Chapter 4 Pathogenesis of Myocarditis and Dilated Cardiomyopathy

CHAPTER

4 Pathogenesis of Myocarditis and Dilated Cardiomyopathy Daniela Cihakova* and Noel R. Rose*,†

Contents

1. Human Myocarditis 1.1. Clinical picture of human myocarditis 1.2. Etiology of Myocarditis 1.3. Genetics of autoimmune myocarditis 1.4. Selected types of myocarditis 2. The Evidence for an Autoimmune Process in Myocarditis 2.1. Autoantibodies 2.2. Immunosuppressive therapy 3. Mouse Models of Myocarditis 3.1. CVB3-induced myocarditis 3.2. Experimental autoimmune myocarditis 4. Role of Proinflammatory Cytokines in Myocarditis 5. Role of T Helper Cells in Myocarditis 5.1. Role of Th1 cells in myocarditis 5.2. Growing evidence of divergent functions of IL-13 and IL-4 5.3. Is myocarditis a Th1- or Th17-driven disease? 6. The Divergent Role of Macrophages in Myocarditis 7. Conclusions/Directions for Future Research Acknowledgments References

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* Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA {

W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA

Advances in Immunology, Volume 99 ISSN 0065-2776, DOI: 10.1016/S0065-2776(08)00604-4

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2008 Elsevier Inc. All rights reserved.

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Myocarditis is a disease with a variable clinical presentation, ranging from asymptomatic to a fatal outcome. Among the recognized causes of myocarditis are mutations in multiple genes; infection by bacterial, rickettsial, mycotic, protozoan, and viral agents; and exposure to drugs, toxins, and alcohol. Some subtypes of myocarditis, such as giant cell myocarditis or eosinophilic necrotizing myocarditis, are suspected to be caused by an autoimmune inflammation. Several lines of evidence support the involvement of autoimmunity in myocarditis. These include the production of antibodies against relevant self-antigens, the fact that myocarditis symptoms can be relieved by immunosuppressive therapy in some patients, and a co-occurrence of myocarditis with other autoimmune diseases. Most of the evidence that myocarditis is an autoimmune disease comes from animal models. In this chapter, we discuss coxsackievirus B3-induced myocarditis and myosin-induced myocarditis as models of both viral and autoimmune inflammation in the heart. The latest advances in the study of autoimmunity have been concentrated on T helper cells, particularly the newly discovered subset, Th17 cells. Experimental autoimmune myocarditis (EAM), a mouse model of myocarditis induced by cardiac myosin, is partly an IL-17-driven disease. However, we have shown recently in IL-13 knockout mice that the disease can be driven through other pathways, and that the Th1 helper cells also lead to severe heart inflammation. Most importantly, IL-17A knockout mice are not fully protected against EAM and still develop mild myocarditis. The most abundant cells in heart infiltrate in human giant cell myocarditis or EAM are monocyte/macrophages, and there is now evidence that macrophages play a decisive role in the course of EAM.

1. HUMAN MYOCARDITIS 1.1. Clinical picture of human myocarditis The clinical manifestation of myocarditis is highly variable, ranging from no symptoms to heart failure (Rose and Baughman, 1998). Common presenting signs include nonspecific flu-like symptoms, arrhythmias, palpitations, dizziness, syncopes, and left ventricular failure. Electrocardiographic changes are relatively nonspecific (ST elevation, heart block, and low voltage QRS complexes). A definitive diagnosis can be made using a biopsy of the myocardium. According to the Dallas criteria, the diagnosis of myocarditis is based on the presence of mononuclear infiltration and myocyte damage. Yet the use of endomyocardial biopsy is limited by its reported lack of sensitivity

