Memoranda

Virus-associated immunopathology:animal models and implications for human disease*1. Effects of viruses on the immune system, immune-complex diseases,and antibody-mediated immunologic injury

The tissue damage caused by virus infection has been traditionally explained by theability of viruses to multiply in cells and thereby injure or destroy them. Recent evidencesuggests, however, that lesions may also be caused by the host's immune response to viralantigens and that the immune system itselfmay be perturbed by some viruses. This memo-randum reviews recent developments in viral immunopathology, with special referenceto animal model systems, and indicates the possible relevance of the new concepts andtechniques for certain diseases of man. Certain viruses, notably the leukaemia virusesand some of those causing persistent infections, depress the host's ability to mount an anti-body response to antigens, while other viruses may enhance the antibody response. Cell-mediated immunity may also be depressed. Another immunopathological manifestationof virus infection is immune-complex disease. When viruses or their antigens persist in thecirculation they combine with specific antibody, and the resulting complexes lodge in varioussites, especially the kidney. Further combination with complement leads to the release oftissue-damaging substances. A third condition associated with virus infection is antibody-mediated immunologic injury. Both oncogenic and non-oncogenic viruses frequentlyinduce new antigens on the surface of the cells they invade. When antibody attaches tothese antigens in the presence of complement, the cells are destroyed.

The lesions associated with virus infections havetraditionally been explained by the ability of virusesto replicate in cells and hence cause cell injury andeven death. However, recent studies indicate thatvirus-associated tissue damage may be due in partto the immune response of the host to viral antigens.The properties of viruses are seemingly ideal forproducing immunopathological damage. Viruses areforeign antigens and, being self-replicating, can conti-nue to produce antigen for long periods of time.Certain viruses are also known to be able to inducenew antigens on the surface of cells they infect.The host's immune system can respond to theseantigens.

In view of these properties, immunopathologicalchanges may be initiated by a number of differentmechanisms in the course of virus infection:

(1) Certain viruses can infect the cells of theimmune system and cause direct immunologic

* This memorandum was prepared by the signatorieslisted on page 262.

derangements. Many processes and parameters ofimmune function may be thus affected, includinggraft rejection, the induction of immunologic toler-ance, antibody production, graft-versus-host reac-tions, lymphocyte transformation, immunoglobulinlevels, phagocytosis, and delayed-type skin reactions.

(2) The host's immune response to viral antigenscan lead to the formation of virus-antibody com-plexes capable of reacting with anti-immunoglobu-lins, rheumatoid factor, and the components ofcomplement.

(3) New antigens produced by viruses on infectedcell surfaces can interact with specific antiviral anti-body plus complement, thus causing cell destruction.

(4) Recent findings suggest that sensitized lympho-cytes can also react with virus-induced cell surfaceantigens and destroy the cell. Furthermore, cell-mediated (or antibody-mediated) immune responsesto viruses may result in the release or activation ofbiological mediators causing immunopathologicalchanges.

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(5) An autoimmune response may be produced ifthe virus (a) releases host-cell antigens, (b) altershost-cell antigens and act as a " helper determinant ",or (c) depresses the host genome, thus increasing theproduction of embryonic or other antigens.

In addition, the genetic makeup of the host, whilenot a mechanism of producing immunopathologicaldamage, can influence the nature and severity ofinjury incurred during virus infection (Notkins et al.,1970).

In some infections, such as lymphocytic chorio-meningitis, the immune response of the host maybe the principal cause of the pathological mani-festations while in other infections it may be ofless importance. In most if not all virus infections,the host's immune response probably contributessomewhat to the pathological picture. It should beemphasized, however, that in the majority of casesthe overall effect of the immune response is morelikely to be beneficial than harmful.Recent studies on virus-induced immunopatho-

logical reactions in domestic and experimental ani-mals have led to the development of concepts andtechnical methods that may be useful in investi-gating certain viral diseases in man, including hepa-titis. Progress in the field of viral immunopathologyhas been rapid, and it was felt that a summary andcritical review of present knowledge would encourageits wider application to clinical problems. Onlyselected references have been included, since thebreadth of the subject made a complete review ofthe literature impracticable. Suggestions for furtherlines of investigation in viral immunopathology ingeneral and in viral hepatitis in particular will beoffered in Part 2 of this Memorandum, to be pub-lished later.

