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Viral myocarditis/pericarditis: pathogenesis Alida LP Caforio, MD, PhD Dept Cardiological ,Thoracic and Vascular Sciences University of Padova E-mail: [email protected] ESC congress 2010 Stockholm, 28 August-1 September 2010 Viral myocarditis/pericarditis: pathogenesis Disclosures: None Viral myocarditis • Challenging diagnosis • Polymorphic presentation • It may heal or lead to dilated cardiomyopathy (DCM) • Pathophysiology of progression to DCM in man incompletely understood • Diagnosis (WHO) based on endomyocardial biopsy (EMB), (histology, immunohistology and molecular techniques) • EMB infrequently used, viral etiology suspected, not proven Etiology of human myocarditis INFECTIOUS IMMUNE-MEDIATED TOXIC Bacterial Allergens: e.g. penicillin Drugs: e.g catecholamine cocaine Spirochetal Fungal Alloantigens: e.g. hearttransplant rejection Heavy metals Protozoal Parasitic Physical agents Rickettsial Viral: coxsackievirus, cytomegalovirus, dengue virus, echovirus, encephalomyocarditis, Epstein– Barr virus, hepatitis A, hepatitis C virus, herpes simplex virus, herpes zoster, HIV, influenza A and B, Junin virus, lymphocytic choriomeningitis, measles, mumps, parvovirus, poliovirus, rabies, respiratory syncytial, rubella, rubeola, vaccinia, varicella–zoster, variola, and yellow fever virus Autoantigens: e.g. myosin Various in giant-cell myocarditis and Agents, e.g in virus-negative myocarditis , myocarditis associated to organ and non-organ-specific autoimmune diseases Caforio A and McKenna WJ, Drugs 1996 sting bites Viral pericarditis • Majority of patients recover spontaneously. • A minority may develop idiopathic recurrent acute pericarditis (IRAP), a likely autoimmune sequela with benign prognosis. • Myocarditis, e.g. small increase in myocytolitic enzymes, may coexist. • Viral etiology of acute pericarditis is often suspected but not proven by current molecular diagnostic tools. Myocarditis/pericarditis: Viral Epidemiology • Temporal changes and population changes. • Historically, group B coxsackieviruses (CVB1 to CVB6), single-stranded RNA cytolytic viruses of the enterovirus (EV) genus within the family of Picornaviridae most frequently associated. • Newly identified agents: adenovirus (ADV), cytomegalovirus (CMV), PVB19 and herpesvirus 6 (HHV6). Myocarditis/pericarditis: Viral Epidemiology • Cardiotropic viruses are common environmental pathogens. • High prevalence of seropositivity in the absence of heart disease. • Only a minority of subjects develop myocarditis/pericarditis during epidemics. • Probable predisposing immunogenetic background. Susceptibility to murine coxsackievirus B3 (CVB3) myocarditis. • Main determinants: – virus genetic background and viral load – genetic control of the immune response in the host, e.g. Major histocompatibility complex (MHC) and non MHC genes – genetically determined and/or acquired dystrophin deficiency? • Additional factors: – Male gender, age (young and old do worse), pregnancy, exercise and malnutrition, selenium deficiency Woodroof JF, 1980; Martino TA, et al 1994; Schmidtke M et al, 2007; Kadokami T, et al, 2000; Yajima T, et al, 2009; Maekawa Y, et al 2007; Wolfgram et al 1986; Badorff C, et al 1999; Xiong D, et al 2002; Beck MA et al. 1995; Gay RT, et al, 2006. Time course of experimental viral myocarditis in mice Innate immunity Adaptive immunity Chronic Immunopathology *Kawai C. Circulation 1999; Feldman AM & McNamara D, N Engl J Med 2000 Mechanisms of viral entry into the cell • CVB1 to CVB6 use the coxsackie and ADV receptor (CAR) for attachment and entry into epithelial cells. • Some CVB strains use decay accelerating factor (DAF, e.g. CD55) and ADV use