The knowns and unknowns of cardiac autoimmunity in viral myocarditis

Figures

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  FIGURE 1. Hypothetical mechanisms of outcomes and immune responses between microbial and self-antigens. Microbes. Exposure to pathogenic microorganisms for the first time (termed hit 1) can lead to the induction of acute or chronic diseases, shown with red and green curves, respectively. As the immune system adapts to infection, acquired immune responses are set (blue curve), and upon re-exposure to the same pathogen (termed hit 2), memory cells swiftly react to prevent infections while strong memory responses continue to build in such future encounters. However, pathogens that induce chronic diseases may develop evasive mechanisms leading to their survival. Self-antigens. Although non-reactivity to self is one of the cardinal features of the adaptive immune system, under the conditions of a break in tolerance, the B cells and T cells can react to self-antigens (red arrow). But it is unknown whether such responses persist (green curve) or whether they recede over time, and if they do, it is unclear whether these responses can be continuously reactivated, leading to the induction of memory responses (blue curve). This figure was created using BioRender.com.

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  FIGURE 2. Generalised autoimmune mechanisms. Peripheral repertoires of healthy individuals may have autoreactive B cells, CD4 and CD8 T cells, but they may remain tolerant, and Treg cells occupy a central role in their maintenance of self-tolerance. However, in genetically susceptible individuals, self-tolerance can be broken under the influence of various environmental factors. While disease associations have been noted with various Major Histocompatibility Complex (MHC) and non-MHC genes, infectious and non-infectious agents can trigger autoimmune responses that may involve more than one mechanism in the genetically predisposed individuals. First, exposure to microbes carrying sequences similar to self-antigens can trigger autoimmunity by producing cross-reactive immune responses as a result of a confused immune state. Second, pathogens that have a tropism for specific tissues can lead to the generation of a de novo/fresh repertoire of autoreactive cells in response to the antigens released from damaged tissue through epitope spreading. Third, although autoreactive cells, if any, in healthy individuals are not expected to react to self-antigens, exposure to infections may stimulate…

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  FIGURE 3. Heat maps display the detection of autoantibodies and autoreactive T cells in myocarditis associated with various virus infections in humans and mice. The left and right panels indicate autoantibodies detected in humans and mice, respectively, affected with various virus infections of viral myocarditis. The top legend represents viruses, and autoantibodies noted for various self-antigens are indicated on the left of each panel. Filled and empty squares represent the presence or absence, respectively, of antibodies noted in each virus infection. The last column in each panel represents detection of autoreactive T cells.

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  FIGURE 4. Autoimmune mechanisms of viral myocarditis in an experimental model system. Viruses can cause cardiac damage by direct injury leading to the development of acute myocarditis as indicated by the infiltration of immune cells that can lead to chronic myocarditis (left panel). During this process, resident dendritic cells (DCs) take up cardiac antigens released from damaged cardiac tissue leading to the generation of autoreactive B cells or CD4 and CD8 T cells by presenting antigens to the respective cell types in the draining lymph nodes that can recirculate back into the heart. A proportion of autoreactive T cells can reside in the liver with a potential for recirculation to the heart, and such emigrations can be potentially inhibited by immune suppressive strategies. Nonetheless, it is critical to confirm that the autoimmune responses are indeed pathogenic by using appropriate model systems (right panel). This figure was created using BioRender.com.

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  FIGURE 5. Potential mechanism of endothelial dysfunction in CVB3 myocarditis. Cardiac antigens such as SERCA2a released from myocardial damage could be taken up by the resident dendritic cells (DCs). They present antigens (eg., SERCA2a) in the draining lymph nodes leading to the generation of SERCA2a-reactive CD4 T cells that can activate endothelial cells (ECs), which facilitate the extravasation of cardiac-reactive T cells into the heart. During this process, the ECs can be killed by the cytotoxic function of SERCA2a-reactive CD8 T cells by an autoimmune reaction. This figure was created using BioRender.com.