EFFECTS OF VIRUSES ON THE IMMUNE SYSTEM

It has long been known that certain virus infec-tions can alter the morphology of lymphoid organs.Electron microscopy studies have demonstrated thepresence of virus particles in cells of the lympho-reticular system, such as macrophages, lymphocytes,neutrophils, thymocytes, Kupffer cells, and stemcells. More recent investigations have shown thatcertain viruses are able to replicate in macrophages(e.g., arboviruses, murine hepatitis virus, lactatedehydrogenase virus (LDV], and herpes simplexvirus (HSV]) while others can replicate in lymphocytes(e.g., lymphocytic choriomeningitis virus [LCMV],leukaemia viruses, and Epstein-Barr virus [EBVD.Several viruses appear to replicate only in lympho-

cytes that have undergone blast transformation fol-lowing exposure to specific antigen or phytohaemag-glutinin. Not all infections of the immune system,however, result in cell destruction; some lead to apersistent infection. For example, infection withEBV can result in the establishment of a continuouslymphoid cell line in vitro, while infection with theleukaemia viruses may be followed by malignanttransformation.

Recent studies indicate that certain virus infectionscan affect the function of the immune system. Theseinvestigations have utilized the immune response to avariety of antigens unrelated to the infecting virusin order to evaluate immunologic function. Mur-ine leukaemia viruses have received the most atten-tion. These viruses usually depress the immunesystem, under certain circumstances to a significantextent (Dent, 1972). For example, the number ofantibody-producing cells as determined by thehaemolytic plaque test (Jeme) may reportedly bedepressed by as much as 99 %. In general, infectionprior to the injection of antigen was found to resultin immunodepression, whereas infection after antigenadministration had considerably less effect. Thedegree of immunodepression was dependent on thedose of virus and on the nature and concentrationof the particular antigen. Moreover, some evidencehas been adduced that the leukaemia viruses (parti-cularly Friend virus) can exert " selectively " depres-sive effects, i.e. that they produce a greater depressionof the 7S than of the 19S immune response. Selectiveeffects also have been described in connexion withother viruses. Infection with Aleutian disease virus(ADV) can result in the appearance in the serumof an excess of monoclonal immunoglobulin. Italso has been claimed that LDV and LCMV canproduce an acute and " selective " depression ofT cells, but these results need to be confirmedand extended. Several non-oncogenic viruses (e.g.,ADV, LCMV, and Junin virus) are also able todepress the humoral immune response. In addition,certain viruses, such as LDV, LCMV, and Venezue-lan equine encephalitis virus (VEEV), can preventthe development of experimentally-induced immuno-logic tolerance.Although most studies of viral effects have been

concerned with the humoral immune response, recentinvestigations ofcell-mediated immunity and reticulo-endothelial function demonstrate that these too canbe depressed. For example, allograft rejection isprofoundly depressed in animals infected with Grossleukaemia virus and mildly depressed in animals in-

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fected with LDV. A number of viruses, includingthe Rauscher and Friend viruses and those causingmeasles and rubella, have been shown to inhibitblast transformation of lymphocytes (Dent, 1972).Not all viruses exert depressant effects on the

immune system. Several, such as LDV and VEEV,can act as adjuvants and potentiate the immuneresponse to certain antigens.A number of mechanisms have been postulated

