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Role of Autoimmunity in Dilated Cardiomyopathy Br Heart J: First Published As 10.1136/Hrt.72.6 Suppl.S30 on 1 December 1994

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Role of Autoimmunity in Dilated Cardiomyopathy Br Heart J: First Published As 10.1136/Hrt.72.6 Suppl.S30 on 1 December 1994 S 30 BrHeartJ 1994;72 (Supplement):S 30-S 34 Role of autoimmunity in dilated cardiomyopathy Br Heart J: first published as 10.1136/hrt.72.6_Suppl.S30 on 1 December 1994. Downloaded from A L P Caforio Persistent viral infection of the myocardium disposition and environmental influences. and autoimmunity are two of the main patho- The genetic predisposition accounts for both genic hypotheses for dilated cardiomyopathy the fact that different autoimmune conditions (DCM). A unifying hypothesis also suggests may be associated in patients or in their family that an initial viral insult may trigger or pre- members and the common finding that single cipitate autoimmunity. Is it becoming clearer autoimmune diseases often run in families. whether DCM is a chronic viral disease, a The inheritance of susceptibility is usually post-infectious autoimmune process, or polygenic. Organ-specific autoimmune dis- genetically determined organ-specific auto- eases are commonly associated with specific immune disease? HLA class II antigens,' but it is not known When tolerance to "self' antigens is lost how the HLA system determines the pre- autoimmune disease results. It is charac- disposition to a specific disease. terised by the presence of circulating autoanti- Most organ-specific autoimmune diseases bodies, which are not necessarily pathogenic are chronic and apparently idiopathic. Organ but represent markers of continuing tissue and disease specific antibodies are found in damage.' In autoimmune disease that is not the affected patients. These antibodies are organ specific there are autoantibodies against also detected in family members, sometimes ubiquitous autoantigens and tissue damage is years before the disease develops, and they generalised. In organ-specific autoimmune identify symptom free relatives who are at disease one organ only is affected and the risk.' autoantibodies react with its unique auto- antigens. Heart muscle is the only organ affected in Is organ-specific auto'imunity involved DCM and thus to test the autoimmune in human acute myocarditis? hypothesis we need to know whether the crite- There is evidence that acute myocarditis is a ria of an organ-specific autoimmune disease continuing autoimmune disease. Many are fulfilled (table 1). Organ-specific autoim- patients have circulating cardiac autoanti- mune diseases occur as a result of genetic pre- bodies (table 2)28 and some have several features of classic organ-specific autoimmu- http://heart.bmj.com/ nity or of insulin dependent diabetes mellitus, Table 1 Features oforgan specific autoimmunity which is an atypical but well established * Middle aged women most frequently affected organ-specific autoimmune disease in which * Familial aggregation viruses may be implicated (table 3). Familial * Organ and disease specific circulating autoantibody in patients and in unaffected family members aggregation of acute myocarditis has not been * Cell mediated autoimmunity impaired systematically investigated, but acute myo- * Associated autoimmune diseases in the same patient or in family members carditis and DCM have been reported in on September 23, 2021 by guest. Protected copyright. * HLA association different members of the same family.9 Little * Mononuclear ceU.infiltration and abnormal HLA molecule expression in the target organ is known about the associations of acute * Disease induced in animal models after immunisation myocarditis with other autoimmune diseases, with relevant autoantigen except that giant cell myocarditis is associated HLA, human leucocyte antigen. with myasthenia gravis ' and pernicious Department of Table 2 Circulating autoantibodies in acute myocarditis Cardiological Sciences, St George's % Antibody positive Hospital Medical School, London and Antibody type Method AM OCD Healthy controls Reference Institute of Clinical Muscle specific: IFL Medicine, ASA 47* NT 25 2 3 Department of AMLA 41* NT 12 2 3 Cardiology, AFA 28* NT 6 2 3 University of Padua, IFA 32* NT 3 2 3 Padua, Italy Heart-reactive IFL 59* NT 0 4 Anti-laminin ELISA 73* NT 6 5 A L P Caforio Anti-mitochondrial: Correspondence to: M7 ELISA 13* 10 0 6 Dr Alida L P Caforio, ANT SPRIA 91*t 0 0 7 Honorary Lecturer, Anti-P receptor Bioassay 96*t 8 0 8 Department of Cardiological Sciences, St George's *P < 0 05 v controls; tP < 0-05 v controls with other cardiac disease. AFA, anti-fibrillary antibody; AM, acute myocarditis; Hospital Medical School, AMLA, anti-myolemmal antibody; ANT, adenine nucleotide translocator; ASA, anti-sarcolemmal antibody; ELISA, enzyme Cranmer Terrace, London linked immunosorbent assay; IWA, anti-interfibrillary; IFL, indirect immunofluorescence; NT, not tested; OCD, other cardiac dis- SW17 ORE. ease; SPRIA, indirect microsolid-phase radioimmunoassay. Role ofautoimmunity in dilated cardiomyopathy S 31 Table 3 A comparison between acute myocarditis and organ-specific autoimmunity affected mice. Two populations of antibodies Features AM Recent