| First Author | Lv H | Year | 2011 |
| Journal | J Clin Invest | Volume | 121 |
| Issue | 4 | Pages | 1561-73 |
| PubMed ID | 21436590 | Mgi Jnum | J:171993 |
| Mgi Id | MGI:5002748 | Doi | 10.1172/JCI44583 |
| Citation | Lv H, et al. (2011) Impaired thymic tolerance to alpha-myosin directs autoimmunity to the heart in mice and humans. J Clin Invest 121(4):1561-73 |
| abstractText | Autoimmunity has long been linked to myocarditis and its sequela, dilated cardiomyopathy, the leading causes of heart failure in young patients. However, the underlying mechanisms are poorly defined, with most clinical investigations focused on humoral autoimmunity as the target for intervention. Here, we show that the alpha-isoform of myosin heavy chain (alpha-MyHC, which is encoded by the gene Myh6) is the pathogenic autoantigen for CD4+ T cells in a spontaneous mouse model of myocarditis. Further, we found that Myh6 transcripts were absent in mouse medullary thymic epithelial cells (mTECs) and peripheral lymphoid stromal cells, which have been implicated in mediating central and peripheral T cell tolerance, respectively. Transgenic expression of alpha-MyHC in thymic epithelium conferred tolerance to cardiac myosin and prevented myocarditis, demonstrating that alpha-MyHC is a primary autoantigen in this disease process. Remarkably, we found that humans also lacked alpha-MyHC in mTECs and had high frequencies of alpha-MyHC-specific T cells in peripheral blood, with markedly augmented T cell responses to alpha-MyHC in patients with myocarditis. Since alpha-MyHC constitutes a small fraction of MyHC in human heart, these findings challenge the longstanding notion that autoimmune targeting of MyHC is due to its cardiac abundance and instead suggest that it is targeted as a result of impaired T cell tolerance mechanisms. These results thus support a role for T cell-specific therapies for myocarditis. |