to explain the immunodepressive effect of certainvirus infections (Allison, 1972; Notkins et al., 1970).These include (1) virus-induced changes in theuptake and processing of antigens, possibly byalteration of cell surfaces; (2) depression of nucleicacid and protein (antibody) synthesis; (3) destructionof antibody-producing cells or their precursors;(4) alteration of thymic function; (5) acceleration ofimmunoglobulin catabolism; (6) antigenic compe-tition; and (7) lymphocytolysis as a result of increasedadrenocortical secretion. Possible explanations ofthe immunologic enhancement associated withvirus infections include (1) altered uptake and pro-cessing of antigens; (2) increase in the number ofantibody-producing cells or their precursors; and(3) enhanced metabolism of antibody-producingcells.The effects of virus infections on immune function

may have several important pathological repercus-sions. Virus-induced immunodepression might allowcertain infections to persist, thereby adding to theantigenic load and increasing the likelihood ofimmunopathological consequences (e.g.. immune-complex disease). Moreover, depression of the im-mune response might trigger or enhance the growthof certain tumours. Virus-induced potentiation ofimmune response might also have immunopatho-logical consequences, such as the development ofautoimmune disorders (WHO Scientific Group onFactors Regulating the Immune Response, 1970).

Recommendations(1) A systematic evaluation of the effects of viruses

on immune function should be undertaken. A num-ber of viruses should be studied and a standardset of immune function tests should be employed.Among the factors that deserve special investigationare antigen types (e.g., thymus-dependent versusnon-thymus-dependent), antigen dose, and the timerelationship between infection and antigen adminis-stration.

(2) The effects of virus infection on different celltypes (e.g., macrophages, T and B lymphocytes)

should be studied in greater detail, with morphologicchanges perhaps serving as an indication of functionalalterations. Since differences in terminology oftenmake it difficult to assess reports of pathologicalchanges in lymphoid tissue, all modifications of thelymphoid organs should be described according tostandardized criteria. Efforts at standardization arecurrently being supported by the World HealthOrganization.

(3) An attempt should be made to ascertain whetherviruses can in fact exert selective effects on immunefunction, e.g., by depressing 7S versus 19S antibody,or by affecting T cell function as opposed to B cellfunction (Allison et al., 1971). The possibility shouldalso be looked into that the immune response tothe virus may itself be impaired if the infecting virusdamages more or less selectively the cells respondingto the viral antigens. If this proves to be the case,virus-induced immunodepression might conceivablybe highly instrumental in prolonging certain virusinfections, such as murine leukaemia, hepatitis, sub-acute sclerosing panencephalitis, or infections causedby LDV, LCMV, or ADV.

IMMUNE-COMPLEX DISEASES

It is well known that the persistence of antigen-antibody complexes in the circulating blood canlead to serum sickness, as manifested by glomerulo-nephritis, polyarteritis, urticaria, arthralgia, andarthritis. Recently, it has been shown in animals thatviruses can persist in the bloodstream in the formof virus-antibody complexes, and that the depositionof these complexes in the kidney can produce animmune-complex type of glomerulonephritis.

Infectious virus-antibody complexes have beendetected in the blood of animals with murine leukae-mias and those infected with LDV, ADV, andLCMV (Mellors et al., 1969; Oldstone & Dixon,1969; Notkins et al., 1966; Porter et al., 1969;Oldstone & Dixon, 1971b, respectively). Prelimi-nary evidence suggests that infectious complexesalso exist in the bloodstream of horses infected withequine infectious anaemia virus (EIAV) (McGuireet al., 1971). Immunopathological studies have re-vealed the presence of viral antigens, specificantiviral antibody, and complement in the kidneysof these animals (Oldstone & Dixon, 1971b).

