mechanically destroys RBC during its ery-throcytic cycle. One must however keep in mindthat mechanisms leading to anemia in mice (whichtend to present high levels of parasitemia) may be

different from those operating in humans wherelow grade chronic infections are recorded, directbinding of Ig to RBC membrane Ag is still amatter of controversy and may not occur withsufficient intensity to lead to cell destruction. (i)the severity of the anemia in malaria is not corre-lated with the degree of parasitemia (Zuckerman,1964); (ii) anemia can appear after the infection iscured and no more parasites can be seen in theperipheral blood (Zuckerman, 1964); (iii) phago-cytosis of non-parasitised RBC has been docu-mented in experimental models more than 60years ago (Taliaferro and Cannon, 1936); (iv)reports of positive direct Coombs test have beendone in natural human infection (Facer et al.,1979; Facer, 1980; Lefrancois et al., 1981); (v)B-cells secreting Ab against crypto-Ag revealed onthe surface of autologous RBC by enzyme brome-lain treatment exist in normal mice, and arepresent at increased numbers in Plasmodiumberghei infected animals (Rosenberg, 1978); (vi) inthe same way, acutely infected individuals as wellas subjects chronically exposed to malaria in hy-per-endemic areas have increased titres of serumAb to the T-erythrocyte crypto-Ag revealed by(neuraminidase) enzymatic treatment of RBC(Zouali et al., 1982); (vii) PBA can induce both invitro (Hammarstrom et al., 1976) and in vivo(Cunningham, 1976) anti-RBC AAb production— and (viii) a marked degree of PBA is recordedin the course of both natural human malaria(Banic et al., 1991) and experimental murine in-fection (Freeman and Parish, 1978; Rosenberg,1978; Mori et al., 1987; Ternynck et al., 1991;Burger-Rolland et al., 1992).

One alternative, and unconventional, manner ofconceiving anti-erythrocyte autoimmunity hasbeen proposed by Sayles and Wasson (1992). Ac-cording to these authors, anti-RBC AAb could beanti-idiotype Ab reacting with anti-plasmodial Abspecific for parasite ligands of erythrocyte recep-tors. In other terms; the conformation of anti-merozoite (blocking?) Ab would resemble that ofthe receptor on the RBC surface. The correspond-ing anti-idiotype Ab, resembling the parasite lig-and (Fig. 1), could bind to the RBC receptor andeither represent a ‘protective’ AAb (by competingwith the parasite and blocking RBC invasion) or

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constitute a ‘pathogenic’ AAb (by destroying thenormal erythrocyte in the presence of complementor through ADCC mechanism). AAb against thetriosephosphate isomerase (TPI) have been foundto be associated with prolonged hemolysis in hu-man malaria (Ritter et al., 1993). Since it is acytoplasmic Ag, TPI could be exposed to theimmune system as a result of mechanical ruptureof parasitised RBC and would have to be at leastpartially in contact with the membrane to betargeted by effector mechanisms involved in im-mune lysis.

However, with the exception of examples (v)and (vi) — which seem to indicate the involve-ment of Ab directed to crypto-Ag, rather than totrue AAg — all these evidences may be indeedpointing to the participation of immune mecha-nisms — some of them effectively involving RBCand Ab — rather than of AI ones. For instance;Facer (1980) has clearly demonstrated that Abbound to the surface of RBC in infected Gambianchildren were in fact directed to plasmodial Agand were not specific of RBC. In addition, study-ing malarious individuals in the Brazilian Ama-zon, we could not observe a direct positiverelationship between the degree of activation ofperipheral plasmocytes secreting Ig of a given

isotype and the intensity of circulating RBC-bind-ing by Ig of the same isotype, suggesting that theerythrocyte bound Ig do not result from a PBA(Daniel-Ribeiro et al., 1986).

Nowadays, it is therefore more reasonable toexplain the malaria associated anemia as a resultof a multi-factorial process which would include:mechanical rupture of erythrocyte by the intra-cellular parasite; immune-destruction (Ab pluscomplement, ADCC, opsonisation and phagocy-tosis) of RBC sensitised by anti-plasmodial oranti-idiotypic Ab as well as by Ab directed toRBC-crypto-Ag that are revealed by parasitederived or induced enzymes; increased sequestra-tion of parasitised and normal RBC at the spleenand decreased myelopoiesis and erythropoiesis(Woodruff et al., 1979), which can be worsenedby the increased tumor necrosis factor-a (TNF-a)production (Clark and Chaudhri, 1988).

The other major group of studies on the partic-ipation of AI responses in the malaria pathologyprovides evidence that the nephritis observed inthe experimental murine models could be relatedto the AAb production recorded during bothacute and chronic infections and has often beenused to explain the nephritis associated to P.malariae human malaria. A major component of

Fig. 1. Hypothetical and unconventional mechanism simultaneously explaining pathological and protective effects of anti-idiotypeAb in malaria: Ab raised against the ligand for RBC on merozoites induce anti-idiotype Ab mirroring the parasite ligand, which canbind to the erythrocyte receptor for merozoite and lead to erythrocyte destruction (pathology) or receptor blockage (protection); (forcomplete explanation see text on ‘Pathogenic auto-antibodies in malaria‘; Section 2).