onset IDDM OSAI developed in these mice: one cross-reacted with skeletal and cardiac myosin and the other Br Heart J: first published as 10.1136/hrt.72.6_Suppl.S30 on 1 December 1994. Downloaded from Clinical presentation Acute Acute Chronic Sex M>F M>F F>M was specific for the cardiac isoform.'6 Age (yr) 20-40 1-19 40 The key experiment to prove the autoim- Familial aggregation Yes? Yes Yes Viral aetiology ? ? ? mune nature of the chronic form of myocardi- Organ specific antibody +ve (%) 40-100 80 80 tis was then performed: immunisation of A-J HLA association ? DR3-4 DR3-4-5 Abnormal cell mediated immunity ? Yes Yes normal mice with cardiac myosin alone, with- Association with other AI disease Yes? Yes Yes out virus, induced histologically and immuno- Mononuclear cell infiltration Yes Yes Yes Abnormal HLA expression: logically identical disease.'7 Immunisation Target cell No Yes Yes with skeletal myosin did not produce Endothelium De novo Enhanced Enhanced Animal models Yes Yes Yes myocarditis, showing that myosin-induced myocarditis was a model for an organ-specific AM, acute myocarditis; IDDM, insulin dependent diabetes mellitus; OSAI, organ-specific autoimmunity. autoimmune heart disease. Humoral and cellular transfer experiments in this auto- immune model showed that the myocarditis process was transferable only by T cells and anaemia."I Important autoimmune features, was inhibited by monoclonal antibodies bind- such as the impairment of cell mediated ing to HLA class II molecules which dis- immunity and HLA association have not yet turbed antigen presentation to the T helper been investigated, but Herskowitz et al did not cells."' find abnormal expression of HLA on the tar- These studies showed that the chronic form get cell, the myocyte, in acute myocarditis."2 of murine myocarditis was an autoimmune This abnormal expression is not an absolute disease triggered by a virus in animals with a prerequisite for autoimmune conditions: in predisposing genetic background, rather than multiple sclerosis, for example, HIA class II a persistent viral infection. In addition, the is not expressed on neurons."3 Importantly, finding that autoimmune myocarditis was (see below) animal models of autoimmune produced after stimulation of the immune myocarditis have been produced. system with complete Freund's adjuvant and autoantigen (myosin) indicates not only that viral infection but also that other external Evidence for autoimmunity in pro-inflammatory stimuli could trigger auto- experimental murine myocarditis immunity in genetically predisposed animals A model for autoimmune myocarditis was and humans. found accidentally when workers trying to unravel the mechanisms of myocardial damage in experimental Coxsackie B virus- Humoral autoimmune phenomena in induced murine myocarditis found that only dilated cardiomyopathy certain strains of mice (A-J background) were Clinical and experimental observations indi- susceptible to acute myocarditis. More cate that myocarditis is a likely candidate for http://heart.bmj.com/ chronic sequelae resembling DCM developed autoimmune pathogenesis. But are organ and in these strains.'4 Early on (7-10 days) in the disease specific circulating cardiac antibodies disease CD8 T cells were cytotoxic for virally detectable in patients with DCM? infected cells. Later (2-3 weeks) they were Several groups have consistently found able to kill cells that were not infected with cardiac antibodies in DCM (table 4),3-8 19-22 viruses, suggesting the generation of auto- but the organ and disease specificities of these immune T cell clones.'4 15 In the late phase of antibody types have not been always evalu- autoimmune myocarditis no infectious virus ated. For instance, using indirect immuno- on September 23, 2021 by guest. Protected copyright. was detectable (by conventional virus culture fluorescence (IFL) earlier studies identified and isolation methods) in the heart of the antibodies to sarcolemmal and myofibrillar antigens, but these were not strictly cardiac specific because they cross reacted with Table 4 Autoantibodies in dilated cardiomyopathy skeletal muscle.' In addition, it was not clear % Antibody positive whether these muscle specific antibodies were Healthy associated with DCM, because controls with Antibody type Method AM OCD controls Reference other cardiac disease and with heart failure Muscle specific: IFL ASA 10 NT 25 3 not caused by DCM were not evaluated. AMLA 9 NT 12 3 When the frequency of cardiac antibodies AFA 24* NT 6 3 IFA 41* NT 3 3 was recently reassessed using IFL on human Organ specific cardiac IFL 26*t 1 3 19 hearts, organ and disease specinfc antibodies Heart reactive IFL 20* NT 0 4 Anti-lamiiin ELISA 78*t NT 6 5 of the IgG class were found in 26% of DCM Anti-mitochondrial patients from England.'9 These antibodies did M7 ELISA 31* 10 0 6 not stain human skeletal muscle and their ANT SPRIA 57*t 0 0 7 Anti-# receptor specificity to the heart was confirmed by Inhibiting LBI 30*t 8 4 20 relevant studies.'9 Interestingly, Inhibiting ELISA 31*t 0 12 21 absorption Stimulating Bioassay 95*t 8 0 8 another group reported that 20% of DCM Anti-a and B AMHC Immunoblot 46*t 8 0 22 patients from the United States had anti- *P < 0 05 v controls; tP < 0 05 v OCD.
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