Identification of cardiac myosin peptides capable of inducing autoimmune myocarditis in BALB/c mice.

Pummerer, Christian; Luze, Kerstin; Grässl, Gerhard; Bachmaier, Kurt; Offner, Felix; Burrell, Sarah K.; Lenz, Douglas M.; Zamborelli, Thomas J.; Penninger, Josef; Neu, Nikolaus

doi:10.1172/jci118642

Cited by 187 publications

(162 citation statements)

References 23 publications

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“…T cell response to myosin peptide 735-747 suggests that autoreactive T cells restricted by DQ8 mediate the response to cardiac myosin in our model although the present data does not exclude the role of other peptides. This peptide is homologous in human and mouse and has been used to induce myocarditis in mice [26]. DR3 mice do not develop myocarditis and also do not respond to this peptide.…”

Section: Discussionmentioning

confidence: 99%

Spontaneous myocarditis mimicking human disease occurs in the presence of an appropriate MHC and non-MHC background in transgenic mice

Taneja

Behrens

Cooper

et al. 2007

Journal of Molecular and Cellular Cardiology

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Most individuals have viral infections at some point in their life, however, only few develop autoreactivity to cardiac myosin following infection resulting in myocarditis suggesting a genetic predisposition. Most mouse models of myocarditis are induced by viral infection or by immunization with cardiac myosin. We generated HLA-DR3.Aβo and HLA-DQ8.Aβo transgenic mice in NOD and HLA-DQ8.Aβo in B10 background to study spontaneous autoimmunity. A high mortality was observed in NOD.DQ8 female mice 16 weeks or older. Echocardiography showed marked systolic dysfunction. Histopathology of various organs revealed an enlarged heart with mononuclear infiltrate consisting of CD4 and Mac-1+ cells and myocyte necrosis. The autoimmunity was associated with the presence of spontaneous autoreactive T cells and antibodies to cardiac myosin. Serologically, mice were negative for all known mouse viruses. NOD.DR3.Aβo, the transgene negative littermates, NOD, and B10.DQ8 Aβo mice had no gross or microscopic cardiac pathology. Spontaneous cellular and humoral response to cardiac myosin suggest that NOD.DQ8 may harbor autoreative cells that can lead to spontaneous myocarditis and dilated cardiomyopathy. HLA-DQ8 is required for predisposition to the spontaneous autoreactivity while NOD background influences onset and progression of disease. This model of myocarditis occurs predominantly in female mice and may provide insight into the pathogenesis of heart disease in women.

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Section: Discussionmentioning

confidence: 99%

Spontaneous myocarditis mimicking human disease occurs in the presence of an appropriate MHC and non-MHC background in transgenic mice

Taneja

Behrens

Cooper

et al. 2007

Journal of Molecular and Cellular Cardiology

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“…Myocarditis can be induced by cardiac myosin in A/J mice, 23,27 BALB/c mice, 56,59 and in Lewis rats. 24,58 However, C57BL/6 mice are resistant to myosin-induced myocarditis.…”

Section: Susceptibilty To Myocarditis In Rodent Modelsmentioning

confidence: 99%

“…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).…”

Section: Susceptibilty To Myocarditis In Rodent Modelsmentioning

confidence: 99%

Cardiac Myosin and the TH1/TH2 Paradigm in Autoimmune Myocarditis

Cunningham

2001

The American Journal of Pathology

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“…CD4 + T-cell-mediated experimental autoimmune myocarditis (EAM) is a model for inflammatory heart disease and is induced in mice either by immunization with α-myosin heavy chain (α-MyHC) derived peptides emulsified in CFA [2][3][4] or by vaccination with α-MyHC-loaded activated dendritic cells (DCs) [5]. Typically, both Th1 and Th17 cells are induced during the course of EAM.…”

Section: Introductionmentioning

confidence: 99%

Absence of nonhematopoietic MHC class II expression protects mice from experimental autoimmune myocarditis

et al. 2015

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Experimental autoimmune myocarditis (EAM) is a CD4 + T-cell-mediated model of human inflammatory dilated cardiomyopathies.Heart-specific CD4 + T-cell activation is dependent on autoantigens presented by MHC class II (MHCII) molecules expressed on professional APCs. In this study, we addressed the role of inflammation-induced MHCII expression by cardiac nonhematopoietic cells on EAM development. EAM was induced in susceptible mice lacking inducible expression of MHCII molecules on all nonhematopoietic cells (pIV−/− K14 class II transactivator (CIITA) transgenic (Tg) mice) by immunization with α-myosin heavy chain peptide in CFA. Lack of inducible nonhematopoietic MHCII expression in pIV−/− K14 CIITA Tg mice conferred EAM resistance. In contrast, cardiac pathology was induced in WT and heterozygous mice, and correlated with elevated cardiac endothelial MHCII expression. Control mice with myocarditis displayed an increase in infiltrating CD4 + T cells and in expression of IFN-γ, which is the major driver of nonhematopoietic MHCII expression. Mechanistically, IFN-γ neutralization in WT mice shortly before disease onset resulted in reduced cardiac MHCII expression and pathology. These findings reveal a previously overlooked contribution of IFN-γ to induce endothelial MHCII expression in the heart and to progress cardiac pathology during myocarditis. Keywords: CD4 + T cells Experimental autoimmune myocarditis (EAM) Endothelial antigen presentation Interferon-γ MHC class IIAdditional supporting information may be found in the online version of this article at the publisher's web-site Correspondence: Prof. Hans Acha-Orbea e-mail: hans.acha-orbea@unil.ch C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2016. 46: 656-664 Immunomodulation 657 IntroductionInflammatory dilated cardiomyopathy is a common cause of heart failure in young patients and often results from myocarditis in predisposed individuals [1]. CD4 + T-cell-mediated experimental autoimmune myocarditis (EAM) is a model for inflammatory heart disease and is induced in mice either by immunization with α-myosin heavy chain (α-MyHC) derived peptides emulsified in CFA [2][3][4] or by vaccination with α-MyHC-loaded activated dendritic cells (DCs) [5]. Typically, both Th1 and Th17 cells are induced during the course of EAM. It is assumed that both of these subsets mediate myocarditis as mice deficient in either interleukin 17 (IL-17) or interferon γ (IFN-γ) develop cardiac pathology [6,7]. Remarkably, heart-specific autoimmune inflammation has been shown to be a consequence of impaired central tolerance induction to α-MyHC during T-cell development in mice and in humans [8]. CD4 + T-cell-orchestrated immune responses are driven by MHC class II (MHCII) mediated antigen presentation. MHCII is primarily expressed on professional APCs. Cardiac APCs were suggested to present cardiac myosin before the onset of cardiac pathology [9], and DCs, the major APC subset able to initiate primary immune responses, were shown to be critical for ...

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Identification of cardiac myosin peptides capable of inducing autoimmune myocarditis in BALB/c mice.

Cited by 187 publications

References 23 publications

Spontaneous myocarditis mimicking human disease occurs in the presence of an appropriate MHC and non-MHC background in transgenic mice

Spontaneous myocarditis mimicking human disease occurs in the presence of an appropriate MHC and non-MHC background in transgenic mice

Cardiac Myosin and the TH1/TH2 Paradigm in Autoimmune Myocarditis

Absence of nonhematopoietic MHC class II expression protects mice from experimental autoimmune myocarditis

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