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and a risk of complications. In a common statement, the American Heart Association, the American College of Cardiology, and the European Society of Cardiology summarized clinical scenarios when endomyocardial biopsy should be performed, and emphasized the usefulness of biopsy in establishing the diagnosis of myocarditis in certain clinical settings (Cooper et al., 2007). The lack of sensitivity of the endomyocardial biopsy is most apparent in lymphocytic myocarditis; however, in giant cell myocarditis (GCM) or eosinophilic necrotizing myocarditis the sensitivity is as high as 80–85%. Patients of the latter types are also more likely to have a poor outcome, or require a heart transplant, and they are likely to benefit from immunosuppressive therapy. Detection of certain types of major histocompatibility complex (MHC) expression in a biopsy sample is highly supportive of a diagnosis of immune-mediated myocarditis (Cooper et al., 2007). Echocardiography, scintigraphy, and contrast-enhanced MRI are other useful tools to help diagnose myocarditis. Myocardial scintigraphy with antimyosin monoclonal antibodies has high sensitivity, but because it shows any myocardial necrosis, its specificity is lower (Bergler-Klein et al., 1993). Serum creatinine kinase and troponin T and I levels can help in assessing the extent of myocyte damage (Magnani and Dec, 2006).

1.2. Etiology of Myocarditis In most cases, the etiology of myocarditis and the consequent dilated cardiomyopathy (DCM) is unknown. Some 30–50% of DCM cases are estimated to be of genetic origin with examples of autosomally dominant but also autosomally recessive, X-linked, and mitochondrial inheritance. Mutations in over 20 genes have been reported as causes of DCM—lamin A/C, b-myosin heavy chain, dystrophin, desmin, and tafazzin are examples of some of them (Karkkainen and Peuhkurinen, 2007; Kamisago et al., 2000); however, in the case of other genes, the mutations were often found only in a single family or a small number of families (Karkkainen and Peuhkurinen, 2007). The list of bacterial, rickettsial, mycotic, protozoan, and viral agents capable of causing myocarditis is constantly growing (Magnani and Dec, 2006). Some of the more common viral agents are hepatitis C virus, influenza virus, herpes simplex virus, Epstein-Barr virus, parvovirus B19, and cytomegalovirus. Adenovirus and enterovirus genomes were frequently found in patients with myocarditis (Eckart et al., 2004; Pauschinger et al., 1999). Other common organisms that cause myocarditis are Corynebacterium diphtheriae or Trypanosoma cruzi. One of the more recently identified causes of myocarditis is vaccinia virus. It made headlines a few years ago, when 67 military personnel developed myocarditis within 15 days after smallpox vaccination (Eckart et al., 2004).

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1.3. Genetics of autoimmune myocarditis 1.3.1. MHC II association with myocarditis and DCM Most of the data on the relationship between The human leukocyte antigen system (HLA) and susceptibility to the inflammatory heart disease are obtained from patients with DCM. Several studies reported significant correlation of DCM with MHC class II antigens, mainly HLA-DR4 (Carlquist et al., 1991, 1994; Limas and Limas, 1989; Rodrı´guez-Pe´rez et al., 2007). In addition to HLA-DR4, other associations have been reported, but seem relevant only for certain populations and are probably affected by ethnic origin, sex, age, and geographic parameters (Liu et al., 2006; Lozano et al., 1997; Rodrı´guez-Pe´rez et al., 2007). The MHC II contributes to susceptibility to myocarditis in mice studies in both coxsackie-induced myocarditis and experimental autoimmune myocarditis (EAM). The mice strains on a A/J background (s, a, and f haplotypes) are able to develop severe myocarditis (A/J, H-2a; A.CA, H-2f; and A.SW, H-2s), while strains with a B10 background such as C57BL/10J, B10.A, B10.S, and B10.PL (H-2 b, a, s, u, respectively) are relatively resistant to myocarditis (Neu et al., 1987; Wolfgram et al., 1986).

1.3.2. Myocarditis and non-MHC gene association About 30% of DCM cases in humans, as discussed above, are due to mutations in various non-MHC genes, but the involvement of these mutations in susceptibility to myocarditis is unknown. A case report of a patient with recurrent myocarditis suggested a possible association between myocarditis susceptibility and an alternative splicing of CD45 gene (Tchilian et al., 2006). It is likely that myocarditis, similar to other autoimmune diseases, has a polygenic basis. Although the MHC haplotype is an important genetic factor for EAM susceptibility, the non-MHC genes are also prominent (Neu et al., 1987). We have discovered that two non-MHC loci on murine chromosomes 1 and 6, referred as Eam1 and Eam2, respectively, influence autoimmune myocarditis (Guler et al., 2005). These loci overlap with loci implicated in other autoimmune diseases, such as lupus and diabetes, suggesting that multiple autoimmune diseases might be controlled by similar genetic mechanisms (Li et al., 2008). Additionally, a Canadian group recently reported three loci on chromosome 1 and 4 that control susceptibility to CVB3-induced myocarditis (Aly et al., 2007).