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the nephritis appears to be the formation anddeposition of immunecomplexes in the kidney re-sulting from high levels of circulating parasite Agand parasite-specific Ab that accompany the dis-ease (Houba, 1979). Some authors however con-sider that Ab directed against AAg, such as DNA(Wozencraft et al., 1990) or even idiotype (Lam-bert et al., 1982) could play a role in the genesis ofthis pathology in malaria.

Murine malaria is accompanied by the forma-tion of AAb reacting with several nuclear Ag;being RNA (Kreier and Dilley, 1969), solublenuclear material (Poels et al., 1980) and DNA(Wozencraft et al., 1990). Wozencraft et al., 1990have postulated that anti DNA Ab productionwould be modulated in mice contingent upon thestage (acute or chronic) of the malaria infection,since anti-DNA Ab produced during rodent infec-tion were usually directed to ssDNA and onlyacute infections increased the levels of those react-ing with dsDNA. Moreover, studies performedwith the aid of monoclonal AAb produced fromeither infected or autoimmune individuals (Lloydet al., 1994) have shown that the malaria associ-ated anti-DNA Ab (preferentially reactive withssDNA) have immunochemical properties similarbut not identical to those obtained from SLE sera(where dsDNA-binding Ab are common).

DNA can bind to normal glomerular structures(Izui et al., 1976) — in the same way that freemalarial Ag probably do (Pakasa et al., 1985) —and could initiate in situ immune complex forma-tion in a way comparable to that which occurs inheterologous immune complex glomerulonephritis(Van Damme et al., 1978). Wozencraft et al.(1990) have indeed observed that anti-DNA mon-oclonal Ab can bind to glomeruli of kidney col-lected from mice with P. berghei infection.However, since anti-DNA AAb were detected inthese mice only at the last stages of infection —when the kidney damage was already initiated —the authors considered that the anti-DNA Abcould only contribute to the worsening of kidneypathology and would not be directly implicated inthe initiation of damage.

Lambert et al. (1982) studied the idiotype–anti-idiotype interaction consisting of anti-phosphoryl-choline (PC) Ab bearing the T15 and anti-T15

anti-idiotype Ab in Balb/c mice. It was observedthat animals exposed to conditions associatedwith PBA (such as injection of lipopolysaccharideor trypanosome or plasmodium infection) pre-sented both T15 and anti-T15 responses andformed immunecomplexes that seemed to bepresent also at the glomerular membrane. How-ever, work conducted by our team several yearslater, demonstrating that anti-T15 anti-idiotypeAb did recognise P. falciparum Ag (Daniel-Ribeiro et al., 1991b) raises the possibility thatthis complex could indeed be formed by parasiteAg and anti-parasite Ab rather than by Aag andAAb.

3. Presence of autoimmune phenomena during thecourse of natural human and experimental rodentinfections

An association between malaria infection andpresence of serum AAb was reported by Shaper etal. (1968) in studies with malarial individuals fromUganda, and by Kreier and Dilley (1969) usingexperimental rat infections. These studies con-cerned Ab reacting with heart and nuclear Ag,detected by the immunofluorescent antibody test(IFAT) (Shaper et al., 1968) and by agglutinationmethods (Kreier and Dilley, 1969). Shaper alsodetected fluorescent Ab against thyroid and gas-tric cells, a report that, to our knowledge, is theonly one associating anti-organ specific AAb withmalaria infection.

Since then, many studies have reported thepresence of biological signs of autoimmunisationin the course of acute (human or experimental)disease or among individuals chronically exposedto infection. The reactivity of the reported AAbrelates to double and single stranded DNA(Quakyi et al., 1979; Adu et al., 1982; Daniel-Ribeiro et al., 1984b; Zouali et al., 1986; Bonfa etal., 1987), erythrocyte (Facer et al., 1979; Facer1980; Lefrancois et al., 1981; Ritter et al., 1993),immunoglobulin (Houba et al., 1966), lymphocyte(De Souza and Playfair, 1983), neutrophil cyto-plasm (Adebajo et al., 1993; Yahia et al., 1997),phospholipid (Bate et al., 1992a,b; Adebajo et al.,1993; Facer and Agiostratidou, 1994) ribonucle-

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oprotein (Greenwood et al., 1970a; Voller et al.,1972; Quakyi et al., 1979; Daniel-Ribeiro et al.,1983; Zouali et al., 1986; Daniel-Ribeiro et al.,1991a; Adebajo et al., 1993), RNA (Kreierand Dilley, 1969), smooth muscle (Quakyi et al.,1979; Phanuphak et al., 1983; Boonpucknavigand Ekapanyakul, 1984; Daniel-Ribeiro et al.,1991a).

