BrHeartJ 1994;72 (Supplement):S 30-S 34

Role of autoimmunity in dilated cardiomyopathy

A L P Caforio

Persistent viral infection of the myocardiumand autoimmunity are two of the main patho-genic hypotheses for dilated cardiomyopathy(DCM). A unifying hypothesis also suggeststhat an initial viral insult may trigger or pre-cipitate autoimmunity. Is it becoming clearerwhether DCM is a chronic viral disease, apost-infectious autoimmune process, orgenetically determined organ-specific auto-immune disease?When tolerance to "self' antigens is lost

autoimmune disease results. It is charac-terised by the presence of circulating autoanti-bodies, which are not necessarily pathogenicbut represent markers of continuing tissuedamage.' In autoimmune disease that is notorgan specific there are autoantibodies againstubiquitous autoantigens and tissue damage isgeneralised. In organ-specific autoimmunedisease one organ only is affected and theautoantibodies react with its unique auto-antigens.

Heart muscle is the only organ affected inDCM and thus to test the autoimmunehypothesis we need to know whether the crite-ria of an organ-specific autoimmune diseaseare fulfilled (table 1). Organ-specific autoim-mune diseases occur as a result of genetic pre-

Table 1 Features oforgan specific autoimmunity

* Middle aged women most frequently affected* Familial aggregation* Organ and disease specific circulating autoantibody in

patients and in unaffected family members* Cell mediated autoimmunity impaired* Associated autoimmune diseases in the same patient or

in family members* HLA association* Mononuclear ceU.infiltration and abnormal HLA

molecule expression in the target organ* Disease induced in animal models after immunisation

with relevant autoantigen

HLA, human leucocyte antigen.

Department ofCardiologicalSciences, St George'sHospital MedicalSchool, London andInstitute of ClinicalMedicine,Department ofCardiology,University ofPadua,Padua, ItalyA L P CaforioCorrespondence to:Dr Alida L P Caforio,Honorary Lecturer,Department of CardiologicalSciences, St George'sHospital Medical School,Cranmer Terrace, LondonSW17 ORE.

disposition and environmental influences.The genetic predisposition accounts for boththe fact that different autoimmune conditionsmay be associated in patients or in their familymembers and the common finding that singleautoimmune diseases often run in families.The inheritance of susceptibility is usuallypolygenic. Organ-specific autoimmune dis-eases are commonly associated with specificHLA class II antigens,' but it is not knownhow the HLA system determines the pre-

disposition to a specific disease.Most organ-specific autoimmune diseases

are chronic and apparently idiopathic. Organand disease specific antibodies are found inthe affected patients. These antibodies are

also detected in family members, sometimesyears before the disease develops, and theyidentify symptom free relatives who are atrisk.'

Is organ-specific auto'imunity involvedin human acute myocarditis?There is evidence that acute myocarditis is a

continuing autoimmune disease. Manypatients have circulating cardiac autoanti-bodies (table 2)28 and some have severalfeatures of classic organ-specific autoimmu-nity or of insulin dependent diabetes mellitus,which is an atypical but well establishedorgan-specific autoimmune disease in whichviruses may be implicated (table 3). Familialaggregation of acute myocarditis has not beensystematically investigated, but acute myo-carditis and DCM have been reported indifferent members of the same family.9 Littleis known about the associations of acutemyocarditis with other autoimmune diseases,except that giant cell myocarditis is associatedwith myasthenia gravis ' and pernicious

Table 2 Circulating autoantibodies in acute myocarditis

% Antibody positive

Antibody type Method AM OCD Healthy controls Reference

Muscle specific: IFLASA 47* NT 25 2 3AMLA 41* NT 12 2 3AFA 28* NT 6 2 3IFA 32* NT 3 2 3

Heart-reactive IFL 59* NT 0 4Anti-laminin ELISA 73* NT 6 5Anti-mitochondrial:M7 ELISA 13* 10 0 6ANT SPRIA 91*t 0 0 7

Anti-P receptor Bioassay 96*t 8 0 8

*P < 0 05 v controls; tP < 0-05 v controls with other cardiac disease. AFA, anti-fibrillary antibody; AM, acute myocarditis;AMLA, anti-myolemmal antibody; ANT, adenine nucleotide translocator; ASA, anti-sarcolemmal antibody; ELISA, enzymelinked immunosorbent assay; IWA, anti-interfibrillary; IFL, indirect immunofluorescence; NT, not tested; OCD, other cardiac dis-ease; SPRIA, indirect microsolid-phase radioimmunoassay.