Severe glomerulonephritis has been found inLCMV carrier mice (Hotchin & Collins, 1964;Oldstone & Dixon, 1969, 1971b). The severity ofthe disease appears to be related to the strain of

9

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MEMORANDA

the mouse, the amount of LCMV, and the amountof antiviral antibody (Oldstone & Dixon, 1969).Aleutian disease of mink also is characterized bysevere glomerulonephritis (Porter et al., 1969). Allmink appear to be susceptible to infection by ADV,but those homozygous for the Aleutian gene developa more severe form of the disease, characterized byheavy deposition of virus, antibody, and complementin the glomeruli. However, relatively mild glomeru-lar lesions are seen in mice infected with LDV.In humans, circulating Australia antigen can existin the form of antigen-antibody complexes (Zucker-man, 1971). One case of immune-complex nephritiswith deposition of Australia antigen, IgG, andcomplement in the glomeruli has been reported,and in 4 cases of hepatitis autopsy disclosed thepresence of Australia antigen, IgG, IgM, and comple-ment in glomerular capillaries.

There is generally little evidence that vasculitiscan be caused by virus-antibody complexes, butvascular lesions suggestive of polyarteritis nodosaand containing immunoglobulins have been reportedlate in the course of infection with ADV and EIAV.Recently, polyarteritis nodosa has been describedin patients with circulating Australia antigen (Gockeet al., 1971); in one such case, Australia antigen,immunoglobulin, and complement were detectedin the arterial wall (Gocke et al., op. cit.). In 5cases of fatal hepatitis, Australia antigen, immuno-globulin, and complement were found in the intimaof arterioles exhibiting changes typical of periarte-ritis. It has also been suggested that immune com-plexes may be causally involved in the urticaria andarthritis (Alpert et al., 1971) sometimes associatedwith hepatitis.Although deposition of circulating immune com-

plexes appears to be the most likely explanation ofthese findings, the possibility has not been excludedthat viral antibody might attach to viral antigensreleased locally from infected cells or to virus-inducedantigens on the surface of infected cells (see sectionentitled " Antibody-mediated immunopathologicalinjury "). In several autopsy studies of patientswith various forms of hepatitis, intracellular andextracellular deposits of Australia antigen, immuno-globulins and complement were reportedly foundin liver parenchymal and Kupffer cells (Nowos-lawski et al., 1972). In these cases, immunoglobulinsdirected specifically against Australia antigen wereeluted from the liver with 2.5 M thiocyanate. Atpresent, however, there is very little informationavailable to pinpoint the factors responsible for

producing virus-induced immune-complex disease.Whether the causal factor is the size of the complex,the nature of the viral antigen, the amount or typeof antibody, the attachment of accessory factorssuch as complement (Winchester et al., 1971) orrheumatoid factor (Notkins, 1971; Winchester et al.,1971; Ziegenfuss et al., 1971), or the rate at whichthe antigen and antibody turn over (in the glomeru-lar lesions) remains to be determined.To date, virus-induced immune-complex disease

has been attributed to the deposition of virus-antibody complexes during persistent virus infections(Oldstone & Dixon, 1971b). Conceivably, immune-complex disease also could occur from the repeateddeposition of such complexes during various acuteand recurrent virus infections. It should be empha-sized that, in addition to virion-antibody complexes,antibody bound to virus-induced membrane anti-gens, soluble viral antigens, and viral nucleoproteinsmight contribute to the pool of circulating immunecomplexes.The mechanism of tissue injury associated with

deposition of virus-antibody complexes is presu-mably similar to that involved in the deposition ofnonviral antigen-antibody complexes. It is knownthat activation of the complement sequence byimmune complexes can effect the release of sub-stances that have the capacity to increase vascularpermeability, contract smooth muscle, and attractpolymorphonuclear and mononuclear leucocytes.These factors would seem to play a role in the tissueinjury associated with immune-complex disease.In addition, it has been postulated that immunecomplexes might activate components of the clottingsystem and thereby cause the deposition of fibrin.

Recommendations(1) The presence of immune complexes in the

kidney, arterial walls, or other tissues should beconfirmed by demonstrating viral antigens, specificantiviral antibody, and complement in the lesionsby immunofluorescence. If, however, the antigencannot be detected because antigenic sites have beensaturated by antiviral antibody, the antibodyshould if possible be dissociated by standard tech-niques (e.g., acid buffer, pH 2.0-3.0). The elutedantigen or antibody may be characterized by im-munodiffusion, complement fixation, virus neutrali-zation, or other techniques.