However, even if the list of published studies islong, two main aspects deserve to be introducedfor analysis and reflection. The first one raises aquestion that will be discussed deeper in Section 4of this paper: in some cases, the specificity ofobserved AAb differs according to the degree ofclinical immunity of infected man and experimen-tal animals. For instance; anti-nuclear Ab (ANA)are often observed in immune animals (Poels etal., 1980) and among individuals chronically ex-posed to infection (Greenwood et al., 1970a;Voller et al., 1972; Adu et al., 1982; Daniel-Ribeiro et al., 1983), while smooth muscle Ab(SMA) seem to be detected in the course of theacute infection (Quakyi et al., 1979; Poels et al.,1980; Ben-Slama, 1982; Phanuphak et al., 1983;Boonpucknavig and Ekapanyakul, 1984; Daniel-Ribeiro et al., 1991a).

The observation that ANA are associated withchronic infection (mainly represented by Africanindividuals) could in fact reflect an associationbetween ANA and Africans. However, threekinds of findings seem to indicate that AAb for-mation during the malaria infection is not contin-gent upon racial or other extrinsic factors: (i)AAb production has been observed not only inAfricans chronically exposed to malaria but alsoamong infected Caucasians (Quakyi et al., 1979;Adu et al., 1982; Daniel-Ribeiro et al., 1991a),Asians (Phanuphak et al., 1983; Boonpucknavigand Ekapanyakul, 1984; Daniel-Ribeiro et al.,1991a) and even in Brazilian mixed-race popula-tions (Bonfa et al., 1987); (ii) a comparativeanalyses, conducted in two African populationshaving the same genetic background, has clearlyshown that malarious subjects, but not the non-infected population living at higher altitudes, pre-sented ANA of the speckled pattern offluorescence in their sera (Voller et al., 1972); and(iii) we have observed that individuals from differ-

ent ethnical groups (Africans, Asians and Cau-casians) with similar past malaria experience,presented comparable prevalence of ANA andSMA (Daniel-Ribeiro et al., 1991a). Taken to-gether, these data seem to indicate the existence ofa correlation between the autoreactivity profileand the degree of immune-protection or exposureto malaria.

The second aspect is that not all AAg seem tobe touched by the AI phenomena that accompanyplasmodial infection. An exhaustive screening,performed by IFAT on eight different tissues andallowing the detection of 14 anti-tissue AAb, hasbeen conducted in the sera of individuals chroni-cally exposed to malaria infection in an holoen-demic area of malaria in Africa (Daniel-Ribeiro etal., 1983). Surprisingly, it was observed that, inspite of the marked degree of PBA that usuallyaccompanies both human malaria (Banic et al.,1991) and the experimental infection (Freemanand Parish, 1978; Rosenberg, 1978; Mori et al.,1987; Ternynck et al., 1991; Burger-Rolland et al.,1992), no overall increase was observed in thefrequencies of AAb but, on the contrary, a spe-cific rise in the frequency of ANA with no effecton those of organ specific AAb was recorded. Inaddition, Ab directed against thyroglobulin — anAAg that corresponds to a demonstrated specific-ity of autoreactive B-cells in normal individuals— are absent during the course of human andmurine malaria (Daniel-Ribeiro et al., 1982,1984a) but can be induced in experimentally in-fected mice, if the animals receive an injection ofthyroglobulin simultaneously with the infectionby Plasmodium yoelii (Daniel-Ribeiro et al., 1982).These data seem to indicate that AAb formationduring malaria can not be explained solely by ageneralised PBA (that theoretically would haveactivated clones; of all specificities of autoreactiveB-cells) and, instead, result from a specific activa-tion of autoreactive B-lymphocytes (Daniel-Ribeiro et al., 1984a; Daniel-Ribeiro, 1988). Wehave proposed (Burger-Rolland et al., 1992) a twostep mechanism simultaneously dependent bothon the presence of immunogenic amounts of AAg(signal 1) and on parasite mitogens (Greenwoodand Vick, 1975; Freeman and Parish, 1978;

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Kataaha et al., 1984) that would replace the sec-ond signal usually delivered by T-cells that — inthe case of AI responses — are under efficientand stringent control.

The origin of the first — antigenic — signalcould be situated at the level of either the parasite(plasmodium DNA?) or the host (nuclear antigensdelivered in the circulation at the moment ofhepatic schizont rupture?). One other possiblesource of first signal and potential participant inthe origin of ANA in both malaria and SLE,involves the over-exposure of apoptosis relatednuclear Ag that may also be the driving force tothe somatic mutation class switching and theaffinity maturation of germ-line ANA in SLE(Souza-Passos, 1997). This hypothesis can indeedbe considered as a reasonable proposal, if we keepin mind the following data: (i) high rates oflymphocyte apoptosis are recorded in SLE pa-tients and (ii) the highest rates are seen inpatients with high SLAM (systemic lupusactivity measure) index scores (Emlem et al.,1994), (iii) high rates of lymphocyte apoptosishave also been recorded in malarious patients(Balde et al., 1995) possibly as a result of the veryimportant PBA that accompanies the disease(Banic et al., 1991), (iv) high incidences of ANAare observed in both conditions (although at dif-ferent titres), (v) immunisation with apoptoticcells can induce ANA at high levels in mice(Merovac et al., 1997) and (vi) the presence ofclustered nuclear Ag in the membrane of apop-totic cells has already been reported (Casciola-Rosen et al., 1994).

