Novel Nonmajor Histocompatibility Complex–Linked Loci From Mouse Chromosome 17 Confer Susceptibility to Viral-Mediated Chronic Autoimmune Myocarditis

Abstract

Background-Development of viral-induced chronic myocarditis is thought to involve both environmental and genetic factors. However, to date, no susceptibility genes have been identified. Methods and Results-We sought to identify loci that confer susceptibility to viral-induced chronic myocarditis with the use of chromosome substitution strain mice that are composed of 1 chromosome from the disease susceptible A/J strain on an otherwise resistant C57BL/6 background. By this method, we identified chromosome 17 to confer susceptibility. To further isolate the region of susceptibility, 8 strains of mice congenic for different portions of chromosome 17 were generated. Characterization of these strains identified at least 4 susceptibility loci on the chromosome. Three of these loci are located in the proximal 22.8 cM, whereas the fourth locus is located in the portion of the chromosome distal to 34.3 cM. Conclusions-We have identified 4 loci that confer susceptibility of viral-induced chronic myocarditis. Of these loci, 3 were distinct from the major histocompatibility complex locus and thus represent novel susceptibility loci. The close proximately of the 2 novel loci with susceptibility loci for other autoimmune diseases such as type 1 diabetes and chronic experimental autoimmune thyroiditis suggests the presence of global autoimmune susceptibility genes. (Circ Cardiovasc Genet. 2010;3:399-408.)

Quantitative Trait Locus Analysis, Pathway Analysis, and Consomic Mapping Show Genetic Variants of Tnni3k, Fpgt, or H28 Control Susceptibility to Viral Myocarditis

“…The MHC genes have been linked to susceptibility to myocarditis in both humans and experimental mouse models (13,14).…”

The Key Players of Coxsackievirus-Induced Myocarditis

“…Poffenberger et al demonstrated that in the absence of IL-6, a greater early immune response occurred, instigating a severe chronic disease pathology (Poffenberger et al 2009). Recently, Poffenberger et al described susceptibility loci on chromosome 17 that implicate the highly suggested genetic component as a factor dictating viral myocarditis pathogenesis (Poffenberger et al 2010). Though work from our lab has contributed a great deal to the understanding of coxsackievirus B3-induced myocarditis, there remains many unanswered questions with regards to the true key immune players that dictate disease pathogenesis.…”

“…It has been demonstrated that the induction of disease by immunization with cardiac myosin can only be successful in genetically susceptible mice . We suggest that the complex genetics of the host therefore determines whether an infection will resolve or proceed to an adverse autoimmune outcome (Poffenberger et al 2010). Identifying particular traits that favour susceptibility or resistance to an autoimmune incidence helps us understand how infectious diseases culminate in autoimmune disease.…”

A Family History of Dilated Cardiomyopathy Induced by Viral Myocarditis

“…In mice, several genes have been identified conferring susceptibility for viral induced-chronic myocarditis. Some of them belong to major histocompatibility complex, others are close to loci for autoimmune diseases, highlighting the link between genetics and immune response to viral injury and DCM [4]. The link between genetic susceptibility, related immune response, and DC is not proven in human.…”