Development Of Autoimmune Myocarditis Research Articles

Complete atrioventricular block as the first manifestation of dermatomyositis

Dermatomyositis is a rare systemic autoimmune disease characterized by primary damage of the skin and striated muscles with the development of chronic muscle weakness. Due to the polymorphic nature of the clinical picture, early diagnosis of dermatomyositis is challenging since patients may visit different specialists depending on predominating symptoms. This entails a late diagnosis and, as a result, the absence of necessary treatment. The article presents a clinical case of a late diagnosis of dermatomyositis, which resulted in the development of autoimmune myocarditis with complete atrioventricular block in a female patient.

T follicular helper cells are elevated in a rat model of autoimmune myocarditis.

Myocarditis is an inflammatory disease of the myocardium that is associated with immune dysfunction. Earlier studies have suggested that T helper 1/2 cell imbalance plays an important role in the development of myocarditis, but the role of T follicular helper (Tfh) cells in the development of autoimmune myocarditis has not previously been reported. Here, we investigated this involvement by using a rat model of experimental autoimmune myocarditis (EAM). Inflammatory cell infiltration, myocardial structure destruction and tissue necrosis were observed in EAM myocardial tissues, and the percentages of CD4+CXCR5+ Tfh cells and CD19+ B cells were both significantly higher in spleen and myocardial tissues of the EAM model as compared with the control group. Furthermore, the expression levels of interleukin‐21, CXCL13 and myosin antibody were significantly higher in the serum of rats with EAM compared with the control group on days 14 and 35 after immunization. Fourteen or 35 days after immunization, the expression levels of interleukin‐21 and CXCL13 were both significantly higher in myocardial tissues of rats with EAM as compared with the control group. Our findings suggest that Tfh cell balance is disrupted during the pathological process of autoimmune myocarditis.

FN14 Signaling Plays a Pathogenic Role in a Mouse Model of Experimental Autoimmune Myocarditis

BackgroundThe pathogenesis of inflammatory cardiomyopathy is affected by the activation of autoimmune-mediated cascades. To study these cascades, we developed an experimental model of troponin I (TnI)-induced autoimmune myocarditis (EAM). One factor playing a pivotal role in the context of autoimmune disorders is the receptor fibroblast growth factor-inducible 14 (FN14). Thus, the impact of FN14 in the development of autoimmune myocarditis was investigated. Methods and ResultsTnI-immunization led to a significantly increased myocardial FN14 mRNA and protein expression in wild-type (wt) mice. To investigate the precise role of FN14 in EAM, FN14 knockout (ko) and wt littermates were immunized with TnI or control buffer. The animals were evaluated for cardiac parameters and indicators of myocardial injury. FN14 deficiency resulted in better cardiac performance, less myocardial inflammation, fibrosis, and cardiac damage. A lower myocardial mRNA expression of inflammatory cytokines and chemokines as well as their receptors could be demonstrated in TnI-immunized FN14ko compared to wt mice also immunized with TnI. Western blot analysis revealed a contribution of nuclear factor kappa-light-chain-enhancer of activated B cells to FN14-induced signaling cascades. ConclusionsIn the pathogenesis of autoimmune myocarditis, the inflammatory response to cardiac injury is attenuated in FN14ko mice. Thus, inhibition of FN14 in patients might represent a novel therapeutic strategy in the treatment of inflammatory cardiomyopathy.

Targeting androgen receptor with ASC-J9 attenuates cardiac injury and dysfunction in experimental autoimmune myocarditis by reducing M1-like macrophage

BackgroudMacrophages are important mediators in inflammatory cardiovascular diseases. Experimental autoimmune myocarditis (EAM) is characterized by pronounced macrophages infiltration, cardiac necrosis and cardiac fibrosis. Androgen receptor (AR) is a regulator of immune system which can control macrophages' infiltration and function in various inflammatory-related diseases. However, the effect of AR on the inflammatory response in EAM is unknown. Our study aims to investigate the potential role of AR on the development of autoimmune myocarditis. Methods and resultsIn our study, we found that AR was increased in the myocardium and was associated with the time-course of EAM progression, which motivated us to use ASC-J9 (an enhancer of AR degradation). The results revealed that ASC-J9 administration in EAM mice resulted in an attenuation in the severity of disease and cardiac injury, a reduced CD4+T cell response, reduced monocyte/macrophage infiltration, and decreases in the pro-inflammatory cytokines. Furthermore, ASC-J9 was also found to prevent Raw264.7 cells polarization to M1 macrophages in response to LPS by upregulating suppressor of cytokine signaling 1(SOCS1) and downregulating signal transducer and activator of the transcription 5(STAT5) activity. ConclusionsAR facilitated EAM development, and targeting AR with ASC-J9 attenuated cardiac injury and dysfunction by inhibiting macrophages polarization towards M1 macrophages.