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Role ofautoimmunity in dilated cardiomyopathy

Table 3 A comparison between acute myocarditis and organ-specific autoimmunity

Features AM Recent onsetIDDM OSAI

Clinical presentation Acute Acute ChronicSex M>F M>F F>MAge (yr) 20-40 1-19 40Familial aggregation Yes? Yes YesViral aetiology ? ? ?Organ specific antibody +ve (%) 40-100 80 80HLA association ? DR3-4 DR3-4-5Abnormal cell mediated immunity ? Yes YesAssociation with other AI disease Yes? Yes YesMononuclear cell infiltration Yes Yes YesAbnormal HLA expression:

Target cell No Yes YesEndothelium De novo Enhanced Enhanced

Animal models Yes Yes Yes

AM, acute myocarditis; IDDM, insulin dependent diabetes mellitus; OSAI, organ-specificautoimmunity.

anaemia."I Important autoimmune features,such as the impairment of cell mediatedimmunity and HLA association have not yetbeen investigated, but Herskowitz et al did notfind abnormal expression of HLA on the tar-get cell, the myocyte, in acute myocarditis."2This abnormal expression is not an absoluteprerequisite for autoimmune conditions: in

multiple sclerosis, for example, HIA class IIis not expressed on neurons."3 Importantly,(see below) animal models of autoimmunemyocarditis have been produced.

Evidence for autoimmunity in

experimental murine myocarditisA model for autoimmune myocarditis was

found accidentally when workers trying tounravel the mechanisms of myocardialdamage in experimental Coxsackie B virus-induced murine myocarditis found that onlycertain strains of mice (A-J background) were

susceptible to acute myocarditis. Morechronic sequelae resembling DCM developedin these strains.'4 Early on (7-10 days) in the

disease CD8 T cells were cytotoxic for virallyinfected cells. Later (2-3 weeks) they were

able to kill cells that were not infected withviruses, suggesting the generation of auto-immune T cell clones.'4 15 In the late phase ofautoimmune myocarditis no infectious viruswas detectable (by conventional virus cultureand isolation methods) in the heart of the

Table 4 Autoantibodies in dilated cardiomyopathy

% Antibody positiveHealthy

Antibody type Method AM OCD controls Reference

Muscle specific: IFLASA 10 NT 25 3AMLA 9 NT 12 3AFA 24* NT 6 3IFA 41* NT 3 3

Organ specific cardiac IFL 26*t 1 3 19Heart reactive IFL 20* NT 0 4Anti-lamiiin ELISA 78*t NT 6 5Anti-mitochondrialM7 ELISA 31* 10 0 6ANT SPRIA 57*t 0 0 7

Anti-# receptorInhibiting LBI 30*t 8 4 20Inhibiting ELISA 31*t 0 12 21Stimulating Bioassay 95*t 8 0 8

Anti-a and BAMHC Immunoblot 46*t 8 0 22

*P < 0 05 v controls; tP < 0 05 v OCD.LBI, ligand binding inhibition; MHC, myosin heavy chain. See footnote to table 2 for otherabbreviations.

affected mice. Two populations of antibodiesdeveloped in these mice: one cross-reactedwith skeletal and cardiac myosin and the otherwas specific for the cardiac isoform.'6The key experiment to prove the autoim-

mune nature of the chronic form of myocardi-tis was then performed: immunisation of A-Jnormal mice with cardiac myosin alone, with-out virus, induced histologically and immuno-logically identical disease.'7 Immunisationwith skeletal myosin did not producemyocarditis, showing that myosin-inducedmyocarditis was a model for an organ-specificautoimmune heart disease. Humoral andcellular transfer experiments in this auto-immune model showed that the myocarditisprocess was transferable only by T cells andwas inhibited by monoclonal antibodies bind-ing to HLA class II molecules which dis-turbed antigen presentation to the T helpercells."'