As an introductory summary of what has al-ready been said we could therefore state that theAAb associated with malaria, present at highfrequencies and low titres during the course ofinfection of man and experimental animals, donot seem to result from a generalised PBA —since they are specific of a limited range of AAgand do not relate to partially sequestered organ-specific structures — have specificity which maydiffer according to the degree of clinical immunityand do not seem to be pathogenic, although theycould participate in the lesion process by worsen-ing the already triggered damage.

4. Protective effect exerted by malaria on thedevelopment of autoimmune disease

One other issue that needs to be considered inthe framework of the interactions existing be-tween autoimmunity and plasmodial infections,relates to interesting epidemiological data thatfurther support the idea that malaria associatedAAb are not harmful. Indeed, if they were patho-genic to the host, an increase in the frequencies ofAID would be expected to occur in areas wherethe malaria is endemic. However, on the contrary,30 years have now passed since Greenwood (1968)observed, in a Nigerian hospital, that SLE andrheumatoid arthritis (RA) were four to six timesless frequent than the figures observed in Eu-ropean populations. He proposed that parasiticinfections, especially malaria, could prevent thedevelopment of AID. It is obvious that one couldquestion this interpretation of the facts by arguingthat West-African hospitals could be ‘packed’with infectious disease patients without room forother diseases (mainly the chronic ones such asRA). The ability to screen and diagnose SLEwithin the context of the existing low level oftechnology and clinical expertise in African devel-oping countries in 1968, could be questioned aswell. It could be enlightening if he had provideddata on the frequency of other non-infectious(metabolic, degenerative…) diseases. Nevertheless,upon this initial epidemiological observation,Greenwood et al. (1970b) have shown that experi-mental malarial infection was effectively able toprevent the spontaneous development of the SLE-like AID frequently presented by the NZB×NZW F1 hybrid mice at the adulthood. Inaddition, since then, other studies (Zoutendyk,1970; Tsega et al., 1980) seem to have expandedand confirmed the epidemiological observationsinitially made by Greenwood (1968).

A possible explanation for this inverse relation-ship between malaria and AID involves the TNF-a (Jacob and McDevitt, 1988; Butcher and Clark,1990; Butcher, 1991; Adebajo, 1992; Jacob, 1992;for review see Souza-Passos, 1997) and is synthe-sised in Fig. 2. The promotor segment of the genefor TNF–a has a dual polymorphism: one allelecommanding high and the other low transcription

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Fig. 2. TNF-a levels modulating SLE expression in function of(a) intensity of exposition to malaria and (b) individual geneticprofile of (low or high) TNF-a production: (1) high SLEincidence; (2) expected SLE incidence; (3) malaria toleranceand low SLE incidence; (4) death from severe malaria(adapted from Souza-Passos, 1997; for complete explanationsee text on ‘Protective effect of malaria on the development ofautoimmune disease’, Section 4).

the absence of exposure to malaria — and theresulting low levels of TNF-a — would increasethe risk of lupus development in the Americanblack population (Symmons, 1995), as comparedto the frequencies reported in American Cau-casians (Butcher, 1991). Another interesting ob-servation is the strong correlation existingbetween homozygosis to the TNF2 gene promoterallele, which is associated with higher transcrip-tion levels of the cytokine, and susceptibility tocerebral malaria (McGuire et al., 1994). Despitethis relationship, supposed to be deleterious inareas of high malaria transmission and thus sus-ceptible to negative selection pressure (high TNF-a serum concentrations have found to beassociated with severe disease — for review referto Kwiatkowski et al. (1997) — the TNF2 alleleexists in a relatively high frequency, implying,according to the authors, that the disadvantagefor TNF2 homozygotes is counterbalanced bysome biological advantage. They claim that it ispossible that TNF2 homozygotes are protectedagainst life threatening conditions other than cere-bral malaria. Coming back to the present discus-sion, these life-threatening conditions couldinclude AID such as SLE. As Souza-Passos (per-sonal communication), we may consider that thisnegative TNF-a effect on lupus would actually bepart of a broader beneficial effect resulting fromthe predominant TH1 ambience (TNF, gINF,IL-12) created by plasmodial acute infections.SLE is a Th2/IL10 disease and Th2 stimulli (e.g.pregnancy) tend to worsen the disease. The Th1ambience associated with malaria would improvethe clinical picture (or retard the expression) ofthe disease by inhibiting the Th2 influence, whichis necessary for the expression of lupus. It isindeed assumed that clinical fluctuations of SLEactivity could be due to temporal oscillations inthe Th1/Th2 balance.