Inhibition of microRNA-155 ameliorates experimental autoimmune myocarditis by modulating Th17/Treg immune response.

Experimental autoimmune myocarditis (EAM) is an inflammatory cardiac disease driven by autoantigen-specific CD4+ T cells. Th17 and Treg cells are crucial participants in immune response. A wide variety of immune disorders are associated with Th17/Treg imbalance. MicroRNA-155 (miR-155) is a pivotal regulator of the immune system. However, the modulatory effect of miR-155 on Th17/Treg immune response during EAM is unknown. Our study aims to investigate the potential role of miR-155 on the development of autoimmune myocarditis. In this study, we revealed that miR-155 expression was highly elevated in heart tissue and CD4+ T cells during EAM. Also, we identified a proliferative and functional imbalance of Th17/Treg in EAM, which is due to a more active development of Th17 cells and an increased resistance of Th17 cells to Treg-mediated suppression. MiR-155 inhibition in EAM resulted in attenuated severity of disease and cardiac injury, reduced Th17 immune response, and decreased dendritic cell (DC) function of secreting Th17-polarizing cytokines. Furthermore, CD4+ T cells from miR-155-inhibited EAM mice exhibited reduced proliferation and IL-17A secretion in response to autoantigen. Finally, we confirmed an indispensable positive role of miR-155 on the differentiation of Th17 cells and the DC function of secreting Th17-polarizing cytokines through in vitro studies. These findings demonstrated that miR-155 adversely promotes EAM by driving a Th17/Treg imbalance in favor of Th17 cells, and anti-miR-155 treatment can significantly reduce the autoimmune response thus to ameliorate EAM, suggesting that miR-155 inhibition could be a promising therapeutic strategy for the treatment of autoimmune myocarditis. MiR-155 expression was highly elevated in EAM mice. An imbalance of Th17/Treg existed in EAM mice. MiR-155 inhibition in EAM attenuated disease severity and cardiac injury. MiR-155 inhibition suppressed Th17 immune response in EAM. MiR-155 inhibition reduced DC function of secreting Th17-polarizing cytokines in EAM.

Improvement of Idiopathic Cardiomyopathy After Colon Clear.

BackgroundThe study aimed to illustrate the effect of colon clear on idiopathic myocardial dysfunction. Helicobacter pylori colonized the stomach since an immemorial time, as if both the stomach and the bacterium used to live together in peace harmless to each other. H. pylori could migrate or get forced to migrate to the colon; antibiotics are seldom effective against extra-gastric H. pylori strains. The association of H. pylori and some cardiovascular diseases like myocarditis and cardiomyopaty has been sufficiently mentioned in literature. The role played by the increased mucosal production of inflammatory mediators (cytokines) induced by H. pylori among patients with ischemic heart diseases has been also clearly illustrated. The clinical association of gastritis and carditis is controversial. Active lymphocytic myocarditis manifested by intractable ventricular tachycardia, non-specific intra-ventricular block, and myocardial dysfunction has been described in a young woman infected with H. pylori; an immune influence has been emphasized in that patient as a possible etiology behind the development of autoimmune myocarditis. It has been reported also in literature that a possible role of autoimmunity induced by H. pylori in cardiomyopathy cannot be excluded.MethodsThree female patients with frank history of H. pylori dyspepsia and an age range of 41 - 47 years have developed myocaditis complicated with cardiomyopathy as confirmed by echocardiography (ECG) and magnetic resonance imaging (MRI). Existence of H. pylori in the colon was confirmed by H. pylori fecal antigen. Colon clear was done for them.ResultsSymptomatic improvement and clinical recovery to sinus rhythm with minimal supra-ventricular extra-systoles occurred for all patients after colon clear. Patients continued improvement to normal cardiac tracing and normal left ventricular ejection function within further 3 - 4 weeks.ConclusionColon clear could be a simple and safe measure to improve changes in cardiac rhythm, heart rate and myocardial function developing in association with H. pylori due to inflammatory, toxic or immune reasons.

