Characterization of T Cell Receptor β Chains of Accumulating T Cells in Chronic Ongoing Myocarditis Demonstrated by Heterotopic Cardiac Transplantation in Mice

Abstract

yocarditis is defined as an inflammatory disorder of the heart muscle and the most common etiological agents are viruses. 1 Although a link between viral myocarditis and dilated cardiomyopathy (DCM) has long been recognized, the nature of this relationship remains unclear. The progression from viral myocarditis to DCM is thought to involve autoimmunity and the presence of persistent viral infection. 2 When viral genome was detected in the myocardium of heart transplant patients with DCM, the persistent viral infection theory gained prominence. However, recent data demonstrated that the number of transplant cases with such viral infection was less than expected. 3 And in fact, abnormal immunologic responses are seen in patients with DCM; responses that include the presence of anti-heart antibodies, increased serum concentration of the soluble interleukin-2 receptor, and differences in IgG subclasses. 4 To clarify the pathogenic mechanism of these diseases, we developed a murine model of chronic ongoing viral myocarditis in Coxsackievirus B3 inoculated A/J mice. During chronic ongoing myocarditis, CD4 + T cells were found to be the main infiltrates in the myocardium. Intercellular adhesion molecule-1 (ICAM-1) was expressed on the endothelial cells of vessels in and around the infiltrated lesions. In contrast, major histocompatibility complex (MHC) class I antigen and MHC class II antigen were expressed on infected myocardial cells. More interestingly, the Coxsackievirus B3 genome was not detected in the myocardia of animals with chronic ongoing myocarditis, 5 and, moreover, we showed that myocarditis was transferred to a normal heart transplanted into a mouse with chronic ongoing myocarditis. 6 These results lead to speculation that an autoimmune response, not persistent viral infection, may play a key role in the progression of chronic ongoing myocarditis.In the present study, to prove an autoimmune mechanism of chronic ongoing myocarditis, we characterized the accumulating T cells in the donor heart that was transplanted Characterization of T Cell Receptor Chains of Accumulating T Cells in Chronic Ongoing Myocarditis Demonstrated by Heterotopic Cardiac Transplantation in MiceHiroshi Nakamura, MD; Tomohiro Kato, MD*; Taisei Yamamura, MD; Takuo Yamamoto, MD; Seiji Umemoto, MD; Taichi Sekine*; Kusuki Nishioka, MD*; Masunori Matsuzaki, MD Autoimmne mechanisms have been implicated in the pathogenesis of chronic ongoing mycarditis. An earlier study of murine chronic ongoing myocarditis reported that infiltrating T cells and macrophages were prominent in the normal donor heart, in a heterotopic cardiac transplantation model. It was demonstrated that myocarditis was transferred to a normal heart transplanted into a mouse with chronic myocarditis. The present study investigated an autoimmune link to the pathogenesis of chronic ongoing myocarditis by analyzing the T cell clonalities in the model. To characterize the accumulating T cells in the donor heart, the T cell receptor genes (TCRBG) were amplified by reverse trans...

Sex chromosome complement contributes to sex differences in coxsackievirus B3 but not influenza A virus pathogenesis

“…In the current study, XY mice developed less severe CVB3-induced myocarditis and had more T regulatory cells in their hearts than XX mice. T regulatory cells inhibit proinflammatory responses through direct cell-cell contact with effector T cells, interaction with antigen presenting cells resulting increased indoleamine-2,3-dioxygenase (IDO) production, and secretion of soluble factors including IL-10 and transforming growth factor (TGF)β [54-56]. The effect of sex chromosome complement on T regulatory cells was not addressed in previous experiments of EAE and lupus in FCG mice [27]; T regulatory cells, however, are associated with resistance against EAE [57].…”