Mast Cells and Innate Cytokines are Associated with Susceptibility to Autoimmune Heart Disease Following Coxsackievirus B3 Infection
Abstract
The development of autoimmune disease involves a combination of genetic and environmental factors. Many autoimmune diseases are believed to be triggered by viral infections. Since the early, natural immune response to infection can determine the later development of the adaptive immune response, innate immunity likely influences the progression from viral immunity to autoimmunity. To investigate the role of the innate immune response on susceptibility to autoimmune disease, we compared the early cytokine response of mice susceptible or resistant to the development of autoimmune heart disease following viral infection. We found that susceptible BALB/c mice produced elevated levels of TNF-alpha, IL-1beta, and IL-4 within hours of Coxsackievirus B3 (CB3) infection. These cytokines are known to be critical for the development of autoimmune heart disease, and are also rapidly produced from activated mast cells (MC). Degranulating MC were observed as early as 6 h following CB3 infection in the heart, and significantly higher numbers of MC were found in the spleen of susceptible BALB/c mice at this time. Thus, susceptibility to autoimmune heart disease can be determined as early as 6 h following viral infection in susceptible strains of mice.
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Mast cells work in cooperation with macrophages to increase profibrotic inflammation and remodeling that leads to scar and DCM.
“Mast cells work in cooperation with macrophages to increase profibrotic inflammation and remodeling that leads to scar and DCM (Figure 4). 129,157,158,160”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [160]
Mast cells are the first APCs to respond to CVB3 within 15 minutes of intraperitoneal infection during autoimmune CVB3 myocarditis, leading to upregulation of TLR4, and this response leads to rapid increases in TNF, IL-1β, IL-6, and IFNγ in many organs including the heart.
“We showed that mast cells are the first APCs to respond to CVB3 within 15 minutes of intraperitoneal infection during autoimmune CVB3 myocarditis, leading to upregulation of TLR4, and that this response leads to rapid increases in TNF, IL-1 β , IL-6, and IFN γ in many organs including the heart. 124,146,160”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [160]
IL-18 strongly drives Th1 immune responses, but in BALB/c mice, this produces a mixed Th1/Th2 response that promotes fibrosis and DCM rather than a classical STAT-driven Th1 response.
“IL-18, originally named IFNγ -inducing factor, strongly drives Th1 immune responses, 143-145 but in BALB/c mice, this produces a mixed Th1/Th2 response that promotes fibrosis and DCM rather than a classical STAT-driven Th1 respo nse. 115,146,160,165”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [160]
Increased TNFα and IL-1β in the heart and perivascular fibrosis were found, which typically indicates perivascular mast cell degranulation.
“They also found increased TNF α and IL-1 β in the heart and perivascular fibrosis, which in our experience typically indicates perivascular mast cell degranulation. 157,160,182,183”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [160]
Investigators found viral replication in a number of organs with the highest expression in the lung and brain and increased serum cytokines including IFNγ; however, the mouse background used in these models was C57BL/6, which responds to antigens with elevated Th1-type immune responses because they have few mast cells.
“Investigators found viral replication in a number of organs with the highest expression in the lung and brain and increased serum cytokines including IFN γ ; however, the mouse background used in these models was C57BL/6, which responds to antigens with elevated Th1-type immune responses because they have few mast cells. 160,177,178”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [160]
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From Infection to Autoimmunity
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- Authors
- Fairweather, D., Frisancho-Kiss, S., Gatewood, S., Njoku, D., Steele, R., Barrett, M., & Rose, N. R.
- Affiliations
- Johns Hopkins University (US)
- Department of Pathology, Johns Hopkins Medical Institutions, 720 Rutland Avenue, 21205, Baltimore, MD, USA
- Corresponding author
- Rose, Noel R.
- Venue
- Autoimmunity
- Publisher
- Informa UK Limited
- Published
- 2004-03
- Volume
- 37
- Issue
- 2
- Pages
- 131-145
- ISSN
- 0891-6934 (ISSN-L)
- 1607-842X
- OpenAlex
- W2085467917
- Cited by
- 115
- References
- 4
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 7 · 2023: 7 · 2022: 6 · 2021: 4 · 2020: 8 · 2019: 8 · 2018: 4 · 2016: 1 · 2015: 2 · 2014: 5 · 2013: 3 · 2012: 7
- FWCI
- 3.92
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Autoimmunity (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 › Mast cells and histamine
- Keywords
- mast cells, innate immunity, autoimmune heart disease, coxsackievirus B3, viral infection, cytokines, TNF-α, IL-1β, IL-4, mast cell degranulation, strain susceptibility, BALB/c mice
- MeSH terms
- Animals, Autoimmune Diseases, Coxsackievirus Infections, Liver, Male, Mast Cells, Myocarditis, Myocardium, Pancreas, Spleen, Time Factors, Cytokines, Enterovirus B, Human, Mice
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