These studies showed that the chronic formof murine myocarditis was an autoimmunedisease triggered by a virus in animals with apredisposing genetic background, rather thana persistent viral infection. In addition, thefinding that autoimmune myocarditis wasproduced after stimulation of the immunesystem with complete Freund's adjuvant andautoantigen (myosin) indicates not only thatviral infection but also that other externalpro-inflammatory stimuli could trigger auto-immunity in genetically predisposed animalsand humans.

Humoral autoimmune phenomena indilated cardiomyopathyClinical and experimental observations indi-cate that myocarditis is a likely candidate forautoimmune pathogenesis. But are organ anddisease specific circulating cardiac antibodiesdetectable in patients with DCM?

Several groups have consistently foundcardiac antibodies in DCM (table 4),3-8 19-22but the organ and disease specificities of theseantibody types have not been always evalu-ated. For instance, using indirect immuno-fluorescence (IFL) earlier studies identifiedantibodies to sarcolemmal and myofibrillarantigens, but these were not strictly cardiacspecific because they cross reacted withskeletal muscle.' In addition, it was not clearwhether these muscle specific antibodies wereassociated with DCM, because controls withother cardiac disease and with heart failurenot caused by DCM were not evaluated.When the frequency of cardiac antibodies

was recently reassessed using IFL on humanhearts, organ and disease specinfc antibodiesof the IgG class were found in 26% of DCMpatients from England.'9 These antibodies didnot stain human skeletal muscle and theirspecificity to the heart was confirmed byrelevant absorption studies.'9 Interestingly,another group reported that 20% of DCMpatients from the United States had anti-bodies that gave a diffuse cytoplasmic stainingpattem on rat heart.4 The cardiac specificityof these antibodies was not investigated by

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testing on skeletal muscle and by absorptionstudies, but their IFL pattern on rat heart wasindistinguishable from that given on humanheart by the organ-specific cardiac antibodies.This suggests that the antibodies detected byIFL on human and on rat heart recognise thesame organ-specific cardiac autoantigen(s).Two of the autoantigens recognised by theseantibodies have already been identified as the aand /3 heavy chains of myosin; additional andas yet unknown antigens are also present.22The /3 chain is expressed in skeletal and car-diac myosin and is therefore not specific tothe heart. The a isoform is expressed solelywithin the myocardium. Antibodies to thismolecule are truly organ-specific cardiacautoantibodies.2The identification of a and /B heavy chains

of myosin as relevant autoantigens in DCMpatients parallels what is seen in the experi-mental model of autoimmune myocarditisDCM.'6--8 But what is the pathogenic rele-vance of these findings? Until recently it wasthought unlikely that any intracellularautoantigen would be of primary importancein pathogenesis, but it is now clear thatendogenous peptides derived from the intra-cellular processing of self cytoplasmic proteinsare normally present in the cleft of surfaceHLA molecules.23'Thus intracellular autoanti-gens can be seen by the immune system andunder normal conditions tolerance is main-tained. In the presence of appropriate triggers(for example, viral infection or other inflam-matory stimuli) and of genetic predisposition,tolerance could break down and autoimmu-nity to these self intracellular autoantigensmight ensue. Recent work with T cellhybridomas showed that residential antigenpresenting cells (APC) in the normal mouseheart process and express myosin/MHC com-plexes (MHC is the mouse equivalent of theHLA system). Expression of these myosincomplexes was increased by the induction ofautoimmune myocarditis.24 Clearly there islocal turnover of myosin molecules by thelocal APCs in the absence of cardiac damage.This strongly accords with myosin being animportant cardiac autoantigen. The release orexposure of antigen may be a vital step in thedisease process but only in those individualsthat are susceptible to the disease. It may bethat part of this susceptibility to autoimmunemyocarditis is conferred both by MHC andnon-MHC genes.'4