In addition to these epidemiological, geographi-cal, genetical and racial factors; other componentsof the SLE/TNF-a/malaria interplay would in-clude Plasmodium-derived phospholipids (PL)and anti-PL AAb (aPL-AAb), which could modu-late the severity of both malaria and SLE (inlupus-prone malaria exposed individuals) throughTNF-a regulation (Fig. 3). At least theoretically,

Fig. 3. Additional interconnections of the SLE/TNF-a/malariainterplay involving PL and aPL-Ab that can positively ornegatively influence the severity of both diseases (in lupus-prone malaria exposed individuals) through the TNF-a regula-tion (for complete explanation see text on ‘Protective effect ofmalaria on the development of autoimmune disease’, Section4).

levels (Richaud-Patin et al., 1995). People fromWest Africa have low transcription phenotypeand, consequently, would be more prone to thedevelopment of SLE than Caucasians (low levelsof TNF-a and immunoglobulin overproductionare a sine qua non factor for SLE). They are,however, protected against AID by the increasedlevels of TNF-a produced during malaria infec-tion and they present much lower frequencies ofSLE than the American black populations, whichhas the same geographical and racial origins andpresent the same genetic background. Conversely,

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anti-PL AAb produced either in response to PLderived from the plasmodium or as a result ofSLE activity, could neutralise the TNF-a induct-ing property of PL (Bate et al., 1992a) and eitherdiminish the malaria severity or worsen the SLEactivity. At the present moment there are no dataavailable that show clearly that the SLE inducedanti-PL AAb could act by blocking the effect ofplasmodium derived PL, and/or that the plasmod-ium derived PL could have any beneficial effecton the SLE activity or severity through TNF-aup-regulation. However, although the malaria in-duced anti-PL Ab do not seem to be pathogenicin non AI malarious individuals (Hunt et al.,1992), we can not exclude the possibility of‘pathogenic’ anti-PL AAb produced, in responseto plasmodium derived PL, in SLE pronesubjects.

TNF-a is certainly not the only way wherebymalaria would prevent or retard the developmentof AID. In RA, for instance, increased expressionof this cytokine and its presence in the synovialtissues are associated with active disease (seeKlareskog and McDevitt, 1999 for review) andAb against TNF-a has been remarkably successfulin the treatment of some RA patients (Maini etal., 1998), although little or no beneficial effect(beyond diminishing fever intensity) has been ob-served in the treatment of human malaria (seeKwiatkowski et al., 1997 for review). Other mech-anisms, such as production of a network ofpolyreactive AAb interactions (Greenwood,1968), may therefore participate in the protectionoffered by malaria against the development of RAin areas of high endemicity.

Studying the experimental model of NZB×NZW F1 mice, Hentati et al. (1994) were able toobserve a 6-month delay in the occurrence of SLEin Plasmodium chabaudi infected mice. The levelof anti-DNA AAb, particularly those of the IgG1isotype, in the mice surviving the development ofthe AI diseases was diminished. The injection ofpolyclonal IgG, IgM or of cryoglobuline frominfected mice had the same — although lessmarked — property. Compared to normal Ig, thepolyclonal Ig had an increased quantity of naturalAAb bearing the D23 idiotypes that are charac-teristic of natural polyreactive AAb (Guilbert et

al., 1982; Dighiero et al., 1982) with anti Fc andanti-Fab activities. The authors concluded thatthe malarial infection induces the synthesis of IgGand IgM natural AAb endowed with immunoreg-ulating properties able to restore — at least tem-porarily — the natural AAb network which isdeficient in B/W mice and, thus, to prevent thedevelopment of AID. In other words, they mighthave been suggesting that AID are not caused byan excess of ‘bad’ AAb but rather by a lack of the‘good’ ones.

The good (natural) AAb could act by blockingthe first signal of autoreactive lymphocyte activa-tion. They are indeed able to do so since they canbind to nuclear Ag (signal one) exposed on thesurface of apoptotic cells. In the situations ofSLE-prone individuals exposed to malaria and ofthe autoimmunity associated malaria (see below),they could also react with PL that may be en-dowed with mitogenic and PBA properties (signaltwo) and block their effects. By neutralising thesemolecules, the natural AAb could prevent ANAproduction and retard SLE generation.

Not only the AI disease of NZB×NZW F1mice but also the biological AI phenomena associ-ated with malaria can be prevented if an injectionof cryoglobulin (obtained from infected mice) isdone prior to P. berghei experimental infection.The animals thus treated developed lower levels ofcirculating immune-complexes and of AAbagainst nuclear and cytoplasmatic Ag and did notproduce cryoglobulin. This is a long-lasting effect,since the administration of cryoglobulin has anidentical effect either 10 days or 9 months beforeinfection, suggesting that mice can be activelyimmunised against the production of AAb(Fawcett et al., 1989).

Other mechanisms through which malariacould modulate the expression or the severity ofAID would include the production, by the para-site, of mediators such as prostaglandins (Kubataet al., 1998) that can either negatively influencethe TNF-a level or act, together with other infl-ammatory mediators, at the site of the lesion(potentiating the development of the destructivepannus at the site of the synovitis, for instance —Dayer and Fenner, 1992).