(2) Attempts should be made to recover and iden-tify infectious virus from the kidney, extrarenal

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tissue, and circulating blood by standard virusisolation techniques. To determine whether the iso-lated virus exists in the form of an infectious virus-antibody complex, the anti-immunoglobulin neu-tralization technique should be used.

(3) Efforts should also be made to detect non-infectious virus-antibody complexes in the circu-lation. Upon incubation with the Clq componentof complement or rheumatoid factor (Winchesteret al., 1971), these complexes may precipitate outdemonstrably. Conversely, incubation in an acidbuffer may dissociate the complexes and permit theviral antigens and specific antiviral antibody to beidentified as described in (1) above.

(4) If virus cannot be recovered by any of theabove techniques, the animals should be immunizedwith isolated complexes and their sera tested forantibodies to a variety of viruses.

(5) When DNA-anti-DNA complexes are pre-sent in the glomeruli, an endeavour should be madeto distinguish between viral nucleic acids and nucleicacids of nonviral origin.

(6) Since glomerulonephritis of differing degrees ofseverity can be produced in the same host by differentviruses (e.g., LCMV versus LDV), attention shouldbe focused on the factors involved in the initiationand production ofimmune-complex disease. It wouldbe desirable to develop models to study the clearanceof virus-antibody complexes from the bloodstreamand the rate at which these complexes deposit andturn over in the kidney.

(7) Animals with infections characterized by per-sistent or recurrent viraemia (e.g., feline leukaemia,African swine fever, hog cholera, and avian lympho-matosis) should be examined for antiviral antibodycirculating virus-antibody complexes, and immune-complex nephritis.

(8) A major effort should be made to elucidate therole of immune complexes in the pathogenesis ofviral hepatitis in man.

ANTIBO)Y-MED)IATED IMMUNOLOGIC INJURY

In the last decade it has been shown that thetransformation of cells by oncogenic viruses resultsin the appearance of new antigens on the cell sur-face and that immune responses to these antigensmay be involved in tumour rejection. Non-onco-genic viruses can also produce new antigens on thesurfaces of infected cells, but the biological signi-

ficance of these antigens has received relatively littleattention. Evidence is now beginning to emerge,however, suggesting that the interaction of specificantiviral antibody and complement with surfaceantigens induced by non-oncogenic viruses can leadto cell destruction and may contribute to the patho-genesis of the lesions associated with certain virusinfections.

In vivo, the best experimental evidence that anti-body can play such a pathogenetic role comes fromthe demonstration that the passive administrationof specific antiviral antibody to animals infected withLCMV (Oldstone & Dixon, 1970), ADV, or JapaneseB encephalitis virus produces or intensifies the charac-teristic lesions associated with these infections. Inaddition, it has been speculated that the interactionof specific antiviral antibody and complement withantigens induced by the respiratory syncytial,measles, hepatitis, dengue, and equine infectiousarteritis viruses may be partly responsible for thepathological picture seen in these infections. Anothersuggestion has been that the passive attachment ofvirus, antiviral antibody, and complement to thesurface of platelets or erythrocytes may result incell injury and might give rise to some of the haema-tologic abnormalities associated with virus infections,such as dengue shock syndrome (Russell, 1971)-the most severe form of dengue haemorrhagic fever-and equine infectious anaemia.The strongest evidence that antiviral antibody and

complement can injure virus-infected cells has beenproduced by in vitro experiments. It has been shownthat the infection of cells with viruses that do notproduce cytologic injury (rabies (Wiktor et al.,1968), LCMV) (Oldstone & Dixon, 1971a), or withviruses that ultimately do cause cell damage (HSV,vacciniavirus, influenzavirus, Newcastle diseasevirus [NDV] (Brier et al., 1970) is followed by theappearance of new antigens on the surface of theinfected cells and that the interaction of specificantiviral antibody and complement with these anti-gens can produce immunologic injury. In theabsence of either specific antiviral antibody or com-plement, such injury does not occur. The degree ofinjury may depend on a number of factors (Brier etal., 1970), including (1) the density of viral antigenson the infected cell surfaces; (2) the inherent sus-ceptibility of the cells to lysis by complement;(3) the nature and concentration of the antiviralantibody; (4) the ratio of complement-fixing tonon-complement-fixing antibody in the particularserum; and (5) the presence of inhibitors, such as