1.4. Selected types of myocarditis 1.4.1. Lymphocytic myocarditis Based on the character of the inflammatory infiltrate in the heart, the most common form of myocarditis is lymphocytic myocarditis. Patients diagnosed with lymphocytic myocarditis are characterized by a sudden onset

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of left ventricular failure typically shortly after a respiratory tract infection, often with a biopsy identifying myocyte necrosis and lymphocytic infiltration. In Europe and North America, the most common viruses associated with myocarditis are the coxsackieviruses of group B (CVB3) and adenoviruses, which share the same cellular receptor (Baboonian and McKenna, 2003). Parvovirus B19 and human herpesvirus 6 have been also frequently reported (Ku¨hl et al., 2005). We can draw a parallel between lymphocitic myocarditis and acute viral myocarditis in CVB3-induced myocarditis in mice. Persistent viral genome can be found in about 70% of the DCM cases, suggesting that the remainder may be due to host response induced by a preceding viral infection (Ku¨hl et al., 2005). How the persistence of viral genomes contributes to the development of DCM is unclear; however, this result suggests that DCM is indeed preceded by subclinical viral myocarditis.

1.4.2. Giant cell myocarditis One of the most rapidly progressing forms of myocarditis is GCM, characterized by the presence of multinucleated giant cells in the heart infiltrate. The prognosis is serious. Immunosuppressive therapy is able to improve survival, but without transplantation only 11% of GCM patients survive 4 years, compared with 44% of patients with lymphocytic myocarditis surviving until this benchmark (Cooper et al., 2007). An autoimmune response is the probable cause of GCM.

1.4.3. Eosinophilic myocarditis The most severe form of eosinophilic myocarditis is necrotizing eosinophilic myocarditis (NEM), which is characterized by acute onset, rapid progression, predominantly diffuse eosinophilic infiltrate, and extensive necrosis. Intensive immunosuppressive treatment is indicated, but prognosis remains dire. The acute onset of NEM, even in previously healthy patients, its poor outcome, and the absence of extracardiac involvement contrast with eosinophilic myocarditis found in hypersensitivity syndrome. Hypersensitivity myocarditis could be accompanied by rash, fever, and peripheral eosinophilia and is often associated with hypersensitivity to a medication. Eosinophilic myocarditis can be also found as a part of hypereosinophilic syndrome, parasite infection, malignancy, and endocardial fibrosis (Cooper et al., 2007).

1.4.4. Dilated cardiomyopathy There is likely a casual relationship between myocarditis and some cases of subsequent DCM, because 9–16% of new onset DCM patients have evidence of prior myocarditis (Felker et al., 2000; Herskowitz et al., 1993). DCM is characterized by chronic left and right ventricular dilatation with normal or reduced left ventricular wall thickness and impaired

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contraction (Daubeney et al., 2006). Patients may present with asymptomatic cardiomegaly or severe congestive heart failure. DCM is the major cause of heart failure in individuals below the age of 40 and a major indication for cardiac transplantation. The 5-year survival rate of patients with DCM is less than 50% (Magnani and Dec, 2007). A large number of etiologic mechanisms have been implicated in DCM, including various infections, metabolic disorders, nutritional deficiency, neuromuscular diseases, toxins, and drugs. In a number of cases, a progression from myocarditis can be traced, and often there is a history suggesting a preceding viral infection.

