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Article: Generation of humanized mice susceptible to peptide-induced inflammatory heart disease

TitleGeneration of humanized mice susceptible to peptide-induced inflammatory heart disease
Authors
KeywordsMyocarditis
Genes
Cardiomyopathy
Molecular biology
Issue Date1999
Citation
Circulation, 1999, v. 99, n. 14, p. 1885-1891 How to Cite?
AbstractBackground - Dilated cardiomyopathy (DCM) is a major cause of sudden cardiac death. In certain mouse major histocompatibility complex (MHC) backgrounds, myocarditis and inflammatory cardiomyopathy can be triggered by immunization with heart muscle-specific proteins. Similarly, chronic heart disease in humans has been linked to certain HLA alleles, such as HLA-DQ6. However, there is no experimental evidence showing that human MHC class II molecules and peptides derived from human proteins are involved in the pathogenesis of myocarditis and DCM. Methods and Results - We generated double CD4- and CD8-deficient mice transgenic for human CD4 (hCD4) and human HLA-DQ6 to specifically reconstitute the human CD4/DQ6 arm of the immune system in mice. Transgenic hCD4 and HLA-DQ6 expression rendered genetically resistant C57BL/6 mice susceptible to the induction of autoimmune myocarditis induced by immunization with cardiac myosin. Moreover, we identified heart- specific peptides derived from both mouse and human α-myosin heavy chains capable of inducing inflammatory heart disease in hCD4 and HLA-DQ6 double transgenic mice but not in hCD4 single transgenic littermates. The autoimmune inflammatory heart disease induced by the human heart muscle-specific peptide in hCD4 and HLA-DQ6 double transgenic mice shared functional and phenotypic features with the disease occurring in disease-susceptible nontransgenic mice. Conclusions - Our data provide the first genetic and functional evidence that human MHC class II molecules and a human α-myosin heavy chain- derived peptide can cause inflammatory heart disease and suggest that human inflammatory cardiomyopathy can be caused by organ-specific autoimmunity. The humanized mice generated in this study will be an ideal animal model to further elucidate the pathogenesis of inflammatory heart disease and facilitate the development of rational treatment strategies.
Persistent Identifierhttp://hdl.handle.net/10722/291497
ISSN
2023 Impact Factor: 35.5
2023 SCImago Journal Rankings: 8.415
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorBachmaier, Kurt-
dc.contributor.authorNeu, Nikolaus-
dc.contributor.authorYeung, Rae S.M.-
dc.contributor.authorMak, Tak W.-
dc.contributor.authorLiu, Peter-
dc.contributor.authorPenninger, Josef M.-
dc.date.accessioned2020-11-17T14:54:30Z-
dc.date.available2020-11-17T14:54:30Z-
dc.date.issued1999-
dc.identifier.citationCirculation, 1999, v. 99, n. 14, p. 1885-1891-
dc.identifier.issn0009-7322-
dc.identifier.urihttp://hdl.handle.net/10722/291497-
dc.description.abstractBackground - Dilated cardiomyopathy (DCM) is a major cause of sudden cardiac death. In certain mouse major histocompatibility complex (MHC) backgrounds, myocarditis and inflammatory cardiomyopathy can be triggered by immunization with heart muscle-specific proteins. Similarly, chronic heart disease in humans has been linked to certain HLA alleles, such as HLA-DQ6. However, there is no experimental evidence showing that human MHC class II molecules and peptides derived from human proteins are involved in the pathogenesis of myocarditis and DCM. Methods and Results - We generated double CD4- and CD8-deficient mice transgenic for human CD4 (hCD4) and human HLA-DQ6 to specifically reconstitute the human CD4/DQ6 arm of the immune system in mice. Transgenic hCD4 and HLA-DQ6 expression rendered genetically resistant C57BL/6 mice susceptible to the induction of autoimmune myocarditis induced by immunization with cardiac myosin. Moreover, we identified heart- specific peptides derived from both mouse and human α-myosin heavy chains capable of inducing inflammatory heart disease in hCD4 and HLA-DQ6 double transgenic mice but not in hCD4 single transgenic littermates. The autoimmune inflammatory heart disease induced by the human heart muscle-specific peptide in hCD4 and HLA-DQ6 double transgenic mice shared functional and phenotypic features with the disease occurring in disease-susceptible nontransgenic mice. Conclusions - Our data provide the first genetic and functional evidence that human MHC class II molecules and a human α-myosin heavy chain- derived peptide can cause inflammatory heart disease and suggest that human inflammatory cardiomyopathy can be caused by organ-specific autoimmunity. The humanized mice generated in this study will be an ideal animal model to further elucidate the pathogenesis of inflammatory heart disease and facilitate the development of rational treatment strategies.-
dc.languageeng-
dc.relation.ispartofCirculation-
dc.subjectMyocarditis-
dc.subjectGenes-
dc.subjectCardiomyopathy-
dc.subjectMolecular biology-
dc.titleGeneration of humanized mice susceptible to peptide-induced inflammatory heart disease-
dc.typeArticle-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1161/01.CIR.99.14.1885-
dc.identifier.pmid10199887-
dc.identifier.scopuseid_2-s2.0-0033551090-
dc.identifier.volume99-
dc.identifier.issue14-
dc.identifier.spage1885-
dc.identifier.epage1891-
dc.identifier.isiWOS:000079635900017-
dc.identifier.issnl0009-7322-

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