integrins ( 3 and 5) as coreceptors. • The majority of CAR localizes at the intercalated disks in adult cardiac myocytes, as well as at the cell-cell junctions of the atrioventricular node. • CAR is colocalised with integrins 3 and 5 on the cardiac myocyte sarcolemma and CAR expression is upregulated at the intercalated disks, the sarcolemma and interstitial cells in DCM hearts and in a myosin-induced autoimmune myocarditis rat model. • In the absence of CAR expression in the cardiac myocyte the virus does not infect the cardiac myocyte. Yajima T & Knowlton KU, Circulation 2009; Shi Y, et al JACC 2009; Noutsias M, et al Circulation 2001; Ito et al, Circ Res 2000 Positive strand Negative strand Positive strand>Negative strand =acute infection Positive =Negative strand =persistent infection, restricted viral replication Mechanisms of direct CVB-mediated myocardial injury in experimental models (I) Mechanism Virus type Reff Picornavirus protease 2A cleavage of of eukariotic initiation factor-4G, leading to inhibition of host cell protein synthesis CVB Lamphear,1993 Enteroviral protease 2A cleavage of the hinge 3 region of dystrophin, leading to loss of sarcolemmal integrity CVB3 Badorff,1999 Inducible cardiac-restricted expression of CVB3 protease 2A alone, leading to cleavage of dystrophin and DCM None Xiong, 2007 Viral propagation to adjacent cardiac myocytes increase with dystrophin deficiency CVB Xiong, 2002 CVB3 proteases 2A and 3C induction of apoptosis, via activation of the extrinsic caspase-8 mediated pathway and intrinsic mitochondria-mediated apoptosis pathway CVB3 Chau, 2007 Pathogenesis in experimental CVB3 models: lymphocyte-mediated myocardial injury • After 6 to 7 days after experimental infection, the adaptive (antigenspecific) immune response begins, leading to infiltration of T lymphocytes in the heart. • Infiltration of T lymphocytes in the heart peaks at 7-14 days when tissue damage is also highest and may lead to clearance of virusinfected myocytes (beneficial) by cytotoxic MHC class I restricted lymphocytes, and/or to autoimmune cell-mediated myocardial injury or necrosis of uninfected myocytes (detrimental) • Infectious CVB3 undetectable by culture in the blood and in the myocardium after day 15 and most animals recover. • In susceptible mouse strains myocarditis persists weeks or months, resulting in chronic pathological changes that resemble human DCM, due to immunopathology (driven by persisting viral or virusinduced antigen) and/or virus-triggered autoimmunity (driven by host determinants). Kawai C. Circulation 1999; Feldman AM & McNamara D, N Engl J Med 2000 Yajima T & Knowlton KU, Circulation 2009 Features of persistent CVB infection in murine models • Decrease in the total amont of viral RNA. • Decrease in the ratio of positive- to negative-strand viral RNA • Low levels of viral protein expression reflecting restricted virus replication at the level of viral positivestrand genomic RNA synthesis • Inability to isolate infectious virus from in vivo samples during chronic disease Klingel K et al 1992; Muir P, et al, 1994; Kyu 1992, Wessely R, et al, 1998; Conaldi PG, et al, 1997 Gullberg M, et al 2010 Evidence for persistent Enteroviral infection in DCM • In vivo and in vitro evidence that some picornaviruses, e.g. poliovirus, Theiler’s murine encephalomyocarditis virus, foot-and-mouth disease virus, CVB3, CVB4 and CVB5 may establish persistent, noncytolytic experimental infections. • Persistence of Enteroviral RNA in human DCM myocardial tissue by PCR • Cytopathic effects in myocyte cultures transfected with mutant CVB3 cDNA with restricted or defective replication without generation of infectious virus progeny • Transgenic expression