2. THE EVIDENCE FOR AN AUTOIMMUNE PROCESS IN MYOCARDITIS It is difficult to prove that an autoimmune process causes myocarditis in humans, instead of autoimmunity developing after injury to the heart. There is no report of transient myocarditis in the fetus of a mother with myocarditis, which would clearly show that autoantibodies are involved directly in the pathogenesis of the disease in a way similar to Graves’ disease (Brown, 1996). The heterogeneity of myocarditis is another factor in the difficulty of establishing autoimmunity as one of the etiologic factors causing myocarditis. We have only indirect evidence to suggest that some types of myocarditis are caused by autoimmunity. One of them is the association of myocarditis with other autoimmune diseases, such as lupus or celiac disease. The incidence of myocarditis in lupus is reported to be 3–15%; additionally, patients with lupus often have some kind of pericardial involvement, ranging from asymptomatic pericardial effusion to acute pericarditis (Apte et al., 2008; Tincani et al., 2006). The prognosis of myocarditis associated with lupus is relatively good if immunosuppressive treatment is started in time (Tincani et al., 2006).

2.1. Autoantibodies Immunofluorescence tests using normal human heart tissue as substrate revealed that 59% of patients with myocarditis had cardiac-specific antibodies (Neumann et al., 1990). Konstadoulakis et al. (1993) and Caforio et al. (1992) showed that antibodies to cardiac myosin were present in 66% and 86%, respectively, of patients with DCM. However, many patients with other forms of heart disease also have antibodies to myosin. A further step toward characterizing the antibodies has been taken by distinguishing the subclass of antibodies to myosin in DCM patients. The antimyosin-specific antibodies typical of DCM are mainly in the IgG3 subclass (Warraich et al., 1999). Lauer et al. (2000) found that clinical

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symptoms and left ventricular ejection fraction improved significantly more in myosin antibody-negative group compared with antibodypositive myocarditis patients. In another study, Warraich et al. (2000) found that patients with cardiac myosin antibodies rejected transplanted hearts earlier then antibody-negative patients. It is still unclear, however, whether antibodies to myosin are directly involved in cardiac dysfunction, although immunoabsorption with an anti-IgG column showed clinical benefit in patients with DCM (Felix et al., 2001). In addition to antimyosin antibodies, about 50% DCM patients have antibodies to cardiac b1-adrenoreceptor (Limas et al., 1990). Rats immunized against the second extracellular b1 receptor loop developed severe left ventricular dilatation and dysfunction, suggesting that b1-adrenoreceptor antibodies are likely to play a causal role in DCM. Moreover, serum from these animals can transfer the disease to healthy rats (Jahns et al., 2004). In EAM model myocarditis, a transfer by antimyosin-specific sera was observed only in DBA/2 mice but not in BALB/c or A/J mice (Kuan et al., 1999; Cihakova, unpublished observations). The susceptibility of the DBA/2 strain to antibody-induced myocarditis is due to the extracellular expression of myosin in their heart, supporting the notion that antimyosin antibodies are not able to induce disease in the undamaged heart (Kuan et al., 1999). However, when the injury has already occurred, the antimyosin antibodies can contribute to the damage of cardiac myocytes. Passive transfer of antimyosin antibodies after myocarditis is induced with cardiac myosin led to a greater disease severity compared to mice treated with isotype control (Cihakova, unpublished observation).

2.2. Immunosuppressive therapy The benefits of immunosuppressive therapy constitute additional indirect evidence of the autoimmune origin of some types of myocarditis. Some patients with GCM, eosinophilic myocarditis, granulomatous myocarditis, and lymphocytic myocarditis associated with another autoimmune disease seem to benefit from immunosuppression, which is consistent with the hypothesis of autoimmune origin of these types of myocarditis (Cooper et al., 1997, Ku¨hl et al., 2005). However, placebo-controlled trials did not show increased survival in myocarditis patients treated with immunosuppressive agents (Mason et al., 1995, Parrillo et al., 1989). To fully explore the benefits of immunosuppressive therapy for myocarditis, it may be necessary to distinguish viral and autoimmune myocarditis. Frustaci et al. (2003) found that myocarditis patients who did not respond to therapy with prednisone and azathioprine had viral genome in their hearts, in contrast to patients who benefited from the treatment and usually had heart-reactive autoantibodies. However, the study was not randomized and lacked control groups. It therefore still remains an

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unresolved question whether the patients whose myocarditis or DCM is most likely caused by autoimmune process should be treated differently from patients with myocarditis and DCM of other etiologies.

