Two Autoimmune Diabetes Loci Influencing T Cell Apoptosis Control Susceptibility to Experimental Autoimmune Myocarditis

Abstract

The pathogenesis of immune-mediated myocarditis depends on genetic and environmental factors. To study the genetic mechanisms, we have developed a model of experimental autoimmune myocarditis in the A.SW mouse. Here we provide evidence that loci on murine chromosome 6, and possibly chromosome 1, are involved in regulating susceptibility. Moreover, these loci overlap with loci implicated in other autoimmune diseases including diabetes in the NOD mouse. These two loci also regulate apoptosis in thymocytes as well as peripheral T cells in the NOD mouse, and we report further that A.SW mice demonstrate the same characteristics in apoptosis. These results suggest that common pathogenetic mechanisms involving apoptosis of both thymic and peripheral T cells are shared by multiple autoimmune diseases.

Complex genetic control of host susceptibility to coxsackievirus B3-induced myocarditis

“…14,15,22,[26][27][28] Inbred mouse strains develop myocarditis that reiterates human disease when infected with CVB3 originally isolated from human patients. In addition, different mouse strains present a range of heterotypic pathologies making the mouse an excellent model to study host determinants of CVB3-induced myocarditis.…”

“…13 Remarkably, many aspects of viral myocarditis may be recapitulated in experimental autoimmune models as induced by cardiac myosin and an adjuvant. 14 Pathological outcome of CVB3-induced myocarditis is determined by a complex interplay between viral [15][16][17][18] and host factors. At least two host proteins, decay accelerating factor (DAF) 19 and coxsackievirus-adenovirus receptor (CAR), 20,21 function as receptors for virus attachment and entry through binding with virus capsid proteins.…”

Genetic Differences in Bone Marrow-Derived Lymphoid Lineages Control Susceptibility to Experimental Autoimmune Myocarditis

“…MHC molecules modulate adaptive immune responses, including autoimmune responses, via their unique role in Ag presentation. Yet, at least seven non-MHC loci have been reported to influence susceptibility to viral or immunization-induced autoimmune myocarditis in mouse (18,35,36). Linkage of these loci to apoptosis or tolerance induction was suggested; however, the mechanisms by which they modulate disease susceptibility remain to be investigated.…”

“…EAM was elicited by immunization with mouse CM as previously described (18). At day 21, the hearts were collected, fixed in 10% formalin, and sent to Histoseve for embedding, sectioning, and H&E staining.…”

Myocarditis in Childhood: An Update on Etiology, Diagnosis and Management

“…Besides the MHC haplotype, non-MHC genes should be considered (Neu et al, 1987). Two non-MHC loci on murine chromosomes 1 and 6, referred as Eam1 and Eam2, respectively, might influence autoimmune myocarditis (Guler et al, 2005). These loci intersect with loci implicated in other autoimmune diseases, such as lupus and diabetes, might give a clue that various autoimmune disease could be controlled by related genetic mechanisms.…”