Although myosin is probably an importantautoantigen, the work on the animal model ofDCM suggests that it is unlikely that the car-diac myosin antibody is directly responsiblefor cardiac damage. Passive transfer of highlyconcentrated autoantibody in the mouse doesnot induce myocarditis in genetically suscepti-ble recipients, and the disease is clearly T cellmediated.25 T cells are also more likely to bethe effector arm of the suggested autoimmunepathogenesis in patients. This does not under-mine the possible importance of the antibodyto cardiac myosin as a disease marker or evenor predictive marker, like the islet cell auto-antibodies in IDDM.I

Antibodies against two distinct mitochon-drial antigens, the M7 antigen6 and the ade-nine nucleotide translocator (ANT),7 havealso been detected in DCM sera. Mito-chondrial antigens have generally been classi-fied as non-organ specific,' thus theirsuggested involvement in a supposedly organ-specific autoimmune disease seemed novel.None the less, the heart-specificity of the M7antibodies was shown by absorption studies;ANT antibodies were not tested. Studiesshould be performed to rule out a potentialcross reactivity with skeletal muscle because itis not known whether there are two distincttranslocator isoforms for cardiac and skeletalmuscle.

Schultheiss et al found that experimentallyinduced affinity-purified anti-translocatorantibodies cross reacted with calcium channelcomplex proteins of rat cardiac myocytes,enhanced transmembrane calcium current,and produced calcium dependent cell lysis inthe absence of complement.26 They suggestedthat these effects may impair the function ofthe carrier protein, imbalance energy deliveryand demand within the cell, and lead to celldeath. They also speculate that this may be animportant pathogenic mechanism of auto-immune myocardial damage in DCM and inmyocarditis. The presence of this novel mech-anism of antibody dependent cell lysis hasnot, however, been shown using the anti-bodies present in patients' sera. Specific con-firmation of binding to and a deleteriouseffect on the calcium channel is now required.

Several groups have demonstrated antibod-ies against the /3, adrenoceptor.8 20 21 Limasand Limas detected these antibodies in30-40% ofDCM patients by a binding inhibi-tion assay.20 Antibody positive DCM serainduced sequestration and endocytosis of /3'receptors that were predominantly dependenton /3 receptor kinase and selectively inhibitedisoproterenol-sensitive adenylate cyclaseactivity.20

Wallukat et al studied another functionalindex of the /,3 receptor antibody. Antibodypositive DCM sera accelerated the beating ofneonatal rat heart myocytes in vitro.8 Theeffect was inhibited by propranolol, bisopro-lol, and metoprolol. It is well known thatsome patients with DCM benefit from treat-ment with /3 blockade. Wallukat et al sug-gested that this permanent humoralstimulation of the 3,' receptor could accountfor the accelerated decline in function of thefailing heart in some patients with DCM. Thishypothesis offers a rationale for the use of/PIantagonists in these patients.

There is a question mark over the organspecificity of the anti-3,B receptor antibodies./3 Receptors are situated in several differenttissues and even the supposedly cardiacspecific /3, receptors are found in low concen-tration in the liver and the kidney. There doesnot appear to be a cardiac specific isoform forthe /3 receptor as there is for the a myosinheavy chain. In addition cross reactivity wasreported between anti-/3, receptor antibodiesand anti-HIA antibodies.27 If this is con-

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Role ofautoimmunity in dilated cardiomyopathy

firmed the incidence of the anti-fl1 receptorantibodies in DCM will be considerably lowerand their projected importance much less.

In other organ-specific autoimmunediseases antibodies in most cases are notcytotoxic; so attempts passively to transferDCM from human to genetically susceptiblemice with one or more antibody wouldprovide conclusive evidence for antibodymediated pathogenesis.The argument that ANT, the M7 antigen,

and fl, receptor are important cardiacautoantigens would also be strengthened ifthey can be shown to induce myocarditis inthe animal model in the same way as myosindoes.