3. MOUSE MODELS OF MYOCARDITIS 3.1. CVB3-induced myocarditis The most persuasive evidence that some forms of myocarditis are driven by autoimmune processes comes from animal models. There are many animal models of myocarditis. Currently, there are two models of CVB3induced myocarditis. The first one induces acute viral myocarditis with a significant damage to cardiomyocytes, and sudden death of majority of animals within a week of infection (Fuse et al., 2005; Huber et al., 1998). The second is based on using the heart-passaged CVB3 virus (Fairweather and Rose, 2007). In this model, a limited number of all strains of mice appear to develop an acute viral myocarditis following an infection with a cardiotropic strain of CVB3. The peak of inflammation of this early viral myocarditis is 9 days after the infection; the mice usually do not die from the viral myocarditis in this model. The heart infiltration is focal with no necrosis or fibrosis, and consists mostly of macrophages, neutrophils, CD4þ, and CD8þ T cells, some B cells, NK cells, eosinophils, and mast cells (Fairweather et al., 2005b). Most strains of mice recover completely, and have no evidence of the previous inflammatory process within 3 weeks after the infection. However, susceptible strains such as BALB/c, A/J, and SJL/J mice progress to a chronic myocarditis with generalized mononuclear infiltration accompanied by the production of antibodies to cardiac myosin (Afanasyeva and Rose, 2004; Rose et al., 1986). The strains that are susceptible to the second phase of CVB3-induced myocarditis do not all share the same H-2 background. The resistance to chronic myocarditis in B10 or C57BL/6 mice can be overcome by a treatment with LPS, IL-1b, or TNF-a (Fairweather et al., 2005a; Lane et al., 1993).

3.2. Experimental autoimmune myocarditis Immunization with cardiac myosin or with a myocarditogenic peptide derived from the a-cardiac myosin heavy chain emulsified in complete Freund’s adjuvant (CFA) induces a similar monocytic myocarditis in mice strains that are susceptible to the late phase of viral myocarditis, but not in the resistant strains (Neu et al., 1987; Donermeyer et al., 1995; Pummerer et al., 1996). Both late phase CVB3-induced myocarditis and myosininduced EAM have similar characteristics; the disease is accompanied

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Fibrosis pericarditis heart failure

Antibodies Infiltration Induction: activation 0

7

Progression: autoimmunity 14

21

Late: Cardiomyopathy 28

35

42

Time (days postimmunization)

FIGURE 4.1 Phases of experimental autoimmune myocarditis in mice. Mice are immunized with myosin in complete Freund’s adjuvant on days 0 and 7. Around day 21, there is a peak in the infiltration in the heart (solid line) and in antimyosin antibodies levels in the sera of immunized mice (dotted line). After day 21, heart infiltration declines and is replaced with fibrosis. After day 35, signs of dilated cardiomyopathy and heart failure could be detected by echocardiography.

by the production of cardiac myosin specific autoantibodies as well as cardiomyosin-specific T cells. We believe that the reason for the similarities in EAM and late phase of CVB3-induced myocarditis is that the viral infection acts as an adjuvant (Fairweather et al., 2005a,b). To produce EAM, CFA is injected with the antigen (myosin or myocarditogenic peptide) twice in 8 days. During the induction phase of EAM, in the first 10 days after the first immunization, there is no inflammation in the heart, and autoantibodies against cardiac myosin cannot be detected in serum (Cihakova et al., 2004). During the progression phase of EAM, between days 10 to day 21 postimmunization, inflammation increases in the heart, as do cardiac myosin-reactive antibodies in sera. During the late phase of EAM, following day 21 postimmunization, inflammation gradually declines and is replaced by fibrosis (Fairweather et al., 2001) (Fig. 4.1). The time course of CD45þ hematopoietic cells infiltrating the hearts of BALB/c mice with EAM correlates well with the known time course of EAM as determined by classical histopathologic methods (Afanasyeva et al., 2004). Since myocarditis involves myocyte injury, cardiac troponin I (cTnI) levels are elevated as they are in myocarditis patients (Smith et al., 1997). In recent research, a new myocarditis model, induced by immunization with troponin I in CFA, emerged. A/J mice immunized with murine cTnI developed severe myocarditis, with cardiomegaly, fibrosis, reduced fractional shortening, and increased mortality (Go¨ser et al., 2006). Several mice models of spontaneous myocarditis were also published. For example HLA-DQ8 transgenic IAb knockout (KO) NOD mice develop