of replication-restricted CVB3 mutant genome in myocardial tissue induces DCM with excitation-contraction coupling abnormalities in mice. Klingel K et al 1992; Muir P, et al, 1994; Kyu 1992, Wessely R, et al, 1998; Reetoo NK et al,2000; Conaldi PG, et al, 1997 Gullberg M, et al 2010 MURINE MODEL OF CVB3-INDUCED AUTOIMMUNE MYOCARDITIS Acute viral Chronic lymphocitic myocarditis myocarditis in the (1-9 days) absence of virus _ __________ ____________ ______________ Heart-specific* antibodies __________ A.BY/SnJ Non resolving Present A.SW/SnJ " " " " A.CA/SnJ " " " " B10.S/SgSf Resolving Absent Absent B10.PL/SgSf Resolving Absent Absent C3H.NB/SnJ Non resolving Present Present Genetic strain Present * Autoantigen: cardiac myosin heavy chain (Wolfgram LJ, J Immunol 1986) MURINE MODEL OF MYOSIN -INDUCED AUTOIMMUNE MYOCARDITIS Genetic strainMyocarditis Anti-myosin antibdies ___________ __________ __________________ A./J Cardiac * myosin + complete Freund's adjuvant Severe High titer A.SW/SnJ " " A.CA/SnJ " " A.BY/SnJ Moderate B10.A/SgSnJ " Low titer " C57BL/6J Absent Absent C57BL/10J Absent Absent * Skeletal myosin did not induce autoimmune myocarditis (Neu N, J Immunol 1987) POSSIBLE MECHANISMS OF VIRUS-INDUCED/PRECIPITATED AUTOIMMUNE HEART DISEASE Virus Molecular Breakdown in Breakthrough Tissue suppressor of "rogue" necrosis mimicry mechanisms autoreactive T cell clones Cross-reaction Disturbance in the host's immune response between anti-viral antibodies and heart antigens Insertion of viral epitopes into myocyte membrane Presentation Induction of of "sequestered" myocardial myocardial "neoantigen" autoantigen Breakdown of T cell tolerance to myocardial self antigens resulting In autoimmune heart disease 1 2 3 4 5 6 7 8 Viral infection leading to cell necrosis and viral Ag presentation CD8+ T-cell response to viral Ag presentation leading to clonal expansion of CD8+ cytotoxic T-cells Molecular mimicry of viral Ags Release of cardiac Ags from necrotic/apoptotic myocytes Endocytosis and cardiac-Ag presentation to CD4 + T-cells CD4+ T-cells activation of B cells Secretion of cardiac-specific AutoAbs AutoAbs bind to cardiomyocyte membrane Receptors and perpetuate cardiac necrosis/apoptosis CBV3, group A Streptococcal M protein and cardiac myosin: is molecular mimicry involved in myocarditis/IDC? • Polireactive autoantibody response against Streptococci , myosin and other -helical proteins in acute rheumatic fever (ARF) • Murine anti-Streptococcus/anti-myosin mAb are cytotoxic to myocytes in culture Adderson EE et al, J Immunol 1998 • Streptococcal M protein peptide (NT4) with similarity to myosin induces autoimmune myocarditis in susceptible mice and induces partial tolerance against CBV3 myocarditis Huber SA et al, J Immunol 1996 Von Landenberg P, et al, 2007 Elliott, et al PNAS 2003:13447 Genetics and Autoimmune Disease • Complex poligenic control of susceptibility and environmental factors are required to cause disease • Major role of HLA class II and class I genes in determining genetic risk of disease • Involvement of genes related to immune regulatory pathways • Same genes may confer increased risk two more than one autoimmune disease (e.g. Type 1 diabetes mellitus and Graves’ disease • Need of massive numbers of study samples and collaboration of large consortia because of the small effect of common alleles in genome-wide association studies (GWAS) N Engl J Med 2007; 357: 1-12 Nature 2007; 447: 661-678 Nature Genet 2007; 39:857-864 Major Criteria of Autoimmune Disease Witebsky E, Rose NR • Mononuclear cell infiltrate and abnormal HLA expression in the target organ (organ-specific disease) or in various organs (nonorgan-specific disease) in the absence of infectious