Innate Immunity in Experimental Autoimmune Myocarditis

Ziya Kaya and Noel R. Rose

1. Introduction

A century has passed since the epic publication by Donath and Landsteiner (1904) on the pathogenesis of paroxysmal cold hemoglobunaria (PCH). The work provided the first hint that autoimmunity could be the cause of human disease. The concept remained fallow for half a century until improved immunologic methods and a broader view of the basis of the immune response validated the idea. Landsteiner associated PCH with his concurrent studies of syphilis, leading to the suggestion that infection may serve as the initiating factor for an autoimmune reaction. The idea became embedded in immunologic thought. Yet there are few firmly established examples of a human autoimmune disease caused by infection and little information about mechanisms by which infection might instigate such a pathologic autoimmune response. With the goal of elucidating the likely mechanisms, our group undertook a detailed study of one clear experimental model in mice of an autoimmune disease triggered by a viral infection, myocarditis (Rose et al., 1988a).

Myocarditis accounts for approximately 25% of all heart failure in North America and is especially prevalent among young adults. Although most viral myocarditis patients recover, a few progress to chronic myocarditis and dilated cardiomyopathy (DCM), an often-fatal condition and a frequent reason for cardiac transplantation. The most common cause of myocarditis in the USA is infection with adenovirus or coxsackievirus. Progressive forms of myocarditis are characterized by the presence of cardiac myosin-specific autoantibodies (Caforio et al., 2001). In this chapter, we review recent studies on the role of the innate immune system in induction, progression, and protection of the disease.

Ziya Kaya and Noel R. Rose • Department of Pathology and Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205.

Molecular Autoimmunity: In commemoration of the 100th anniversary of the first description of human autoimmune disease, edited by Moncef Zouali. Springer Science+Business Media, Inc., New York, 2005.

2. Experimental Models of Myocarditis in Mice

There is strong evidence that cardiac myosin is a dominant autoantigen in virus-induced myocarditis in mice (Neu et al., 1987a). The disease can be reproduced by immunization of susceptible strains of mice with cardiac myosin (Neu et al., 1987b). Myosin-induced myocarditis can be adoptively transferred by CD4+ T lymphocytes (Smith and Allen, 1991). In addition to T cells, passive administration of antimyosin monoclonal antibody was found to induce myocarditis in DBA/2 but not in BALB/c mice because of the presence of myosin or a myosin-like protein in the extracellular matrix of DBA/2 mice (Liao et al, 1995). Therefore, both antibody and T cells may contribute to the pathogenesis of inflammatory myocardial lesions. Gauntt et al. (1995) and Cunningham (2004) investigated the relationship between coxsackievirus and myosin and suggested that molecular mimicry between myosin and coxsackieviruses may play a role in myocarditis. Anti-coxsackievirus-neutralizing antibody produced myocardial inflammation in mice (Gauntt et al., 1995). On the other hand, Horwitz et al. (2000) presented evidence that virus-mediated damage to the heart is necessary for the induction of the autoimmune response, a finding that challenges the idea of molecular mimicry.

Studies to explore the inductive and the effector mechanisms involved in the development of experimental autoimmune myocarditis (EAM) implicate both innate and adaptive immune responses. Thus, important roles have been shown for autoreactive T cells (Smith and Allen, 1991), cardiac-specific autoantibodies (Neumann et al., 1991; Liao et al., 1995), various cytokines and chemokines (Afanasyeva and Rose, 2002a; Eriksson et al., 2003a, 2003b; Fairweather et al., 2003, 2004), natural killer (NK) cells (Fairweather et al., 2001, 2003), and the complement system (Kaya et al., 2001; Afanasyeva and Rose, 2002b) in the development of myocarditis.

2.1. Coxsackievirus B3 (CB3)-Induced Autoimmune Myocarditis

Our murine model of autoimmune myocarditis is based on genetic differences among inbred mouse strains in the immune response to CB3. In certain mouse strains, CB3-mediated myocarditis resolves into an early phase characterized by myocyte damage due to viral cytotoxicity and a late phase that is associated with the production of heart muscle-specific autoantibodies (Rose et al., 1988a). The later phase of CB3-induced heart disease can be mimicked by immunization of mice with purified murine cardiac myosin in the absence of viral infection, and experimental cardiac myosin-induced myocarditis has immuno-logic and histopathologic features that resemble postviral heart disease in mice and myocarditis in humans (Neu et al., 1987b). Thus, the myocarditis model offers a unique opportunity to study the factors contributing to the transition from a viral infection to an autoimmune disease.

2.2. Cardiac Myosin-Induced Autoimmune Myocarditis

Immunization of susceptible mice with cardiac myosin emulsified in complete Freund adjuvant induces myocarditis in mice with a peak of inflammation in the heart around day 21 (Afanasyeva et al., 2001b). This inflammation is similar to that seen in the CB3-induced autoimmune myocarditis during the chronic phase. The immunization with cardiac myosin is linked with production of IgG1 autoantibodies to cardiac myosin and autoreactive CD4 T cells (Afanasyeva et al., 2004).

2.3. Peptide-Induced Myocarditis

Unique epitopes within cardiac myosin have been described to produce myocarditis. Myocarditis can be induced in BALB/c mice by amino acid residues 736-1032 in cardiac myosin (Liao et al., 1993), by amino acid residues 334-352, located in the S1 region of mouse cardiac myosin (Donermeyer et al., 1995), or by acetylated amino acid residues 614-643 of rat cardiac myosin (Pummerer et al., 1996). Myocarditis can also be induced in Lewis rats by amino acid residues 1070-1165 of porcine cardiac myosin (Inomata et al., 1995), by amino acid residues 1107-1186 of the rat myosin heavy chain (Kohno et al., 2002), and by acetylated amino acid residues 1539-1555 of rat cardiac myosin alpha-chain (Wegmann et al., 1994).

3. Susceptibility to Myocarditis

Susceptibility to induction of EAM is dependent on the strain of mice (Table 1.1) (Fairweather et al., 2003). The MHC class II haplotype (e.g., H-2a in highly susceptible A/J mice or H-2b in moderately susceptible A.BY mice) is an important genetic factor for disease susceptibility, but its effects are overshadowed by non-MHC traits (Neu et al, 1987b; Rose et al., 1988b). Thus, C57BL/6 (H-2s) mice are resistant to myosin-induced myocarditis, whereas A.SW mice are susceptible, even though they share the same H-2s haplotype. The same strains of mice susceptible to CB3-induced autoimmune myocarditis develop myocarditis following immunization with cardiac myosin. Susceptibility may be related to many genetic factors including target organ sensitivity or influences upon the immune response itself (Guler et al., 2005).

Table 1.1. Susceptibility to Experimental Autoimmune Myocarditis

Myocarditis

Table 1.1. Susceptibility to Experimental Autoimmune Myocarditis

Myocarditis

Mouse strain

Autoantibody titer

Prevalence

Severity

A/J

++++

++++

++++

A.BY/SnJ

+++

+

++

A.CA/SnJ

++++

+++

+++

A.SW/SnJ

++++

++++

++++

B10.A/SgSnJ

+++

+

+

BALB/c

+++

+++

+++

C57BL/10J

++

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