FIGURE 1.

Proposed mechanisms of inflammatory heart disease. All three layers (pericardium, myocardium, and endocardium) individually or together can be affected by various infectious and non-infectious causes. A variety of innate immune cells like neutrophils, macrophages, dendritic cells including γδ T cells, ILCs, and NK-T cells can infiltrate and take part in tissue destruction. The inflammatory damage can also lead to the release of cardiac antigens such as cardiac myosin, actin, cTnI, ANT, BAR, BCKD, SERCA2a, laminin, muscarinic receptor (MR), and heat shock proteins (HSP). The newly released antigens can trigger autoimmune responses by activating T cells and B cells in the draining lymph nodes, which can in turn infiltrate the heart and aggravate inflammation. It is also possible that the dying cardiac myocytes can be engulfed by macrophages as a part of the cleaning process by phagocytosis, and possibly, autophagy, and trigger pathogenic autoimmune responses in genetically susceptible individuals. Alternatively, misfolded or mutated or modified self-proteins as might occur with mitochondrial proteins can be seen by the immune system as foreign, resulting in pathological autoimmune responses. It also is possible that some of the intracellular proteins like HSPs may bear sequences similar to microbial HSPs leading to the generation of cross-reactive immune responses. In all these scenarios, self-antigens can be presented to both CD4 and CD8 T cells, and B cells. They mediate inflammation through, respectively, DTH, cytolysis and complement activation. However, it is to be noted that several putative cardiac antigens can be promiscuously expressed in non-cardiac tissues such as brain, lungs, liver, pancreas, kidney, and skeletal muscle, raising the question whether autoreactive responses generated in response to cardiac damage can also inflict damage in other organs.