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Generation of humanized mice susceptible to peptide-induced inflammatory heart disease
K Bachmaier1, N Neu, R S Yeung
1mgen Institute, Ontario Cancer Institute, and the Departments of Medical Biophysics and Immunology, University of Toronto, Ontario, Canada.
Insights
Human HLA-DQ6 molecules and alpha-myosin peptides can trigger autoimmune myocarditis in mice, providing evidence for inflammatory heart disease pathogenesis.
Area of Science:
- Immunology
- Cardiology
- Genetics
Background:
- Dilated cardiomyopathy (DCM) is a significant cause of sudden cardiac death.
- Autoimmune myocarditis can be triggered by heart-specific proteins in certain mouse models.
- Human leukocyte antigen (HLA) alleles, like HLA-DQ6, are linked to human heart disease.
Purpose of the Study:
- To investigate the role of human MHC class II molecules and peptides in myocarditis and DCM pathogenesis.
- To establish a humanized mouse model for studying inflammatory heart disease.
Main Methods:
- Generated double CD4- and CD8-deficient mice transgenic for human CD4 (hCD4) and human HLA-DQ6.
- Immunized transgenic mice with cardiac myosin to induce autoimmune myocarditis.
- Identified heart-specific peptides from alpha-myosin heavy chains.
Main Results:
- Transgenic hCD4 and HLA-DQ6 expression induced autoimmune myocarditis in resistant mice.
- Heart-specific peptides from mouse and human alpha-myosin heavy chains induced inflammatory heart disease in double transgenic mice.
- The induced disease shared features with naturally occurring inflammatory heart disease.
Conclusions:
- Human MHC class II molecules and alpha-myosin peptides can cause inflammatory heart disease.
- Organ-specific autoimmunity may cause human inflammatory cardiomyopathy.
- Humanized mice serve as a model for studying inflammatory heart disease and developing treatments.
Background:
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 alpha-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 alpha-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.