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262 MEMORANDA

anti-immunoglobulins or rheumatoid factor, thatmight block complement-fixing sites on the antiviralantibody. The appearance of viral antigens mightin turn be related to other factors, such as the phaseof the cell cycle or coinfection with a second virus.If a particular virus produces few or no new anti-genic sites on the surface of cells or if these antigenicsites are far apart, complement-mediated cell de-struction may not occur. If, however, the densityof virus-specific antigens on the cell surface shouldrise during the course of an infection, this wouldincrease the likelihood of complement-mediated celldestruction. Fluctuations in the density of viralantigens on the infected cell surface might contributeheavily to the pathogenesis of lesions associated with" slow virus " infections (Porter, 1971).

Implications

The attachment of antiviral antibody in sublyticconcentrations to the surface of infected cells mayconceivably be instrumental in deciding the fate ofthe cell. On the one hand, the attachment of anti-viral antibody might accelerate phagocytosis of theinfected cell by activated macrophages. On the otherhand, antiviral antibody might prevent sensitizedlymphocytes from recognizing or reacting with theviral antigens and thereby inhibit the cell-mediatedimmune response. In virus infections, this mightprove to be the counterpart of "blocking" or" enhancing " antibody.Under certain circumstances the destruction of

virus-infected cells by antiviral antibody and comple-ment may be more beneficial than harmful to thehost. Antibody-mediated cell destruction may be oneof the mechanisms by which the host combats thoseviruses that tend to elude neutralization by spread-ing directly from cell to cell. Moreover, the destruc-tion of cells that are actively producing virus wouldslow down viral replication and release or exposethe infectious virus within the cell to neutralizingantibody. Thus, in virus infections, antibody-mediated cell destruction may fulfil many of thefunctions that have been postulated for cell-mediatedimmunity and may serve as a complementary orsupplementary defence mechanism. In addition,in vitro experiments suggest that the release of oneor more chemotactic-generating factors (Brier et al.,1970) from infected cells and/or the interactionbetween antiviral antibody and viral antigens canactivate the complement sequence and cause therelease of mediators able to attract polymorpho-nuclear and mononuclear leucocytes.

Recommendations(1) Although many investigators have speculated

that immunologic injury may contribute to thepathological picture in certain virus infections, ithas been difficult to isolate and evaluate this pheno-menon in vivo. The release of 51Cr from virus-infected cells by antiviral antibody and complementprovides a simple, objective, and quantitative tech-nique for studying immunologic injury in vitro.With this technique it should be possible to (a)investigate a variety of viruses; (b) evaluate virus-induced immunologic injury in different types ofcell; (c) compare the roles of cytolytic and non-cytolytic antibody in the serum of patients duringthe course of various virus infections; (d) determinewhether biological mediators are released or acti-vated as a result of the interaction of antiviralantibody and complement with viral antigens; and(e) investigate the relationship between antibody-mediated and cell-mediated destruction of infectedcells.

(2) In vivo studies should be extended and experi-mental models developed. Additional studies shouldbe conducted to evaluate the results of the passiveadministration of cytolytic antiviral antibody toinfected animals with normal and depleted levels ofcomplement. Efforts should be made to demonstratethe presence of antiviral antibody and complementon the surface of injured cells at the site of the lesion.Further thought should be given to the potentialbeneficial or harmful effects of passive protectionwith immunoglobulins containing cytolytic antiviralantibody or with vaccines (e.g., rabies vaccine)that might induce cytolytic antibody.