Is organ-specific autoimmunity involvedin dilated cardiomyopathy?About 30-40% of patients with DCM haveorgan and disease specific autoantibodies. Inthese patients the disease may be claimed tobe autoimmune. But what about the antibodynegative patients? There are several concomi-tant or alternative explanations. Firstly, DCMmay be an aetiologically heterogeneous condi-tion; the absence of cardiac antibodies couldindicate that cell-mediated autoimmunemechanisms are predominant, or that autoim-munity is not involved in the antibody nega-tive patients, or both.

Secondly, because cardiac antibodies areearly markers of disease that become unde-tectable as the disease progresses, as seen inIDDM, they may not be found in some DCMpatients.28 There is a report that cardiacantibodies are more common in patients withbetter exercise tolerance, as measured by oxy-gen consumption during maximal symptom-limited treadmill exercise testing.29 In anotherpreliminary report, cardiac antibodies weredetected in asymptomatic DCM relatives withearly cardiac dysfunction.30 These data sup-port the possibility that the absence of cardiacantibodies, at least in some DCM patients, isrelated to disease progression. Clinical andserological follow up studies of the antibodypositive patients, and relatives with cardiacantibodies are needed. Finally, differentDCM patients can have antibodies with dif-ferent antigen specificities. Collaborative workwith exchange of sera by different laboratories

Table 5 A comparison between dilated cardiomyopathy and organ specific autoimmunity

LongstandingFeatures DCM IDDM OSAI

Clinical presentation Chronic Chronic ChronicSex M>F M>F F>MAge 20-40 20-40 40Familial aggregation Yes Yes YesViral aetiologyOrgan specific antibody +ve (%) 30 30 80HLA association DRA-5 DR3-4 DR3-4A5Abnormal cell-mediated immunity? ? Yes YesAssociation with other AI disease No? Yes YesMononuclear cell infiltration No No YesAbnormal HLA expression:

Target cell No Yes YesEndothelium De novo Enhanced Enhanced

Animal models Yes Yes Yes

DCM, dilated cardiomyopathy. See footnote to table 1 for other abbreviations.

and assessment of more than one antibodyspecificity in standard positive and negativesamples is likely to clarify this.

In addition to the presence of the antibodymarkers, how many of the criteria for anautoimmune disease are fulfilled in DCM? Aswith myocarditis most features are present(table 5). Myocarditis resembles recentlydiagnosed IDDM, whereas DCM resembleslong-standing IDDM. These common fea-tures include: male predominance, HLA-DR4association,3' familial aggregation of cases(20-25% of DCM cases)32, and a relative lackof mononuclear cell infiltrates in the targetorgan. Indeed most patients with DCM cometo their physician with overt heart failure and ahistory going back several weeks, months, oreven years. It is highly likely that such patientsare presenting at a late stage in the natural his-tory of the disease, when the autoimmunedamage has already occurred and fibrosis is allthat is seen on the cardiac biopsy specimen.

Cell-mediated immunity seems to havebeen less extensively investigated than humoralimmunity in patients with myocarditis orDCM and the results are controversial.'3-36Examination of T cell subsets has revealedisolated abnormalities of T helper/suppressorcell ratios33 and of suppressor cell function.34Natural killer (NK) cell activity has beenshown to be reduced in DCM,35 but thisfinding is not cardiac specific. Leucocytemigration inhibition and lymphocyte transfor-mation assays did not show significant differ-ences between DCM patients and controls,but some DCM patients did show leucocytemigration inhibition with cardiac antigens,suggesting that autoimmunity might beinvolved in this subgroup.36Most of this work was completed before

animal studies and human humoral workestablished that the myosin heavy chain,22 thefl, receptor,8202' and the ANT7 were poten-tially important autoantigens. None of thisprevious cellular work has involved antigenspecific targeting or T cell proliferation stud-ies. None studied patients with early disease,in whom antigen-specific cellular activation ismore likely to be detected. Thus the centralrole of cell-mediated immunity in experimentalDCM is now very clear whereas the potentialrole of the T lymphocyte in human DCMwarrants further investigation. Autoi-mmunityis involved in causing myocardial damage inabout a third of patients with dilated cardio-myopathy.

ALPC is supported by the Veneto region target project oncardiomyopathies (Venice, Italy) and the National ResearchCouncil target project FAT.MA (Rome, Italy).

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