Myocarditis-inducing epitope of myosin binds constitutively and stably to I-Ak on antigen-presenting cells in the heart.

Abstract

SummaryImmune interactions in the heart were studied using a murine model of myosin-induced autoimmune myocarditis. A T cell hybridoma specific for mouse cardiac myosin was generated from A/J mice and used to demonstrate that endogenous myosin/I-A k complexes are constitutively expressed on antigen-presenting cells in the heart. This T cell hybridoma, Seu.5, was used as a functional probe to identify a myocarditis-inducing epitope of cardiac myosin. Overlapping peptides based on the cardiac myosin heavy chain cx (myhcot) sequences were synthesized and tested for their ability to stimulate Seu.5 T cells. One peptide, myhco~(325-357) strongly stimulated the Seu.5 T cells, localizing the epitope to this region of the myhca molecule. Using truncated peptides, the epitope was further localized to residues 334-352. The myhccx(334-352) peptide strongly induced myocarditis when administered to A/J mice, which was histologically indistinguishable from that induced by myosin. The myhcot(334-352) epitope was present in cardiac myosin and not skeletal muscle myosins, providing a biochemical basis for the cardiac specificity of this autoimmune disease. Induction of myocarditis by this epitope was restricted to the myhcot isoform and not the myhc[3 isoform, suggesting there may be a difference in the efficiency of generating tolerance to these isoforms of cardiac myosin, which are differentially developmentally regulated. The myhcot(334-352) epitope bound to purified I-A k molecules in a similar manner to other I-Ak-restricted immunogenic epitopes, HEL(48-61) and R.Nase(43-56). Importantly, the myhc0~(334-352) epitope was able to bind to I-A k molecules on the surface of antigen-presenting cells in a stable manner. These findings demonstrate that autoantigenic epitopes can behave in a dominant manner and constitutively bind to class II molecules in the target organ in a similar manner to foreign immunogenic epitopes.

Myocardial aging as a T-cell–mediated phenomenon

“…Cardiac-resident macrophages exhibiting an M2-like gene expression profile were found to be distributed in close association with the coronary vascular bed (3), and niches for dendritic cells (CD11c + MHC-II high CD80/86 low ) were found near the cardiac valves of the intact heart (1). It was also demonstrated that cardiac-resident MHCII + cells process and present myosin heavy chain-alpha-derived peptides under steady-state conditions (11,12) and prime T cells ex vivo (1). However, whether lymphocytes can seed the intact myocardium and whether T-cell priming with myocardial antigens can occur in the absence of an infection or autoimmune myocarditis remain elusive.…”

Cardiac Myosin and the TH1/TH2 Paradigm in Autoimmune Myocarditis

“…In fact, unique epitopes within cardiac myosin have been described to produce myocarditis. Myocarditis was induced by amino acid residues 334 to 352, located in the S1 region of A/J mouse cardiac myosin, 26 residues 736 to 1032 in BALB/c cardiac myosin, 59 acetylated residues 614 to 643 of rat cardiac myosin produced disease in BALB/c mice, 56 residues 1070 to 1165 of porcine cardiac myosin induced disease in Lewis rats, 57 residues 1107 to 1186 in the Lewis rat, 64 and acetylated Lewis rat LMM region residues 1539 to 1555. 58 Our studies in Lewis rats (Galvin et al, manuscript in preparation) suggest that epitopes within the LMM region produce valvulitis whereas the most severe myocarditis is produced by an epitope within the S2 region of cardiac myosin (Cunningham and Li, unpublished data).…”

Identification of an Epitope from Adenine Nucleotide Translocator 1 That Induces Inflammation in Heart in A/J Mice

“…One such model for cardiac autoimmunity is experimental autoimmune myocarditis (EAM), which involves induction of disease in susceptible rodent strains by immunizing animals with cardiac antigens or their peptide fragments. 23e25 In this study, we used the EAM model in A/J mice to demonstrate that ANT 1 possesses multiple immunodominant epitopes, and one of these, ANT 1 [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40], was found to induce myocarditis in the immunized animals. Furthermore, myocarditogenicity of ANT 1 [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] was associated with the generation of T cells capable of producing predominantly IL-17A, and the antigen-sensitized T cells can transfer the disease to naïve recipients, suggesting that ANT 1 can be a potential autoantigen in the heart autoimmunity.…”