Impaired thymic tolerance to α-myosin directs autoimmunity to the heart in mice and humans
HuiJuan Lv, … , Bruno Kyewski, Myra A. Lipes
HuiJuan Lv, … , Bruno Kyewski, Myra A. Lipes
Published March 23, 2011
Citation Information: J Clin Invest. 2011;121(4):1561-1573. https://doi.org/10.1172/JCI44583.
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Research Article

Impaired thymic tolerance to α-myosin directs autoimmunity to the heart in mice and humans

Abstract

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 α-isoform of myosin heavy chain (α-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 α-MyHC in thymic epithelium conferred tolerance to cardiac myosin and prevented myocarditis, demonstrating that α-MyHC is a primary autoantigen in this disease process. Remarkably, we found that humans also lacked α-MyHC in mTECs and had high frequencies of α-MyHC–specific T cells in peripheral blood, with markedly augmented T cell responses to α-MyHC in patients with myocarditis. Since α-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.

Authors

HuiJuan Lv, Evis Havari, Sheena Pinto, Raju V.S.R.K. Gottumukkala, Lizbeth Cornivelli, Khadir Raddassi, Takashi Matsui, Anthony Rosenzweig, Roderick T. Bronson, Ross Smith, Anne L. Fletcher, Shannon J. Turley, Kai Wucherpfennig, Bruno Kyewski, Myra A. Lipes

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Figure 5

Lack of expression of α-MyHC in thymic and LNSC subsets is associated with reduced T cell tolerance to cardiac myosin.

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Lack of expression of α-MyHC in thymic and LNSC subsets is associated wi...
(A) Expression of control and tissue-restricted genes in whole thymus, purified mTECs, cTECs, DCs, and macrophages (Mϕ) from B6, NOD, and DQ8+NOD mice was determined by RT-PCR. Values represent microarray data (see Supplemental Table 1). Actb, β-actin; Ctsl, cathepsin L, Ctss, cathepsin S; Ins2, insulin II; Myh6, α-MyHC (red); Myh7, β-MyHC; Tnnt2, cardiac troponin T; Tnni3, cardiac troponin I; Chrna1, cholinergic receptor, nicotinic, α polypeptide 1; Co, plasmid DNA as positive control. (B) Relative mRNA expression levels of Myh6, Myh7, and GAD67 were assessed by quantitative RT-PCR in purified mouse mTECs and cTECs and control tissues. Data were normalized to Actb. (C) Analysis of Myh6 and Myh7 expression in purified LNSC subsets: FRCs, LECs, BECs, and DN cells. Mlana, tyrosinase, retinal S antigen (Ag), and Aire are positive control genes for FRC, LEC, BEC, and DN subsets, respectively. (D) T cell tolerance to cardiac and soleus myosin as assessed by in vitro recall proliferative responses of representative B6 and NOD mice 10 days after immunization with cardiac myosin (filled diamonds), and soleus myosin (open circles). Data represent mean ± SD of responses measured in triplicate. (E) Responses to indicated myosins in B6 and NOD mice as assessed by SI. Immunization and recall proliferation responses were performed as in D, and SI at 25 μg/ml antigen concentration was calculated as (counts – background counts/background counts) (*P < 0.05). The solid lines represent the mean values for each group.