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Cited by 89Viral Infections and Immunology ResearchCardiac Fibrosis and RemodelingT-cell and B-cell Immunology

Impaired up-regulation of CD25 on CD4 + T cells in IFN-γ knockout mice is associated with progression of myocarditis to heart failure

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Afanasyeva, Marina, Georgakopoulos, Dimitrios, Belardi, Diego F., Bedja, Djahida, Fairweather, DeLisa, Wang, Yan, Kaya, Ziya, Gabrielson, Kathleen L. +4 more·2005·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0408241102PMC PMC544075
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Abstract

Inflammation has been recognized increasingly as a critical pathologic component of a number of heart diseases. A mouse model of autoimmune myocarditis was developed to study the role of immune mediators in the development of cardiac dysfunction. We have found previously that IFN-γ deficiency promotes inflammation in murine myocarditis. It has been unclear, however, how IFN-γ deficiency in myocarditis affects cardiac function and what underlying immune mechanisms are responsible for these effects. In this work, we show that IFN-γ knockout (KO) mice have more pronounced systolic and diastolic dysfunction and greater frequency of progression to dilated cardiomyopathy and heart failure compared with WT mice. Cardiac dysfunction in the KO mice is associated with the expansion of activated (CD44 high ) CD3 + T cells due to reduced apoptosis of CD4 + , but not CD8 + , T cells. CD4 + T cells in the KO mice show impaired up-regulation of CD25 upon activation, resulting in the expansion of CD4 + CD44 + CD25 - T cells and their infiltration into the heart. CD4 + CD25 - T cells are less apoptosis-prone compared with the CD25 + population, and their infiltration into the heart is associated with greater severity of myocarditis. We conclude that IFN-γ deficiency in autoimmune myocarditis is associated with preferential expansion of CD4 + CD44 + CD25 - T cells resulting in increased cardiac inflammation. An exaggerated inflammatory response in IFN-γ KO mice causes cardiac dysfunction, leading to dilated cardiomyopathy and heart failure.

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  • Both the mRNA against the SARS-CoV-2 spike protein and the lipid nanoparticle vehicle could provide the adjuvant effect needed to promote myocarditis following vaccination with an mRNA vaccine.

    “Possibly both the mRNA against the SARS-CoV-2 spike protein and the lipid nanoparticle vehicle could provide the adjuvant effect needed to promote myocarditis following vaccination with an mRNA vaccine. 35,51,198”

    From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [198]

    The Discussion (page unavailable) describes an enhanced autoimmune response in IFN-γ knockout mice when autoreactive lymphocytes are stimulated in the presence of a strong adjuvant, and the Methods describe a cardiac-myosin immunization model of myocarditis. The paper does not address SARS-CoV-2 spike mRNA, lipid nanoparticles, or myocarditis following mRNA vaccination, so it cannot support the proposed roles of those vaccine components. (LLM, conf=0.87)

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Authors
Afanasyeva, M., Georgakopoulos, D., Belardi, D. F., Bedja, D., Fairweather, D., Wang, Y., Kaya, Z., Gabrielson, K. L., Rodriguez, E. R., Caturegli, P., Kass, D. A., & Rose, N. R.
Affiliations
  • Johns Hopkins University (US)
  • Departments of Pathology, Medicine, and Comparative Medicine and the W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Medical Institutions, Baltimore, MD 21205
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2004-12-20
Volume
102
Issue
1
Pages
180-185
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0408241102
PMC
PMC544075
OpenAlex
W1968343481
Cited by
89
References
41
Citations by year
2026: 2 · 2025: 1 · 2024: 4 · 2023: 5 · 2022: 4 · 2021: 3 · 2020: 2 · 2019: 3 · 2018: 3 · 2017: 2 · 2016: 1 · 2015: 3 · 2013: 6 · 2012: 9
FWCI
3.71
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Heart, Lung, and Blood Institute (HL 67290, R01HL067290, HL 70729, R01HL070729)
  • National Institute of Allergy and Infectious Diseases (AI 51835, R21AI051835)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Viral Infections and Immunology Research
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
IFN-gamma deficiency, autoimmune myocarditis, heart failure, dilated cardiomyopathy, CD4+ T cells, CD44, T cell apoptosis, cardiac inflammation, cardiac dysfunction, T cell infiltration
MeSH terms
Animals, Female, Heart Failure, Interferon-gamma, Myocarditis, Myocardium, Receptors, Interleukin-2, CD4-Positive T-Lymphocytes, Up-Regulation, T-Lymphocyte Subsets, Apoptosis, Mice, Knockout, CD8-Positive T-Lymphocytes, Mice

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