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spontaneous myocarditis as well as NOD mice carrying the human DQ8 molecule (Hayward et al., 2006; Taneja et al., 2007).

4. ROLE OF PROINFLAMMATORY CYTOKINES IN MYOCARDITIS TNF-a is able to drive the pathogenesis in many rheumatoid diseases, and anti-TNF-a drugs become the success story in treatment of many human autoimmune diseases (Alonso-Ruiz et al., 2008). Interestingly anti-TNF-a drugs also seem to reduce the risk of cardiac disease in rheumatoid arthritis patients (Avouac and Allanore, 2008). Blocking IL-1b or TNF-a ameliorates myocarditis in the mouse model if the blocking is done during the onset of the disease (Fairweather et al., 2004). Additionally, the severity of CVB3-induced myocarditis as well as myosin-induced myocarditis correlates with the levels of IL-1b and IL-18 in the heart (Cihakova et al., 2008; Fairweather et al., 2003).

5. ROLE OF T HELPER CELLS IN MYOCARDITIS 5.1. Role of Th1 cells in myocarditis Until recently, organ-specific autoimmune diseases have been thought to be driven through the Th1 pathway (Charlton and Lafferty, 1995; Ichikawa et al., 2000). However, recent studies show a duality in the role of Th1 cytokines in the pathogenesis of autoimmune disease. The studies show that IFN-g deficiency in KO mice or depletion of IFN-g with antibodies lead to remarkably severe myocarditis with pericarditis and severe fibrosis that lead to DCM and heart failure (Afanasyeva et al., 2001, 2005; Eriksson et al., 2001). Similarly, evidence for a disease-limiting function of IFN-g has been also observed in models of experimental autoimmune encephalomyelitis (EAE), thyroiditis, uveitis, and arthritis (Barin et al., 2003; Chu et al., 2000; Jones et al., 1997; Manoury-Schwartz et al., 1997; Willenborg et al., 1996). In these model disease systems, IFN-g-deficiency by targeted KO mutation or by blockade is associated with disease exacerbation, and IFN-g administration by transgenic overexpression or administration of recombinant cytokine is associated with disease amelioration. However, both IL-12Rb1-deficient mice and STAT4-deficient mice were resistant to myocarditis induction, implying that IL-12 is required for myocarditis development while IFN-g protects against disease (Afanasyeva et al., 2001; Eriksson et al., 2001). The receptor IL-12Rb1 is shared by IL-12 and IL-23; therefore, the data from IL-12Rb1-deficient mice required further clarification. IL-12p35 KO

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mice, which lack only IL-12, developed EAM while IL-12p40 KO mice, which lack both IL-12 and IL-23, are resistant to myocarditis induction. These data suggest that IL-23, rather than IL-12, mediates the autoimmune pathology in diseases such as EAE, experimental arthritis, and EAM (Cua et al., 2003; Murphy et al., 2003, Sonderegger et al., 2006).

