Mast Cells and Innate Cytokines are Associated with Susceptibility to Autoimmune Heart Disease Following Coxsackievirus B3 Infection

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122

126

Autoimmune diseases can be reduced or even prevented if proinflammatory immune responses are appropriately down-regulated. Receptors (such as CTLA-4), cytokines (such as TGF-β), and specialized cells (such as CD4+CD25+ T regulatory cells) work together to keep immune responses in check. T cell Ig mucin (Tim) family proteins are key regulators of inflammation, providing an inhibitory signal that dampens proinflammatory responses and thereby reducing autoimmune and allergic responses. We show in this study that reducing Tim-3 signaling during the innate immune response to viral infection in BALB/c mice reduces CD80 costimulatory molecule expression on mast cells and macrophages and reduces innate CTLA-4 levels in CD4+ T cells, resulting in decreased T regulatory cell populations and increased inflammatory heart disease. These results indicate that regulation of inflammation in the heart begins during innate immunity and that Tim-3 signaling on cells of the innate immune system critically influences regulation of the adaptive immune response.

Section: Resultssupporting

confidence: 55%

Cutting Edge: T Cell Ig Mucin-3 Reduces Inflammatory Heart Disease by Increasing CTLA-4 during Innate Immunity

Frisancho-Kiss

Nyland

Davis

et al. 2006

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126

“…We also found that increased TNF-␣ levels in the heart during the innate response to viral infection are associated with the development of chronic myocarditis (4,(35)(36)(37). In contrast, TNF-␣ has been found to play a critical role in the control of certain viral infections such as murine cytomegalovirus (38, 39), but not for other viruses such as LCMV (40).…”

Section: Tnfrp55 Deficiency Does Not Increase Viral Replication or Mymentioning

confidence: 64%

“…that is associated with the development of DCM (3). Susceptible BALB/c mice respond to CVB3 infection with elevated levels of TNF-␣, IL-1␤, and IL-12p70 in the heart during the innate response (4). We have shown that increased IL-1␤ and IL-18 levels in the heart correlate with increased acute CVB3 myocarditis, and are mediated by TLR4 and IL-12R␤1 signaling (5).…”

Section: Il-12 Protects Against Coxsackievirus B3-induced Myocarditismentioning

confidence: 85%

“…But rather, elevated levels of the proinflammatory cytokines TNF-␣ and IL-1␤ are associated with susceptibility to disease (4,5,31), and can induce disease in resistant strains of mice (35,36). Because treatments to reduce Th1 responses in patients with autoimmune diseases are being considered (52), it is important to clarify the role of IL-12 and IFN-␥ in viral myocarditis.…”

Section: Discussionmentioning

confidence: 99%

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IL-12 Protects against Coxsackievirus B3-Induced Myocarditis by Increasing IFN-γ and Macrophage and Neutrophil Populations in the Heart

Fairweather¹,

Frisancho-Kiss²,

Yusung³

et al. 2005

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128

122

Th1-type immune responses, mediated by IL-12-induced IFN-γ, are believed to exacerbate certain autoimmune diseases. We recently found that signaling via IL-12Rβ1 increases coxsackievirus B3 (CVB3)-induced myocarditis. In this study, we examined the role of IL-12 on the development of CVB3-induced myocarditis using mice deficient in IL-12p35 that lack IL-12p70. We found that IL-12 deficiency did not prevent myocarditis, but viral replication was significantly increased. Although there were no changes in the total percentage of inflammatory cells in IL-12-deficient hearts compared with wild-type BALB/c controls by FACS analysis, macrophage and neutrophil populations were decreased. This decrease corresponded to reduced TNF-α and IFN-γ levels in the heart, suggesting that macrophage and/or neutrophil populations may be a primary source of TNF-α and IFN-γ during acute CVB3 myocarditis. Increased viral replication in IL-12-deficient mice was not mediated by reduced TNFRp55 signaling, because viral replication was unaltered in TNFRp55-deficient mice. However, STAT4 or IFN-γ deficiency resulted in significantly increased viral replication and significantly reduced TNF-α and IFN-γ levels in the heart, similar to IL-12 deficiency, indicating that the IL-12/STAT4 pathway of IFN-γ production is important in limiting CVB3 replication. Furthermore, STAT4 or IFN-γ deficiency also increased chronic CVB3 myocarditis, indicating that therapeutic strategies aimed at reducing Th1-mediated autoimmune diseases may exacerbate common viral infections such as CVB3 and increase chronic inflammatory heart disease.

“…Other cells or cellular products including NK cells (2), mast cells (31), and complement (2) also influence disease susceptibility. Interestingly, a subset of TCR␣␤ ϩ CD4 Ϫ CD8 Ϫ double negative cells were found in lesions of autoimmune myocarditis (30), arthritis (32), and encephalomyelitis (33) developed in CD4-deficient mice, suggesting these cells may be capable of obviating the requirement for CD4 ϩ T cells and subserve the effector function.…”

Section: Discussionmentioning

confidence: 99%

Genetic Differences in Bone Marrow-Derived Lymphoid Lineages Control Susceptibility to Experimental Autoimmune Myocarditis

Li¹,

Ligons

Rose

et al. 2008

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Bone marrow (BM) transplantation has been used to study the cellular basis of genetic control of autoimmune diseases, but conclusions remain elusive due to the contradictory findings in different animal models. In the current study, we found that BM cells from myocarditis-susceptible A.SW mice can render irradiated, myocarditis-resistant B10.S recipient mice susceptible to myosin-induced myocarditis, indicating that hematopoietic cells express the genetic differences controlling susceptibility to autoimmune myocarditis. We then sought to differentiate the role of lymphoid vs nonlymphoid components of BM in the pathogenesis of myocarditis by comparing mixed chimeras receiving BM from A.SW wild-type or RAG−/− mice mixed with BM from B10.S wild-type mice. This experiment clearly demonstrated that T and B lymphocytes were indispensable for transferring the susceptible phenotype to disease-resistant recipients. Our findings significantly narrow the cellular expression of genetic polymorphisms controlling the EAM phenotype.