Triggers of Inflammatory Heart Disease

Inflammatory heart disease (IHD) is a group of diseases that includes pericarditis, myocarditis, and endocarditis. Although males appear to be more commonly affected than females, IHD can be seen in any age group. While the disease can be self-limiting leading to full recovery, affected individuals can develop chronic disease, suggesting that identification of primary triggers is critical for successful therapies. Adding to this complexity, however, is the fact that IHD can be triggered by a variety of infectious and non-infectious causes that can also occur as secondary events to primary insults. In this review, we discuss the immunological insights into the development of IHD as well as a mechanistic understanding of the disease process in animal models

Triggers of Inflammatory Heart Disease

Inflammatory heart disease (IHD) is a group of diseases that includes pericarditis, myocarditis, and endocarditis. Although males appear to be more commonly affected than females, IHD can be seen in any age group. While the disease can be self-limiting leading to full recovery, affected individuals can develop chronic disease, suggesting that identification of primary triggers is critical for successful therapies. Adding to this complexity, however, is the fact that IHD can be triggered by a variety of infectious and non-infectious causes that can also occur as secondary events to primary insults. In this review, we discuss the immunological insights into the development of IHD as well as a mechanistic understanding of the disease process in animal models

An evidence for surface expression of an immunogenic epitope of sarcoplasmic/endoplasmic reticulum calcium-ATPase2a on antigen-presenting cells from naive mice in the mediation of autoimmune myocarditis

We recently reported identification of sarcoplasmic/endoplasmic reticulum calcium-ATPase2a (SERCA2a) 971–990, which induces atrial myocarditis by generating autoreactive T cells in A/J mice. However, it was unknown how antigen-sensitized T cells could recognize SERCA2a 971–990, since SERCA2a-expression is confined to an intracellular compartment. In this report, we present evidence that antigen-presenting cells (APCs) from lymphoid and non-lymphoid organs in naïve animals present SERCA2a 971–990 and stimulate antigen-specific T cells. Using major histocompatibility complex (MHC) class II dextramers for SERCA2a 971–990, we created a panel of T cell hybridomas and demonstrated that splenocytes from naïve A/J mice stimulated the hybridoma cells without exogenous supplementation of SERCA2a 971–990. We then recapitulated this phenomenon by using SERCA2a 971–990-specific primary T cells, verifying that the T cell responses were MHC-restricted. Furthermore, SERCA2a 971–990-sensitzed T cells exposed to APCs from naïve mice were found to produce the inflammatory cytokines interferon-γ, granulocyte macrophage colony stimulating factor, and interleukin-17A, which are implicated in the induction of myocarditis. Finally, while T cells exposed to mononuclear cells (MNCs) obtained from heart and liver also responded similarly to splenocytes, endothelial cells (ECs) generated from the corresponding organs displayed opposing effects, in that the proliferative responses were suppressed with the heart ECs, but not with the liver ECs. Taken together, our data suggest that the surface expression of SERCA2a 971–990 by naïve APCs can potentially trigger pathogenic autoreactive T cell responses under conditions of autoimmunity, which may have implications in endothelial dysfunction

Viral myocarditis involves the generation of autoreactive T cells with multiple antigen specificities that localize in lymphoid and non-lymphoid organs in the mouse model of CVB3 infection

Autoreactive T cells may contribute to post-viral myocarditis induced with Coxsackievirus B3 (CVB3), but the underlying mechanisms of their generation are unclear. Here, we have comprehensively analyzed the generation of antigen-specific, autoreactive T cells in the mouse model of CVB3 infection for antigens implicated in patients with myocarditis/dilated cardiomyopathy. First, comparative analysis of CVB3 proteome with five autoantigens led us to identify three mimicry epitopes, one each from adenine nucleotide translocator 1 (ANT), sarcoplasmic/ endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) and cardiac troponin I. None of these induced cross-reactive T cell responses. Next, we generated major histocompatibility complex (MHC) class II dextramers to enumerate the frequencies of antigen-specific T cells to determine whether T cells with multiple antigen specificities are generated by CVB3 infection. These analyses revealed appearance of CD4 T cells positive for SERCA2a 971−990, and cardiac myosin heavy chain-α (Myhc) 334−352 dextramers, both in the periphery and also in the hearts of CVB3-infected animals. While ANT 21−40 dextramer+ T cells were inconsistently detected, the β1- adrenergic receptor 181−200/211−230 or branched chain α-ketoacid dehydrogenase kinase 111−130 dextramer+ cells were absent. Interestingly, SERCA2a 971−990, Myhc 334−352 and ANT 21−40 dextramer+ cells were also detected in the liver indicating that they may have a pathogenic role. Finally, we demonstrate that the SERCA2a 971−990-reactive T cells generated in CVB3 infection could transfer disease to naïve mice. The data suggest that CVB3 infection can lead to the generation of autoreactive T cells for multiple antigens indicating a possibility that the autoreactive T cells localized in the liver can potentially circulate and contribute to the development of viral myocarditis