5.2. Growing evidence of divergent functions of IL-13 and IL-4 In contrast to a mild disease in IL-4 KO BALB/c mice, IL-13 KO BALB/c mice develop severe CVB3-induced autoimmune myocarditis as well as myocarditogenic peptide-induced EAM (Cihakova et al., 2008). The myocarditis in IL-13 KO mice is so severe that the animals develop marked DCM with impaired cardiac function indicative of heart failure. Interestingly, both arms of the adaptive immune response are upregulated during myocarditis in the absence of IL-13. Production of all subclasses of antimyosin antibodies is increased and T cells are more activated and more abundant during EAM in IL-13 KO mice; additionally, CD4þCD25þFoxp3þregulatory T cell numbers are decreased in the spleens of IL-13 KO mice. However, neither T nor B cells express the IL13Ra1 receptor; that is, they are not directly responsive to IL-13. Therefore, cells of innate immune response are probably responsible for the increased myocarditis in the absence of IL-13. Significant changes in the innate immune cell population of IL-13 KO mice were found in the macrophage subtypes in the heart infiltrate (see below) (Cihakova et al., 2008).

5.3. Is myocarditis a Th1- or Th17-driven disease? As was discussed above, IL-23 rather than IL-12 is essential for EAM development. IL-23 promotes survival of a new Th subset (called Th17) that produces proinflammatory cytokines IL-17 (Park et al., 2005), and drives pathology of several autoimmune diseases, including EAE, collagen-induced arthritis, and T cell-mediated colitis (Aggarwal et al., 2003; Chen et al., 2006; Langrish et al., 2005; Yen et al., 2006). Studies using a VLP-based vaccination approach showed that neutralization of IL-17 decreased EAM severity (e.g., Sonderegger et al., 2006). We have recently demonstrated that blocking IL-17 with monoclonal antibodies significantly decreased EAM, again confirming that the IL-17 is pathogenic during EAM (Cihakova et al., unpublished data). These experiments suggest that Th17 is also a driving factor of disease pathogenesis in EAM. However, in severe myocarditis in IL-13 KO mice, the IL-17 levels were significantly reduced in their hearts in the peak of EAM compared to BALB/c controls (Cihakova et al., 2008). The disease in the absence of IL-13 is probably driven through the Th1 pathway, since IFN-g was

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Wild type

IL-17 KO

FIGURE 4.2 Genetic absence of IL-17A in IL-17 knockout mice does not protect mice from development of experimental autoimmune myocarditis (EAM). (Left) Heart on day 21 of EAM in WT mouse. (Right) heart on day 21 of EAM in IL-17 knockout mouse.

increased in hearts of IL-13 KO mice. The increase of IFN-g is also responsible for higher levels of ‘‘classically activated’’ macrophages (cMj), which further intensify the disease severity by producing proinflammatory cytokines (Cihakova et al., 2008). Therefore, our data suggest that Th1 cells can induce myocarditis with severity similar to Th17 cells. Recently, we have obtained additional evidence supporting our view that myocarditis can be driven by either Th17 or Th1 pathway. IL-17A KO mice are still able to develop myocarditis that is only slightly reduced in severity compared to WT mice (Baldeviano, Cihakova, and Rose, unpublished data) (Fig. 4.2). Some of the IL-17A KO mice have infiltration in over 30% of the heart indicating that, even without IL-17A, the disease can progress to a severe stage. This finding shows that IL-17A is not necessary for autoimmune disease development. Similar results have been published in an experimental autoimmune uveitis (EAU) model. Luger et al. (2008) showed that EAU can develop in the absence of IL-17 in IL-17A KO mice with a severity similar to WT controls. Therefore, the lack of IL-23 appears to protect mice from myocarditis better than the absence of IL-17. Mice transgenic for IL-23 have elevated levels of IL-1b and TNF-a; both cytokines are essential for myocarditis development as discussed above

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FIGURE 4.3 Experimental autoimmune myocarditis (EAM) is cytokine regulated (schematic). The schematic shows a healthy murine heart (top) and a severe myocarditis on day 21 of EAM (bottom). Th17 as well as Th1 cells can drive the pathogenesis of EAM. IL-13 is protective in myocarditis partially due to the IL-13 induction of alternatively activated macrophages. (see Color Insert.)