agents • Circulating autoantibodies (Abs) and/or autoreactive lymphocytes in patients (pts) and family members • Abs and/or autoreactive lymphocytes within the affected organ • Identification and isolation of autoantigen(s) (Ags) involved • Disease induction in animals after immunization with Ags and/or passive transfer of serum, Abs and/or lymphocytes • Efficacy of immunosuppression in pts • Autoimmune disease= fullfillment of 2 or more major criteria Methods • Anti-heart autoantibody (AHA) screening – Standard indirect immunofluorescence (IFL) on normal O blood group human atrium and ventricle cryostat sections. Skeletal muscle used to detect cross-reacting antibodies. » Caforio et al. J Am Coll Cardiol 1990; 15 : 1527-34 » Caforio et al. Lancet 1994; 344: 773-77 O-s and AIDA positive patterns Caforio et al. Heart 2010;96:779-84 Frequency of the cardiac antibodies detected by IFL in heart disease Caforio et al, Eur J Heart Fail, 2002; Caforio et al, Lupus 2005 Organ-specific n (%) Cross-reactive-1 Cross-reactive-2 n (%) n (%) Neg n (%) DCM (n=327) 83 (25)*^ 35 (11)*^^ 3 (1) 206 (63) Myocarditis (n=161) 54 (33) *^ 22 (14)**^ 3 (6) 82 (51) Relatives of DCM (n=567) 176 (31)*^ 7 (1) 12 (2) 372 (66) Other heart disease (OCD) (n=160) 1 (1) 7 (4) 5 (3) 147 (92) Ischemic heart failure (IHF) (n=141) 1 (1) 1 (1) 8 (6) 131 (92) 7 (2.5) 8 (3) 9 (3) 246 (91) Normals (n=270) * p=0.0001 vs OCD or IHF; **p=0.0002 vs OCD ^ p=0.0001 and ^^p =0.0003 vs normals MHC as antigens in DCM-immunoblotting Caforio et al, Circulation 1992 Frequency of Ab to myosin heavy chain (MHC) and other contractile proteins in AM and DCM Ag Method AM %Ab pos DCM %Ab pos OCD %Ab pos Norm Ref and MHC Western blotting NT 46 *’** 8 0 Caforio 1992 MLC 1v Western blotting Western blotting NT 35 25 15 Caforio 1992 NT 46 *’** 17 0 Caforio 1992 Western blotting Western blotting NT 67** 42 NT Latif 1993 NT 17** 0 NT Latif 1993 Tropom Western blotting NT 55** 21 NT Latif 1993 Actin Western blotting NT 71** 21 NT Latif 1993 MHC ELISA 17 *’** 20 *’** 4 2 MHC ELISA 37 *’** 44 *’** 16 2.5 Goldman 1995 Caforio 1997 Lauer 1994 Non myofibr MHC MLC-1 *P<0.05 vs normals; **P<0.05 vs other cardiac disease (OCD) Frequency of Ab to non-muscle specific Ag in AM and DCM Ag Method AM %Ab pos DCM %Ab pos OCD Normals Ref %Ab pos s.Na/KATPase M7 ELISA+W NT estern blotting ELISA 13* 26* NT 2 Baba 2002 31* 10 0 Klein 1984 ANT SPRIA 91*’** 57 *’** 0 0 Schulteiss1985 BCKD-E2 ELISA 100*’** 60*’** 4 0 Ansari 1994 Laminin ELISA 73 78 25-35 6 Wolff 1989 HSP-60 Western NT blotting 85** 42 NT Latif 1993 HSP60,70 Western NT blotting 10-14** 1-2 3 Portig 1997 *P<0.05 vs normals; **P<0.05 vs other cardiac disease (OCD) Frequency of Ab to non cardiac-specific receptors in AM and DCM Ab Method AM %Ab pos NT DCM %Ab pos OCD Norm %Ab pos Ref 30-75 *’** 37 18 Limas 1989 Limas 1991 1 adrener. ELISA inhibiting NT 31 *’** 0 12 Magnusson 1990,1994 1 adrener. Bioassay stimulat. 96 *’** 95 *’** 8 0 Wallukat 1991 1 adrener. ELISA stimulat. NT 38** 6 19 Chiale 1995 1 adrener. ELISA stimulat. NT 26** 10 1 Jahns 1999 M2 muscar. ELISA NT 39* NT 7.5 Fu 1993 1 adrener. LBI inhibiting *P<0.05 vs normals; **P<0.05 vs other cardiac disease (OCD) Survival free from any progression (DCM, LVE, DFS) by cardiac antibody status at diagnosis in relatives classified as normal at baseline Caforio et al, Circulation 2007; 115, January 2/9 Viral damage or ‘molecular mimicry’- placing the blame in myocarditis Rose NR, Nature Med 2000:631-2 Warraich et al JahnsR, et al JCI 2004:1419-29 Jane-wit et al, Li et al Myocarditis/pe ricarditis pathogenesis: One face or two faces? Infection and Autoimmunity = Two faces of the same medal M.C. Escher Thank you for your attention!