Autoimmune Myocarditis, Valvulitis, and Cardiomyopathy

Abstract

Cardiac myosin-induced autoimmune myocarditis (EAM) is a model of inflammatory heart disease initiated by CD4+ T cells (Smith and Allen 1991; Li, Heuser et al. 2004). It is a paradigm of the immune-mediated cardiac damage believed to play a role in the pathogenesis of a subset of postinfectious human cardiomyopathies (Rose, Herskowitz et al. 1993). Myocarditis is induced in susceptible mice by immunization with purified cardiac myosin (Neu, Rose et al. 1987) or specific peptides derived from cardiac myosin (Donermeyer, Beisel et al. 1995; Pummerer, Luze et al. 1996) (see Basic Protocol 1), or by adoptive transfer of myosin-reactive T cells (Smith and Allen 1991) (see Alternate Protocol). Myocarditis has been induced in Lewis rats by immunization with purified rat or porcine cardiac myosin (Kodama, Matsumoto et al. 1990; Li, Heuser et al. 2004) (see Basic Protocol 2) or S2-16 peptide (Li, Heuser et al. 2004), or by adoptive transfer of T cells stimulated by specific peptides derived from cardiac myosin (Wegmann, Zhao et al. 1994). Myocarditis begins 12 to 14 days after the first immunization, and is maximal after 21 days. Other animal models commonly used to study myocarditis development include the pathogen-induced models in which disease is initiated by viral infection. The first murine model of acute viral myocarditis causes sudden death via viral damage to cardiomyocytes (Huber, Gauntt et al. 1998; Horwitz, La Cava et al. 2000; Fong 2003; Fuse, Chan et al. 2005; Fairweather and Rose 2007; Cihakova and Rose 2008) whereas the second model is based on inoculation with heart-passaged coxsackievirus B3 (CVB3) that includes damaged heart proteins (Fairweather, Frisancho-Kiss et al. 2004; Fairweather D 2004; Fairweather and Rose 2007; Cihakova and Rose 2008) In addition to the protocols used to induce EAM in mice and rats, support protocols are included for preparing purified cardiac myosin using mouse or rat heart tissue (see Support Protocol 1), preparing purified cardiac myosin for injection (see Support Protocol 2), and collecting and assessing hearts by histopathological means (see Support Protocol 3).

11C-Methionine PET of Myocardial Inflammation in a Rat Model of Experimental Autoimmune Myocarditis

“…To date, several groups have reported induction of autoimmune myocarditis by immunization in the rear footpad using a combination of porcine cardiac myosin and Freund complete adjuvant (24,25). These EAM rats developed myocardial inflammatory cell infiltrates beginning 12-14 d after the first immunization, with a peak around day 21 (29). Immunohistologically, macrophages and CD4-positive T cells are the predominant cell types present in the early infiltrates (30,31).…”

“…In addition to the myosin-induced EAM model, a virus-induced myocarditis model has also been reported (29,33,34), which has only been established in mice, however. Because of the limited resolution of small-animal PET imaging, rat models have the great advantage of better image quality.…”

Unresolved issues in theories of autoimmune disease using myocarditis as a framework

“…This also explains why incomplete Freund’s adjuvant (IFA), without Mycobacterium , is not able to induce autoimmune disease in animal models [31]. Additionally, adjuvant and self peptide must be administered at the same time (i.e., day 0) or autoimmune disease does not develop [8], further indicating the important role the adjuvant plays in driving the innate immune response to self peptide. Many discussions on theories of autoimmunity continue to “ignore” the role the adjuvant plays in driving disease and focus only on the self peptide.…”

“…This data suggest that if autoAbs against hidden antigens are present and the antigens are made available, possibly through physical, infectious or chemical damage to the heart [42–45], then autoimmune disease could develop. Evidence that cardiac myosin and troponins are primary targets of the immune response comes from the ability of these proteins to induce myocarditis if administered with an adjuvant like CFA in mice [8, 46]. AutoAbs against all of these major cardiac antigens are found during myocarditis [44].…”

“…When IL-33 was administered with CVB3, mice developed severe myocarditis and rapidly progressed to DCM and heart failure [51]. In fact the model used in these experiments pairs a mild CVB3 infection with injection of damaged heart protein, rather than purified cardiac myosin [8]. This damaged heart includes proteins like IL-33, cardiac myosin and actin.…”