(Wiekowski et al., 2001). Additionally, mice deficient in receptor IL-12Rb1 (which is common for both IL-12 and IL-23) had reduced levels of IL-1b that correlated with reduced myocarditis (Fairweather et al., 2003). It is possible that IL-23 promotes inflammatory responses by stimulating production of other proinflammatory cytokines. Thus, IL-23 might be the preferred target for therapeutic intervention in human autoimmune diseases rather than IL-17A. There is also a great need to reexamine role of IFN-g in autoimmune diseases. Our findings from the IFN-g KO mice suggested that IFN-g can be a protective cytokine; however, the protective effect takes place mainly by downregulating IL-17. In certain circumstances, as discussed above, Th1 cells are able to induce a disease comparable in severity to Th17-driven myocarditis (Fig. 4.3).

6. THE DIVERGENT ROLE OF MACROPHAGES IN MYOCARDITIS Macrophages constitute a population that is very diverse in terms of function and phenotype. Traditionally, Th1-derived IFN-g was thought to be a prime activator of T cell-driven macrophage responses, upregulating MHC Class II, iNOS, IL-12, the B7 co-stimulators, and ICAM1 (Adams and Hamilton, 1984). In contrast to IFN-g-elicted cMj, Th2 cytokines IL-4 and IL-13 induce the expression of arginase-1, YM1 (Chi3l3), type A

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scavenger receptor (CD204), and the macrophage mannose receptor (CD206). These ‘‘alternatively activated’’ macrophages (aMj) contrast with the IFN-g-elicted cMj not only in phenotype but also in function. Indeed, IL-13 deficiency leads to decreased numbers of alternatively activated CD206þ and CD204þ macrophages, and increased numbers of cMj. The increased number of cMj in the hearts of IL-13 KO mice with EAM is associated with increased caspase-1 activation. Caspase-1 is an enzyme necessary for the production of an active form of IL-1b and IL-18, which both are also greatly increased in the hearts of IL-13 KO mice (Cihakova et al., 2008). The disease-limiting role of CD11bþ monocytes in EAM was also shown by Valaperti et al. (2008). Similarly, in SIV-infected rhesus monkeys (a model of human HIV-induced myocarditis), Yearley et al. (2007) found that CD163 positive non-cMj are protective.

7. CONCLUSIONS/DIRECTIONS FOR FUTURE RESEARCH As mentioned above, we have assembled evidence that EAM is driven in part by the Th17 pathway in the mouse; however, in the absence of IL-17A an equally severe disease can be driven through the Th1 pathway. It is not yet known whether IL-17 plays a similarly dominant role in the pathogenesis of human myocarditis. Given a lack of immunomodulatory treatments for myocarditis, blocking of the IL-23/IL-17 pathway could be very attractive option. Thus, in myocarditis different pathways can result in comparable disease (Cihakova et al., 2008). Further studies examining the pathogenesis of IL-23/IL-17 in both animal models and humans are needed. Carefully distinguishing the presence or absence of replicating virus in the heart from the presence of an autoimmune response is necessary. We presume that blocking the IL-17/IL-23 pathway might benefit only myocarditis of autoimmune origin. We also need to revisit the role of the Th1 pathway and the role of IFN-g in myocarditis. There is currently no agreement about the role of Th1 cells, since it was shown that Th1 cell lines can induce EAU comparable to the Th17-induced disease (Cox et al., 2008); however, in models of autoimmune colitis and EAE, Th1-induced diseases were milder to Th17-induced diseases (Elson et al., 2007; Langrish et al., 2005). Another new direction in myocarditis research is emphasis on the innate immune response. Monocytes/macrophages are the most abundant cell type in the heart during myocarditis, both in mice and in humans. It is often viewed as a homogenous population with either pathogenic or disease-regulating roles; however, it is possible that the macrophage populations in heart infiltrates are functionally, phenotypically, and kinetically highly heterogenous. Understanding the different functions of the various populations and their interactions with pathogenic

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Th17 cells may reveal previously unappreciated therapeutic targets for new intervention strategies.

ACKNOWLEDGMENTS Authors are pleased to acknowledge funding from NIH grants 5R01HL077611 and 5R01HL067290 from the National Heart, Lung, and Blood Institute, and the Myocarditis Foundation. Jobert Barin and G Christian Baldevianno, graduate students in our laboratory, are currently working on the role of macrophages in EAM and the role of IL-17 in EAM, respectively.

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