Complement Receptor 1 and 2 Deficiency Increases Coxsackievirus B3-Induced Myocarditis, Dilated Cardiomyopathy, and Heart Failure by Increasing Macrophages, IL-1β, and Immune Complex Deposition in the Heart
Open accessAbstract
Complement and complement receptors (CR) play a central role in immune defense by initiating the rapid destruction of invading microorganisms, amplifying the innate and adaptive immune responses, and mediating solubilization and clearance of immune complexes. Defects in the expression of C or CR have been associated with loss of tolerance to self proteins and the development of immune complex-mediated autoimmune diseases such as systemic lupus erythematosus. In this study, we examined the role of CR on coxsackievirus B3 (CVB3)-induced myocarditis using mice deficient in CR1/2. We found that CR1/2 deficiency significantly increased acute CVB3 myocarditis and pericardial fibrosis resulting in early progression to dilated cardiomyopathy and heart failure. The increase in inflammation was not due to increased viral replication, which was not significantly altered in the hearts of CR1/2-deficient mice, but was associated with increased numbers of macrophages, IL-1β levels, and immune complex deposition in the heart. The complement regulatory protein, CR1-related gene/protein Y (Crry), was increased on cardiac macrophage populations, while immature B220low B cells were increased in the spleen of CR1/2-deficient mice during acute CVB3-induced myocarditis. These results show that expression of CR1/2 is not necessary for effective clearance of CVB3 infection, but prevents immune-mediated damage to the heart.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
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 [157]
The section “CR1/2 deficiency increases IL-1β levels in the heart” reports increased IL-1β but significantly decreased TNF-α in CR1/2-deficient hearts—the opposite of the attributed TNF-α finding. The fibrosis section reports pericardial, not perivascular, fibrosis. The mast-cell interpretation is explicitly the citing authors’ own experience, so it is not judged as a finding attributed to this source. (LLM, conf=0.89)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredMast 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 [157]
The Discussion (page unavailable in our copy) links increased macrophages and the profibrotic cytokine IL-1β to fibrosis and DCM in CVB3-infected mice. It also names mast cells as a source of inflammatory cytokines, but does not say they cooperate with macrophages to drive fibrosis, scarring, or remodeling. (LLM, conf=0.86)
Experimental — accuracy not yet measuredMice with EAM or autoimmune CVB3 myocarditis upregulate complement components during innate immune response and acute myocarditis including C3, CD11b, C3aR, and C5aR.
“Mice with experimental autoimmune myocarditis (EAM) or autoimmune CVB3 myocarditis also upregulate complement components during the innate immune response and acute myocarditis including C3, CD11b (also known as CR [complement receptor] 3), C3aR, and C5aR. 155-157”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [157]
The section on immune-complex deposition reports C3 deposition in hearts during acute CVB3 myocarditis, and the References list a study of C3 upregulation in autoimmune myocarditis. Neither passage establishes that mice upregulate CD11b, C3aR, or C5aR during the innate response or acute myocarditis. Page numbers are unavailable in our copy. (LLM, conf=0.83)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 62 · Cited by 82
Research works printed but not linked: 7
- Morgan, B. P., and C. L. Harris. 1999. The complement system: a brief overview. In Complement Regulatory Proteins, B. P. Morgan and C. L. Harris, eds. Aca- demic Press, San Diego, pp. 1-31.
- Holers, V. M. 2005. Complement receptors and the shaping of the natural anti- body repertoire. Springer Semin. Immunol. 26: 405-423.
- Morgan, B. P., and C. L. Harris. 1999. Complement regulatory proteins in other species. In Complement Regulatory Proteins, B. P. Morgan and C. L. Harris, eds. Academic Press, San Diego, pp. 226 -242.
- Dec, G. W. 2003. Introduction to clinical myocarditis. In Myocarditis: From Bench to Bedside. L. T. Cooper, Jr., ed. Humana Press, Totowa, pp. 157-281.
- Cotran, R. S. 1999. Tissue repair: cellular growth, fibrosis, and wound healing. In Robbins Pathologic Basis of Disease. R. S. Cotran, V. Kumar, and T. Collins, eds. Saunders, Philadelphia, pp. 89 -112.
- Molina, H., V. Holers, B. Li, Y. Fung, S. Marianthasan, J. Goellner, J. Strauss-Schoenberger, R. Karr, and D. Chaplin. 1996. Markedly impaired hu- moral immune response in mice deficient in complement receptors 1 and 2. Proc. Natl. Acad. Sci. USA 93: 3357-3361.
- Moder, G. K., T. D. Miller, and H. D. Tazelaar. 1999. Cardiac involvement in systemic lupus erythematosus. Mayo Clin. Proc. 74: 275-284.
- Authors
- Fairweather, D., Frisancho-Kiss, S., Njoku, D. B., Nyland, J. F., Kaya, Z., Yusung, S. A., Davis, S. E., Frisancho, J. A., Barrett, M. A., & Rose, N. R.
- Affiliations
- Johns Hopkins University (US)
- Department of Pathology,Johns Hopkins School of Medicine and Bloomberg School of Public Health , Baltimore, MD 21205
- Corresponding author
- Fairweather, DeLisa
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2006-03
- Volume
- 176
- Issue
- 6
- Pages
- 3516-3524
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W1488394168
- Cited by
- 82
- References
- 62
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 8 · 2023: 8 · 2022: 2 · 2021: 3 · 2020: 4 · 2019: 2 · 2018: 2 · 2017: 2 · 2016: 1 · 2015: 3 · 2014: 4 · 2012: 7
- FWCI
- 5.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- National Institutes of Health
- National Heart, Lung, and Blood Institute (HL 67290, R01HL067290, HL 70729, R01HL070729)
- National Institute of Allergy and Infectious Diseases (AI 51835, R21AI051835)
- National Institute of Environmental Health Sciences (ES03819, P30ES003819)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Viral Infections and Immunology Research
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Keywords
- complement receptor 1, CR2, coxsackievirus B3, viral myocarditis, dilated cardiomyopathy, heart failure, macrophages, IL-1β, immune complex deposition, Crry, pericardial fibrosis, B cells, complement regulation, autoimmunity
- MeSH terms
- Animals, B-Lymphocytes, Cells, Cultured, Enterovirus, Fibrosis, Heart, Interleukin-1, Macrophages, Male, Myocarditis, Receptors, Complement, Spleen, T-Lymphocytes, Tumor Necrosis Factor-alpha, Receptors, Complement 3b, Mice, Knockout, Cell Proliferation, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
