Critical Cytokine Pathways to Cardiac Inflammation

Departments of Pathology and of Molecular Microbiology and Immunology, The Johns Hopkins Schools of Medicine and Public Health, Baltimore, Maryland 21205, USA.
Journal of interferon & cytokine research: the official journal of the International Society for Interferon and Cytokine Research (Impact Factor: 2). 08/2011; 31(10):705-10. DOI: 10.1089/jir.2011.0057
Source: PubMed


Infectious disease is frequently cited as a precursor of subsequent autoimmune disease in genetically susceptible hosts. However, the precise mechanisms required for the transition from infection to autoimmunity have not been well defined. We have developed a mouse model of autoimmune myocarditis initiated by infection with Coxsackievirus B3 to trace the cytokine pathways involved. We found that greater production of interleukin-1β (IL-1β) and tumor necrosis factor-α during the early innate response to virus infection is necessary and sufficient to induce a later heart-specific autoimmune disease. Severity of the autoimmune myocarditis is determined by the profile of a number of T helper 1 (Th1) and Th2 cytokines. Th2 responses are especially pronounced in the most severe forms of myocarditis where eosinophils are prominent. The Th1 pathway can lead to infiltration of the heart, but may be dampened by concurrent INF-γ production. Th17 cytokines also contribute to disease, but the signature Th17 cytokine, IL-17A, is not required for cardiac inflammation. Rather, IL-17A is needed for progression to dilated cardiomyopathy. These findings may provide useful markers to identify individuals prone to develop an autoimmune sequel after infection and suggest future early interventions.

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    ABSTRACT: Cytokines play a pivotal role in the pathogenesis of autoimmune diseases. The precise triggers for the breakdown of self-tolerance and the subsequent events leading to the induction of pathogenic autoimmune responses remain to be defined for most of the naturally occurring autoimmune diseases. Studies conducted in experimental models of human autoimmune diseases and observations in patients have revealed a general scheme in which proinflammatory cytokines contribute to the initiation and propagation of autoimmune inflammation, whereas anti-inflammatory cytokines facilitate the regression of inflammation and recovery from acute phase of the disease. This idea is embodied in the T helper (Th) 1/Th2 paradigm, which over the past two decades has had a major influence on our thinking about the role of cytokines in autoimmunity. Interestingly, over the past decade, the interleukin (IL)-17/IL-23 axis has rapidly emerged as the new paradigm that has compelled us to critically re-examine the cytokine-driven immune events in the pathogenesis and treatment of autoimmunity. In this 2-volume special issue of the journal, leading experts have presented their research findings and viewpoints on the role of cytokines in the context of specific autoimmune diseases.
    Full-text · Article · Sep 2011 · Journal of interferon & cytokine research: the official journal of the International Society for Interferon and Cytokine Research
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    ABSTRACT: To present recent findings on the pathogenesis of coxsackievirus B3 (CVB3) myocarditis based on animal models, with a focus on the role of T helper (Th) immune responses in disease progression. Acute CVB3 myocarditis is known to be increased by Th1 immune responses, but recent findings indicate that Th1-type immunity protects against acute myocarditis by reducing viral replication and prevents the progression to chronic myocarditis and dilated cardiomyopathy (DCM) by inhibiting Th2 responses. Th2 responses reduce acute myocarditis by inhibiting Th1 responses via regulatory T cells and anti-inflammatory cytokines, but can be deleterious when they induce acute cardiac remodeling leading to chronic myocarditis/DCM. Th2-skewed immune responses allow resistant strains of mice to progress from myocarditis to DCM. In contrast, Th17 responses are elevated during acute and chronic myocarditis and have been found to contribute to cardiac remodeling and DCM. Recent data indicate that elevated Th2 and Th17 responses during acute CVB3 myocarditis are critical for the progression from myocarditis to DCM and heart failure because of their ability to induce cardiac remodeling. Th1 responses protect against CVB3 myocarditis by inhibiting Th2 responses and viral replication, but increase acute inflammation.
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