(3) Attempts should be made to compare thein vitro and in vivo effects of antibody and comple-ment on the lysis of virus-infected cells. Whether theattachment of nonlytic antibody to infected cellscan inhibit the cell-mediated immune response shouldbe investigated.

* **

A. C. ALLISON, Clinical Research Centre, NorthwickPark Hospital, Harrow, Middlesex, England

W. I. B. BEVERIDGE, Veterinary Public Health Consultant,World Health Organization, Geneva, Switzerland

W. C. COCKBURN, Chief Medical Officer, Virus Diseases,World Health Organization, Geneva, Switzerland

JUNE EAST, Department of Environmental Carcino-genesis, Imperial Cancer Research Fund, Mill Hill,London, England

VIRUS-ASSOCIATED IMMUNOPATHOLOGY. 1 263

H. C. GOODMAN, Chief Medical Officer, Immunology,World Health Organization, Geneva, Switzerland

H. KOPROWSKI, The Wistar Institute of Anatomy andBiology, Philadelphia, Pa., USA

P.-H. LAMBERT, World Health Organization HaematologyResearch Unit, Cantonal Hospital, Geneva, Switzerland

J. J. vAN LOGHEM, Department of Immunopathology,University of Amsterdam, The Netherlands

P. A. MIESCHER, Haematology Division, Cantonal Hospi-tal, Geneva, Switzerland

C. A. MIMMs, Microbiology Department, The John CurtinSchool of Medical Research, Australian National Uni-versity, Canberra City, Australia

A. L. NOTKNS, Chief, Virology Section, National Instituteof Dental Research, Bethesda, Md., USA

G. TORRIGIANI, Medical Officer, Immunology, WorldHealth Organization, Geneva, Switzerland

RtSUMAETATS IMMUNOPATHOLOGIQUES INDUITS PAR LES VIRUS: MODLLES ANIMAUX

ET RELATIONS AVEC LES MALADIES HUMAINES:1. EFFETS DES VIRUS SUR LE SYSTEME IMMUNITAIRE, MALADIES DUES A DES IMMUNCO)APLEXES

ET LtSIONS IMMUNOLCGIQUES PROVCQUVES PAR L'INTERMtDIA]RE DES ANTICORPS

On sait depuis longtemps que les virus produisentdes lesions en endommageant et parfois en detruisantles cellules a l'int6rieur desquelles ils se multiplient.Plus recemment, on a decouvert que des alterationstissulaires peuvent aussi r6sulter d'interactions entre levirus et le systeme immunitaire de l'h6te. L'etude dediverses maladies des animaux a permis de deceler uncertain nombre de mecanismes immunopathologiquesresponsables des lesions provoquees par des infectionsvirales. Ces mecanismes - ainsi que les concepts et lestechniques issus de ces recherches - scnt d6crits dans lalre et dans la 2e partie du present memorandum. Leursconsequences eventuelles au regard des maladieshumaines sont examinees et plusieurs de leurs appli-cations sont envisag6es.Un premier type de lesion immunologique est diu

aux effets directs exerc6s par certains virus sur le systWmeimmunitaire. Des virus, notamment les virus des leuc&mies et des virus responsables d'i nfections de longue dur6e,diminuent la capacite de production des anticorps chezl'h6te; d'autres agissent en renforgant la reponse immuni-taire a divers antigenes. Dans certains cas, il est manifesteque les virus inhibent 6galement l'immunite a supportcellulaire. Cette action des virus sur la fonction immuni-taire pourrait avoir de nombreuses et importantes cons&quences du point de vue clinique; c'est ainsi que l'affai-blissement de l'immunit6 serait susceptible de favoriserle d6veloppement de tumeurs.