CYTOPLASMIC PROTEINS AS AUTOANTIGENS IN THE DEVELOPMENT OF INFLAMMATORY HEART DISEASE

Inflammatory heart disease can result from infectious or non-infectious etiologies. When infectious causes are involved, autoimmune responses are commonly suspected to explain persistence of inflammation, leading to the suggestion that pathogens primarily affecting the target organs can lead to a secondary generation of autoimmune responses. In addressing this hypothesis, we had previously reported that Coxsackievirus B3 (CVB) infection accompanies the generation of cardiac myosin-specific T cells, which can transfer disease to naïve mice. This work led us to propose that the postinfectious phase of CVB infection involves the generation of autoreactive T cells with multiple antigen specificities. To this end, we made efforts to identify cardiac autoantigens that can potentially become immune targets in the CVB pathogenesis. First, by establishing T cell hybridoma technology, we generated T cell hybridomas for cardiac myosin that may be helpful in tracking cells expressing viral proteins in vivo. Second, we demonstrated that mitochondrial protein, branched chain α-ketoacid dehydrogenase kinase (BCKDk) can act as a target antigen in the mediation of both autoimmune myocarditis and hepatitis. Third, we identified an antigenic determinant from sarcoplasmic/endoplasmic reticulum calcium-ATPase (SERCA2a) that induces mainly atrial inflammation. The implications of our observations are two-fold: (a) the new disease models (BCKDk and SERCA2a) can be used to determine inflammatory events arising from autoimmune responses in both the heart and liver, and (b) identification of immunodominant epitopes in BCKDk and SERCA2a proteins is helpful in evaluating the relevance of epitope spreading as an autoimmune mechanism in the development of CVB-induced chronic myocarditis in future studies

CYTOPLASMIC PROTEINS AS AUTOANTIGENS IN THE DEVELOPMENT OF INFLAMMATORY HEART DISEASE

Inflammatory heart disease can result from infectious or non-infectious etiologies. When infectious causes are involved, autoimmune responses are commonly suspected to explain persistence of inflammation, leading to the suggestion that pathogens primarily affecting the target organs can lead to a secondary generation of autoimmune responses. In addressing this hypothesis, we had previously reported that Coxsackievirus B3 (CVB) infection accompanies the generation of cardiac myosin-specific T cells, which can transfer disease to naïve mice. This work led us to propose that the postinfectious phase of CVB infection involves the generation of autoreactive T cells with multiple antigen specificities. To this end, we made efforts to identify cardiac autoantigens that can potentially become immune targets in the CVB pathogenesis. First, by establishing T cell hybridoma technology, we generated T cell hybridomas for cardiac myosin that may be helpful in tracking cells expressing viral proteins in vivo. Second, we demonstrated that mitochondrial protein, branched chain α-ketoacid dehydrogenase kinase (BCKDk) can act as a target antigen in the mediation of both autoimmune myocarditis and hepatitis. Third, we identified an antigenic determinant from sarcoplasmic/endoplasmic reticulum calcium-ATPase (SERCA2a) that induces mainly atrial inflammation. The implications of our observations are two-fold: (a) the new disease models (BCKDk and SERCA2a) can be used to determine inflammatory events arising from autoimmune responses in both the heart and liver, and (b) identification of immunodominant epitopes in BCKDk and SERCA2a proteins is helpful in evaluating the relevance of epitope spreading as an autoimmune mechanism in the development of CVB-induced chronic myocarditis in future studies

Cytoplasmic Proteins as Autoantigens in the Development of Inflammatory Heart Disease

Inflammatory heart disease can result from infectious or non-infectious etiologies. When infectious causes are involved, autoimmune responses are commonly suspected to explain persistence of inflammation, leading to the suggestion that pathogens primarily affecting the target organs can lead to a secondary generation of autoimmune responses. In addressing this hypothesis, we had previously reported that Coxsackievirus B3 (CVB) infection accompanies the generation of cardiac myosin-specific T cells, which can transfer disease to naïve mice. This work led us to propose that the postinfectious phase of CVB infection involves the generation of autoreactive T cells with multiple antigen specificities. To this end, we made efforts to identify cardiac autoantigens that can potentially become immune targets in the CVB pathogenesis. First, by establishing T cell hybridoma technology, we generated T cell hybridomas for cardiac myosin that may be helpful in tracking cells expressing viral proteins in vivo. Second, we demonstrated that mitochondrial protein, branched chain α-ketoacid dehydrogenase kinase (BCKDk ) can act as a target antigen in the mediation of both autoimmune myocarditis and hepatitis. Third, we identified an antigenic determinant from sarcoplasmic/endoplasmic reticulum calcium-ATPase (SERCA2a) that induces mainly atrial inflammation. The implications of our observations are two-fold: (a) the new disease models (BCKDk and SERCA2a) can be used to determine inflammatory events arising from autoimmune responses in both the heart and liver, and (b) identification of immunodominant epitopes in BCKDk and SERCA2a proteins is helpful in evaluating the relevance of epitope spreading as an autoimmune mechanism in the development of CVB-induced chronic myocarditis in future studies