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One additional explanation for the low AIDincidence in malaria endemic areas would involvethe effector and regulatory roles played by naturalkiller (NK) cells on the immune system (seeHorowitz et al., 1997 for review). NK cells arenon-T non-B lymphoid cells that may either stim-ulate or inhibit the development of an immuneresponse. They are thought to play importantroles in suppressing autoimmunity and blockingfetal-maternal immune responses, for instance.These suppressive activities have been shown tobe mediated mainly by the production of TGF-b.On the other hand, NK cells are actively involvedin immune responses and in malaria, NK cellshave been shown to be required in adaptive im-munity against P. yoelii liver stages initiated byCD8 cells (Doolan and Hoffman, 1999). In the P.chabaudi model, passive transfer of NK cells frommalaria immune mice had no effect on the out-come of the infection in recipient animals, butinjection of anti-NK cell Ab resulted in muchhigher mortality of mice (Kitaguchi et al., 1996).Malaria activated NK cells could therefore, be-sides their effector activity against the parasite,lead to TGF-b production which could inhibit orimpair the development of AI responses in AID-susceptible individuals living in malaria endemicareas.

In this section we have learnt that malaria mayoffer a protective effect against AID disease byimproving its clinical picture, or either preventingor retarding its expression. This has been ob-served during epidemiological studies in Africanmalaria endemic areas and confirmed with theexperimental malaria infection of the hybridNZB×NZW F1 mice, who spontaneously de-velop a SLE-like AID. This effect could resultfrom the neutralisation of the Th2 influence (nec-essary to the SLE development) by the predomi-nant Th1 ambience created by malaria infection,there including the rise in the TNF levels incom-patible with SLE development or expression. Onealternative mechanism by which malaria couldprotect against AID would include the develop-ment of high levels of an immunoregulating popu-lation of natural ‘good’ AAb that could also bindto nuclear and/or PL Ag and block (respectively)signals 1 and/or 2 of auto-reactive B-cellactivation.

5. Can autoimmunity ever protect againstmalaria?

This approach to the autoimmunity andmalaria inter-relationships has been analysed andtaken-up again as a more sustainable hypothesisby one of us recently (Daniel-Ribeiro, 2000) butone could consider that the hypothesis that au-toimmunity has a protective effect against malariainfection was first clearly formulated by Jarra(1983). According to him, induction of protectionagainst blood stage parasites would not be possi-ble without the simultaneous induction of an anti-erythrocyte AI response, even if this could resultin immunopathology. The author proposed thatthe intra-erythrocytic development of the plas-modium would result in significant alterations ofthe RBC membrane. The resulting expression ofneo- and crypto-antigens could lead to the breakof the tolerance of lymphocytes to integer ormodified AAg.

This hypothesis could have been based on anolder idea, by the late Jayawardena, that part ofthe malaria associated IgM response could beconstituted by ‘protective AAb’ directed to RBCmodified determinants or against crypto-Ag ex-posed at the erythrocyte membrane, as a conse-quence of the parasitisation. Even admitting thathe did not know how the alterations induced byAAb could contribute to the control of the pri-mary infection, Jayawardena considered that theanti-erythrocyte autoreactivity could be an essen-tial component of protective immunity (Jayawar-dena et al., 1979).

Immunological response to autologous orcrypto-Ag of RBC has indeed been demonstratedon several occasions in the course of malariainfection in humans and experimental animals(refer to Section 2 of this article). However, asseen before, the RBC specific AI response ob-served during the infection has always been pro-posed as an explanation for the anemia ofmalaria. The originality of Jayawardena and col-laborators and of Jarra has thus been to proposea protective role for these AAb. Literature effec-tively provides a certain number of argumentssupporting this hypothesis, as shown below, andsuggests that it should not be restricted to theanti-erythrocyte AAb.

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The extensive RBC modification and destruc-tion, artificially generated by treatment of micewith phenylhydrazine, are in fact followed by anincrease in immunity against P. chabaudi infection(Jarra, 1983). Since mature RBC and reticulocytesare equally susceptible to P. chabaudi infection,the increase in the proportion of circulating retic-ulocytes — resulting from the destruction of RBC— could not explain the protection of treatedanimals. Instead, one possible explanation, couldbe the expression of neo- or crypto-Ag on theRBC surface as a result of phenylhydrazine treat-ment, leading to anti RBC AI response, destruc-tion of (infected and non-infected) erythrocytes,anemia and decrease in parasitemia.

A relationship between the property shown byimmune serum to transfer protection against P.berghei infection and the content of anti-erythro-cytic Ab in the protective immune serum has alsobeen described (Schetters et al., 1989). The protec-tive effect was reflected by a decrease in theparasitemia 7 days after challenge of mice thatreceived immune serum containing anti-RBC Ab.The protective activity of the serum was positivelyand strongly correlated with its titre of Ab againstautologous and heterologous RBC as well as withits total immunoglobulin content, which, accord-ing to the authors, could be indicative of thedegree of PBA.

