Abstract
Myocarditis, the principal cause of dilated cardiomyopathy and heart failure in young adults, is associated with autoimmunity to human cardiac α-myosin (hCAM) and the DR4 allele of human major histocompatibility II (MHCII). We developed an hCAM-induced myocarditis model in human HLA-DR4 transgenic mice that lack all mouse MHCII genes, demonstrating that immunization for 3weeks significantly increased splenic T-cell proliferative responses and titres of IgG1 and IgG2c antibodies, abolished weight gain, provoked cardiac inflammation and significantly impaired cardiac output and fractional shortening, by echocardiography, compared to adjuvant-injected mice. Neither cardiac dilatation nor fibrosis occurred at this time point but prolonging the experiment was associated with mortality. Treatment with mixtures of hCAM derived peptides predicted to have high affinity for DR4 significantly preserved ejection fraction and fractional shortening. Our new humanized mouse model of autoimmune cardiomyopathy should be useful to refine hCAM-derived peptide treatment.
Highlights
Myocarditis is the leading cause of heart failure in people under 40 years of age
Addition of human cardiac α-myosin (hCAM) significantly increased proliferation relative to medium controls of splenic T-cells from DR4 mice injected with hCAM/complete Freund's adjuvant (CFA) and pertussis toxin similar to positive control ConA (Fig. 1A)
Immunization with hCAM greatly increased serum anti-hCAM IgG1 and IgG2c antibody levels, which were undetectable in the phosphate buffered saline (PBS)/CFA treated mice (Fig. 1B, C), indicating a strong B-cell response
Summary
Myocarditis is the leading cause of heart failure in people under 40 years of age. Viral (frequently Coxsackievirus B3, Parvovirus B19, adenoviruses or herpes viruses), bacterial (e.g. Corynebacterium diphtheriae, Staphylococcus aureus, Borrelia burgdorferi or Ehrlichia species) and some parasitic (e.g. Trypanosoma cruzi) infections are implicated in acute myocarditis, which becomes chronic and progresses towards dilated cardiomyopathy (DCM) in one fifth of cases [1]. Many chronic patients have autoimmunity to cardiac muscle derived antigens [2], including (in 41%) cardiac specific human α-myosin (hCAM) [3]. As with other autoimmune diseases, there is familial aggregation, autoantibody presence in unaffected relatives [4] and association with specific MHCII genotypes [5]. A recent meta-analysis of 19 independent studies totalling 1378 cases and 10,383 controls demonstrated a statistically elevated frequency of the human leukocyte antigen HLA-DR4 allele [5]. Myocarditis and DCM can be induced in genetically susceptible rodent strains by immunization with hCAM in complete Freund's adjuvant (CFA) but humanized mouse models are needed to evaluate immunotherapies because they bear human rather than mouse MHCII genes. Mice transgenic for the HLA-DQ8 allele on a non-obese, diabetic
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