Genetic mechanisms of autoimmune myocarditis

Johns Hopkins University, Baltimore MD

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Abstract

Autoimmune myocarditis develops due to an immune response to cardiac-specific antigens expressed in the heart. The MHC is important in determining susceptibility to autoimmune myocarditis;however other genetic factors are also critical. We propose to study these genetic mechanisms using a mouse model, cardiac myosin-induced experimental autoimmune myocarditis (EAM). The goal of the present proposal is to further localize the genetic differences between susceptible and resistant mouse strains, and to distinguish the roles of several cell lineages in genetic susceptibility to autoimmune myocarditis. We will investigate two costimulatory candidate genes, ICOS (Specific aim 1) and CD27 (Specific aim 2). Both of these genes are located in susceptibility regions on chromosomes 1 and 6 respectively. Additionally, both ICOS and CD27 are differentially regulated following immunization with cardiac myosin in the susceptible and resistant mice. Specific aim 1 will examine in depth our preliminary finding that resistant B 10.S mice have higher ICOS expression on CD4+T cells after myosin immunization. This finding suggests that at least part of the ICOS expressing CD4+ T cells are regulatory in EAM. Therefore we will assess the expression of ICOS on subsets of CD4+ T cells and determine the role of ICOS in effector and regulatory T cells during EAM by adoptively transferring ICOS deficient and/or IL-10 deficient CD4+ T cells into Rag-/- mice. We will also identify polymorphism in the ICOS gene. Specific aim 2 CD27 is significantly down regulated in A.SW but not B10.S mice following immunization with cardiac myosin, suggesting that CD27 is a candidate gene influencing EAM susceptibility in the Eam2 region. We will first examine the CD27 gene for polymorphisms. Next, we will determine the kinetics and function of CD27 on T cells during EAM in A.SW and B10.S mice and test our hypothesis that down regulation of CD27 on T cells in early activation phase is essential for their differentiation to pathogenic effector cells. We have established that genetic control of EAM is mediated by cells of the hematopoietic lineage including T and/or B cells. Specific aim 3 will examine if genetic factors modulate Th17 cells, NK cells, macrophages, B cells and T regulatory cells in mediating EAM. We will transfer bone marrow from cell specific knockout mice of the susceptible strain into the irradiated resistant strain. We have found that IL-23 production was less in B10.S mice than AS.W mice during EAM, which suggest that B10.S mice might be resistant to myocarditis due to their decrease and ability to induce differentiation or sustain survival of Th17 cells in heart. Therefore we will identify polymorphisms and the protein expression profile of cytokines and chemokines related to Th17 pathway following immunization with cardiac myosin in A.SW and B10.S mice.