A very interesting work (Hogh et al., 1994)refers to the immune response developed againstband 3 neo-Ag of P. falciparum infected erythro-cytes in humans. The band 3 Ag is a host derivedprotein that integrates, together with Ag from theparasite, the ‘knob’ proteic complex, a protrusionof the infected RBC that is related to the adhe-siveness of infected RBC to endothelium and tonormal erythrocytes. Ab against the band 3 neo-Ag block the cytoadherence of infected RBC.Currently it is not known whether reactivity tothese Ag simply reflects the exposure to themalaria parasite or is correlated with protectiveimmunity. However, children and adults living inan area of intense malaria transmission showed amuch higher reactivity with the band 3 peptidesthan those from non-immune individuals. Highreactivity to the loop 3 peptides was correlatedwith lower mean parasite density in children in

the 5–9-year-old age group. In the same way,higher than average reactivity against loop 3 and7 peptides were positively correlated with highhematocrit values, indicating that these Ab arenot involved in hemolysis (through an anti-RBCautoimmunity) and, on the contrary, suggestingthat they can be involved in protection. In thiscase protection against plasmodium could resultfrom the diminished RBC adhesiveness to othererythrocytes or to endothelial cells decreasingchances of ‘rosetting’, cytoadherence and RBCinvasion by parasite. However, an Ab mediatedinterference on penetration of RBC by the plas-modium or on its intra-cellular proliferation, cannot be discarded.

As aforementioned, it is possible that the AAbprotective against malaria are not exclusively par-asite reactive and can also be (anti-idiotypic) Abspecific of parasite ligands on erythrocyte. Theycould also bind (and neutralise) parasite derivedmaterial (PL) which are endowed with propertiesof mitogenicity, PBA or TNF-a induction andhave a defined participation in the physiopatho-genesis of the disease (Bate et al., 1992a,b; forreview refer to Kwiatkowski et al., 1997).

A potential role for aPL-AAb in the anti-malaria protective (anti-toxic as well as anti-para-site) immunity can indeed be postulated andbetter accepted if the following observations aretaken into account: (i) parasite PL (for reviewrefer to Kwiatkowski et al., 1997) may induce theexpression of inflammatory cytokines such asTNF (Bate et al., 1992b), (ii) aPL-AAb maymodulate the synthesis of TNF in mice (Bate etal., 1992a), (iii) Gambian children with cerebralmalaria present significantly, less IgM anti-phos-phatidylinositol Ab than those with non severemalaria (Facer and Agiostratidou, 1994), and (iv)immunisation of mice with PL, such aspliosphatidylcholine, induces partial protectionagainst the infection by P. chabaudi (Bordmann etal., 1998). Although item (i) is subject to discus-sion, since it has been shown that mycoplasmacontaminating in vitro plasmodium cultures couldexplain the induction of high levels of TNF-a(Rowe et al., 1998), taken together, the resultscited above represent strong evidence that anti-PLAb may play a role in protection against malaria.

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Work conducted at the Pasteur Institute(Ternynck et al., 1991) shows that mice experi-mentally infected with P. chabaudi develop, simul-taneously to a marked degree of PBA, intenseimmunological activity against the actin, myo-globin, myosin, spectrin and tubulin AAg as wellas against trinitrophenylated (TNP)-ovalbumin.The response, detected at the level of RBC mem-brane Ag (such as spectrin and band 3 Ag) as wellas of Ag studied on fibroblast preparations (suchas tubulin, actin and the 70 Kd heat shockprotein) persisted for several weeks after parasiteclearance before returning to pre-infection values.The detection of these natural AAb at high fre-quencies and levels could indicate the attempt ofthe infected organism to mobilise the relevantimmune response for its defense. This could alsoexplain — at any rate, in part — the severity ofthe experimental infection of the CBA/N mice,incapable of developing AAb against bromelaintreated mouse RBC (Jayawardena et al., 1979).These mice are deficient in CD5+ B cells, be-lieved to be the source of virtually all naturalAAb (Sidman et al., 1986).

In Ternynck’s work, following a challenge withparasitised erythrocytes, and curiously after injec-tion of normal RBC to animals that had alreadycleared the parasitemia, a similar increase of AAbwas consistently observed. The polyreactivity ofthese ‘natural’ AAb must be emphasised: afterabsorption and elution from infected mouse RBCor affinity-purification on a mouse tubulin im-munoadsorbent, they react with all Ag of thepanel, and, more surprisingly, with parasiteextracts.

The existence of such cross-reactions betweenAAg and parasite is effectively an important pointconsidering that, if we claim that autoimmunitycan protect against the disease and/or the infec-tion, one must also admit that at least part of theprotective response acts on the parasite itself. Thenotion of Ag-sharing between parasites and theirhosts is currently common place (Damian, 1964;Capron et al., 1968) and the close relationshipbetween plasmodium and mammal Ag has al-ready been demonstrated at several occasions (forreview refer to Mattei and Scherf, 1991), includingwith the aid of parasite specific and even anti-idio-

type monoclonal Ab (Daniel-Ribeiro et al., 1984c,1991b). One unconventional proof of the existenceof Ag-sharing between the human host and plas-modium comes from the work presently beingundertaken in our laboratory. Studying the cross-reactivity of sera from SLE patients against plas-modial Ag, we have observed that 51% of the 80tested sera reacted by Elisa with either the wholeparasite extract or one of the 13 synthetic peptidesor recombinant proteins corresponding to malariavaccine candidate Ag from sporozoite, erythro-cytic or hepatic stages of P. falciparum. A propor-tion (32%) of sera also reacted in IFAT withFCR3 P. falciparum isolate and this reaction wasclosely related to the presence of serum ANA butnot with disease activity. Preliminary results ob-tained in collaboration with Drs Karima Brahimiand Pierre Druilhe (Laboratory of BiomedicalParasitology — Pasteur Institute, France) showthat both murine monoclonal Ab and human seracontaining AAb of different specificities also re-acted in IFAT and Western blotting with P. yoeliiand with different strains of P. falciparum.

