Editors' ChoiceMyocarditis

A Little Tolerance Can Prevent a Broken Heart

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Science Translational Medicine  13 Apr 2011:
Vol. 3, Issue 78, pp. 78ec53
DOI: 10.1126/scitranslmed.3002484

Myocarditis, or inflammation of the heart muscle, has multiple, heterogeneous causes. Patients with myocarditis experience symptoms that range from a subacute illness to heart failure or dangerous heart rhythms. Treatment includes antimicrobial drugs because infection is a major cause of disease. However, immunosuppressive medications may also be used to treat myocarditis. One rationale for suppressing the immune system even in the setting of a potential infection is that many individuals with cardiac muscle injury harbor circulating autoantibodies to cardiac proteins; these data suggest that autoimmune reactions targeting the heart may contribute to propagating inflammation. Yet it remains unclear why patients with cardiac damage would be susceptible to heart-directed autoimmunity. A recent paper by Lv et al. provides a potential mechanism with which to explain autoimmune-mediated myocarditis.

The authors examined a transgenic mouse with a human major histocompatibility complex (MHC) class II allele, DQ8, which has previously been associated with autoimmune diabetes. In prior work, this same group found that when they expressed DQ8 in nonobese diabetic (NOD) mice, animals normally prone to autoimmune diabetes, the mice instead developed autoimmune myocarditis. In the current study, the authors used serum autoantibodies from DQ8+NOD mice to identify a dominant antigen targeted in the heart, the α-isoform of cardiac myosin heavy chain (α-MyHC). They showed that CD4+ T cells specific for α-MyHC isolated from diseased hearts were capable of inducing myocarditis when transferred into unaffected animals. Interestingly, they found that the levels of α-MyHC transcripts were nearly absent in the thymic epithelium, which suggested that a defect in thymic tolerance to the α-MyHC antigen might play a role in the onset of disease. In order to test this directly, the authors created another transgenic mouse in which they introduced the α-MyHC protein back into the thymic epithelium. These animals were completely protected from disease. Lastly, the authors found that human patients with myocarditis also lacked thymic α-MyHC expression. These patients had high numbers of circulating lymphocytes specific for α-MyHC in their peripheral blood. Because nontransgenic NOD mice and healthy control patients also do not express the α-MyHC antigen within the thymus, there clearly must be other tolerance mechanisms that are crucial for the prevention of disease. However, the current study provides convincing evidence to show that thymic tolerance plays an important role in myocarditis in DQ8+NOD mice and also identifies an antigen, α-MyHC, that may serve as a potential biomarker and therapeutic target in patients with autoimmune-mediated myocardial disease.

H. Lv et al., Impaired thymic tolerance to α-myosin directs autoimmunity to the heart in mice and humans. J. Clin. Invest. 121, 1561–1573 (2011). [Full Text]

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