Les maladies dues a des immuncomplexes represententune autre forme de l6sion immun opathologique provoqu6epar des virus. Dans les infections virales persistantes,les anticorps specifiques se combinent parfois aux virus

ou aux antiggenes viraux pour former des immuncom-plexes qui sont ensuite deposes dans divers endroits del'organisme, et en particulier dans le rein. Dans cettedernie eventualite, on peut voir apparaitre ult6rieure-ment une glomerule-nephrite caus&e par la combinaisondes immuncomplexes et du complement entrainant laliberation de substances qui lesent les tissus. Les depotsd'immunocomplexes dans la paroi des petites arterespeuvent provoquer des lesions vasculaires rappelant cellesde la periarterite noueuse.

Enfin, un troisieme type de lesion immunologiqueest celui realise a l'intervention des anticorps. I1 s'agitde la reaction produite lors de la fixation des anticorpsspcifiques sur les antigenes cellulaires de surface induitspar les virus. Le complement, normalement present, peutalors leser les cellules et meme provoquer leur lyse.On connalt un certain nombre de virus, en dehors desvirus oncogenes, qui produisent des antigenes a la surfacedes cellules dans lesquelles ils ont penere. L'exp6ri-mentation in vitro montre qu'en l'absence d'anticorpssp&cifiques ou de complement il ne se produit aucunel6sion immunologique. Dans certaines conditions, ladestruction des cellules infectees par le virus se revele,en depit du dommage cause, favorable pour l'h6teen ralentissant ou en arretant la multiplication du virus.Dans d'autres cas, et notamment lorsqu'un grand nombrede cellules d'un organe vital sont atteintes, la lesion peutavoir des consequences graves et meme fatales.

D'autres formes d'interaction entre les virus et lesysteme immunitaire entrainant egalement des lesionssont decrites dans la 2e partie du mimorandum.

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Allison, A. C. et al. (1971) Cooperating and controllingfunctions of thymus-derived lymphocytes in relationto autoimmunity, Lancet, 2, 135

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Brier, A. M. et al. (1970) Inflammation and herpessimplex virus: release of a chemotaxis-generating factorfrom infected cells, Science, 170, 1104

Dent, P. (1972) Immunodepression by oncogenic viruses,Progr. med. Virol., 14, 1

Gocke, D. J. et al. (1971) Vasculitis in association withAustralia antigen. J. exp. Med., 134, 330S

Hotchin, J. & Collins, D. N. (1964) Glomerulonephritisand late onset disease of mice following neonatal virusinfection. Nature (Lond.), 203, 1357

McGuire, T. C. et al. (1971) Immunofluorescent locali-zation of equine infectious anemia virus in tissue.Amer. J. Path., 62, 283

Mellors, R. C. et al. (1969) Further implication of murineleukaemia-like virus in the disorders of NZB mice,J. exp. Med., 129, 1045

Notkins, A. L. et al. (1966) Infectious virus-antibodycomplex in the blood of chronically infected mice,J. exp. Med., 124, 81

Notkins, A. L. et al. (1970) Effect of virus infectionson the function of the immune system, Ann. Rev.Microbiol., 24, 525

Notkins, A. L. (1971) Infectious virus-antibody com-plexes: interaction with anti-immunoglobulins, comple-ment, and rheumatoid factor, J. exp. Med., 134, 41S

Nowoslawski, A. et al. (1972) Australia antigen andhepatitis: pathogenic considerations and practicalimplications, Recent Adv. clin. Path. (in press)

Oldstone, M. B. A. & Dixon, F. J. (1969) Pathogenesisof chronic disease associated with persistent lymphocy-tic choriomeningitis viral infection. I. Relationshipof antibody production to diease in neonatally infectedmice. J. exp. Med., 129, 483

Oldstone, M. B. A. & Dixon, F. J. (1970) Pathogenesisof chronic disease associated with persistent lympho-cytic choriomeningitis viral infection. II. Relationshipof the anti-lymphocytic choriomeningitis immuneresponse to tissue injury in chronic lymphocyticchoriomeningitis disease, J. exp. Med., 131, 1

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