Genetic complexity of autoimmune myocarditis

Abstract

Autoimmune myocarditis, a chronic stage of myocardial inflammation, occurs in a small subset of patients after acute cardiotropic viral infection and can lead to dilated cardiomyopathy (DCM). This disease can be recapitulated in susceptible mouse strains by infection with coxsackievirus B3, or by immunization with cardiac myosin or cardiac troponin I. The etiologies of myocarditis are multifactorial and genetically complex. Genetic linkage between susceptibility to myocarditis/DCM and the major histocompatibility complex (MHC) genes has been reported in both humans and experimentally induced mouse models. However, unlike other autoimmune diseases, the non-MHC genes seem to have greater impact than MHC genes on disease susceptibility. Several myocarditis-related non-MHC loci have been identified by our laboratory and others in different models. Most of these loci overlap with other autoimmune disease susceptibility loci, suggesting common or shared genetic traits influencing general autoimmunity. For example, we have demonstrated that Eam1 and Eam2 may influence disease susceptibility via regulating T cell apoptosis at different developmental stages. Blockade of signaling through specific genes, such as CTLA4, ICOS and PD-1, can either enhance or prevent the development of experimental autoimmune myocarditis, but it remains unclear whether functional polymorphisms in these genes are involved in predisposition to disease. In humans, mutations/deletions in immunologically important genes such as CD45, and genes encoding cardiac proteins, have been reported in patients with recurrent myocarditis or DCM. Identification of genetic polymorphisms controlling autoimmune myocarditis will help us understand the mechanisms underlying autoimmune diseases in general, thereby improving potential therapies in patients.

Figures

Figure 1. Loci important in autoimmune myocarditis also play a role in other autoimmune diseases

Genetic mapping data suggest that loci on Chrs. 1 and 6 play a role in susceptibility to experimental autoimmune myocarditis. These loci have been tentatively named Eam1 and Eam2. Eam1 overlaps with loci found to be important in human diabetes (IDDM7), and autoimmune thyroid disease, and murine diabetes (Idd5). This locus harbors important immune genes like IL1r2, caspases 8, CD28, CTLA4 and ICOS. Eam2 harbors genes like CD27, IL17rc, IL17re and Bid, as well as overlaps with other loci important for murine diabetes (idd6 and idd19), Bphs (Bordetella pertussis-induced histamine sensitization) and Dxm-resistance to apoptosis.