Summarising what has been seen in this section,AAb could participate in the immune protectionagainst malaria in several ways: (i) AAb directedto Ag of the RBC membrane modified in confor-mation by the co-expression of plasmodial Agduring parasitisation as well as (ii) AAb reactivewith crypto- or neo-Ag expressed on both normaland infected RBC (as a consequence of RBCexposure to parasite derived or induced — neu-raminidase like — soluble enzymes), by destroy-ing infected (in case (i)) or both infected andnormal (in case (ii)) erythrocytes; (iii) anti-idio-type AAb specific of the binding site of anti-mero-zoite Ab, which would mimic the parasite ligandfor the RBC receptor, by competing with para-sites and blocking RBC invasion; (iv) AAb cross-reactive with parasite material — such as nuclearor cyto-skeleton Ag — throughout a direct para-siticide activity; (v) the natural AAb network —potentiated during the course of the infection —through its ‘anti-bacterial first defense barrier’;and finally (vi) anti-PL AAb by neutralising thepathogenic (mitogenic and TNF-inducing) prop-erties of parasite derived PL.

C.T. Daniel-Ribeiro, G. Zanini / Acta Tropica 76 (2000) 205–221 217

If we consider that autoimmunity participatesin the immune protection against malaria infec-tion or disease, a last question needs to be ad-dressed: could the host response be efficient interms of protection (or as anti-parasite het-erologous response) without being offensive to thehost (or without being efficient as an autologousresponse)?

The most important argument in favor of theidea that the AAb is not necessarily associatedwith any immunopathology is based on the workconducted by Avrameas and Dighiero’s groupshowing that around 6% (35) of 612 monoclonalproteins obtained from patients with multiplemyeloma or Waldenstron macroglobulinemia pre-sented a natural AAb activity (against actin for 32of them!) without evidence of any clinical mani-festation of AID (Dighiero et al., 1982, 1983).

It is also important to draw attention to thefact that the AAb formed in the course of severalinfectious and parasitic diseases and those en-countered in AID often recognize the same AAg,but have neither the same fine specificity nor thesame biological properties, even though they oftenshare idiotypes in common and even similar struc-tures. In this respect, reference should be made tothe work done by Lloyd et al. (1994) comparingmonoclonal AAb obtained from AI mice withthose produced by splenocytes of P. berghei in-fected animals. While presenting public idiotypeof the same family as those usually encountered inanti-DNA AAb associated with SLE and otherAID, the latter presented specificities differentfrom those of the first group and reacted also withparasite infected erythrocytes. In the same way ithas been observed that aPL-AAb present differentprofiles of epitopic specificities in syphilis,malaria, and a subset of thrombotic lupic pa-tients, although presenting comparable anti-cardi-olipin (CL) activity (Colaco and Male, 1985).Similarly, Hunt et al. (1992) reported that purifiedanti-CL AAb from AI patients reacted with aplasma protein binding to b2 glycoprotein I incontrast with those isolated from patients withmalaria, infectious mononucleosis, turberculosis,hepatitis A or syphilis that did not require thepresence of this ligand to react with CL. The AAbfrom the first group, and not those from infected

patients, were associated with thrombotic compli-cations. Different Th1 and Th2 lymphokine profi-les in malaria (Perlman et al., 1998) and in AID(reviewed by Singh et al., 1999) could also influ-ence the determinism of isotype and affinity matu-ration patterns of the secreted AAb in these twoconditions (Rizzo et al., 1992).

Finally, according to these and other evidencesthat have been cited in this paper, AAb are notalways pathogenic being the ‘natural’ (Dighiero,1997), the ‘reactive’ (e.g. malaria induced), the‘fortuit’ (multiple myeloma, Waldenstrommacroglobulinemia — Dighiero et al., 1983) andeven those associated with AID such as the SLEin which AAb with demonstrated pathogenicityare a minority (Hahn, 1998), and a susceptibilityof the target-organ as well as the existence ofpro-inflammatory polymorphism may be determi-nant factors. In this fashion, the price for an‘autoimmunity mediated’ protection in malariawould not necessarily be immunopathology andclinical autoimmunity, as has been formerly pos-tulated (Jarra, 1983), and a protective roleof AAb could be exerted with no danger to thehost.

Acknowledgements

CTDR and GZ are recipients of a fellowshipfrom the ‘Conselho Nacional de DesenvolvimentoCientıfico e Tecnologico’ (CNPq), Brazil. The au-thors are indebted to Drs Jean Louis Perignon(Institut Pasteur — Paris) and Luis Fernando deSouza Passos (Fundacao Universidade do Ama-zonas) for their valuable suggestions and discus-sions, to Hugo Spınola G. Pereira for putting indrawings the schemes we had in mind and toMarjolein Snippe for help in the editorial work.The several and thorough revisions of the Englishtext by Ana Maria Mendes allowed the article toreach its final version.

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