IL-17 contributes to cardiac fibrosis following experimental autoimmune myocarditis by a PKCβ/Erk1/2/NF-κB-dependent signaling pathway.

Myocarditis is a common clinical cardiovascular disease, and some patients progress to dilated cardiomyopathy (DCM) with chronic heart failure. Common viral infections are the most frequent cause of myocarditis, but other pathogens and autoimmune diseases have also been implicated. T(h)17 cells are novel IL-17-producing effector T helper cells that play an important role in the development of autoimmune myocarditis. Furthermore, IL-17 is also important in post-myocarditis cardiac remodeling and progression to DCM. However, the mechanisms whereby IL-17 and IL-17-producing cells promote the progression of cardiac fibrosis remain unclear. We therefore investigated whether IL-17 directly induced cardiac fibrosis in experimental autoimmune myocarditis (EAM) and explored the possible molecular mechanisms. The EAM model was induced and serum IL-17 level was detected by ELISA; western blot, immunofluorescence and sirius red staining were used to analyze the collagen expression. PCR was used to assay the IL-17RA and IL-17RC. The results indicated that IL-17 induced cardiac fibrosis both in vitro and in vivo. The protein kinase C (PKC)β/Erk1/2/NF-κB (Nuclear Factor κappa B) pathway was involved in the development of myocardial fibrosis and IL-17 contributed to cardiac fibrosis following EAM via this pathway. These results provide the first direct evidence for the involvement of the PKCβ/Erk1/2/NF-κB signaling pathway in IL-17-induced myocardial fibrosis.

Dynamics of development of autoimmune myocarditis in rats

The development of autoimmune myocarditis in rats after a single subcutaneous injection of rat myosin mixed with a complete Freund's adjuvant (CFA) (400 µg/kg in 200 µl) was studied. The rats from the control group were injected with only CFA. The titer of antibodies to myosin, infiltration of lymphocytes into the myocardium, ultrastructural damage of myofibrils, mitochondria, and nuclei of cardiomyocytes were maximally pronounced on days 14-21 after the immunization with myosin, which indicates a peak of the inflammatory reaction. The content of nitrites and nitrates in the blood serum and myocardium of immu� nized rats were also studied. A certain contribution to the development of the inflammation is made by CFA: in rats injected with only CFA, morphological signs of myocarditis were found, but to a much lesser degree than in the group immunized with myosin.

Constitutively active Stat3 triggers the development of autoimmune myocarditis

Constitutively active Stat3 triggers the development of autoimmune myocarditis

Immunoglobulin treatment suppressed adoptively transferred autoimmune myocarditis in severe combined immunodeficient mice

We investigated the suppressive effects of immunoglobulin (Ig) on effector T cells in autoimmune myocarditis. Treatment with Ig reduced production of the so-called T-helper type 1 (Th1) cytokines stimulated by concanavalin A or cardiac myosin in cultured lymph node (LN) cells from rats with myocarditis. The cytotoxic activities of LN cells from rats immunized with myosin and treated with Ig were reduced against cardiomyocytes and F-2 cells compared with those treated without Ig. The adoptive transfer of myocarditis from LN cells of Lewis rats with myocarditis to severe combined immunodeficient (SCID) recipients was successfully achieved. Treatment with Ig, but not with F(ab')2 fragments of Ig, reduced the mortality and severity of myocarditis in SCID recipient mice. Decreased ability of LN cells of Ig-treated rats, but not rats treated with F(ab')2 fragments, to transfer autoimmune myocarditis was also demonstrated. The findings of the present study suggest that autoimmune myocarditis was successfully transferred to SCID mice and that treatment with Ig ameliorated autoimmune myocarditis by inducing selective myosin unresponsiveness via the Fc portion, resulting in suppression of Th1 cytokine production and cytotoxic activities of LN cells, which operated together in the development of autoimmune myocarditis.

Activation of dendritic cells through the interleukin 1 receptor 1 is critical for the induction of autoimmune myocarditis.

Dilated cardiomyopathy, resulting from myocarditis, is the most common cause of heart failure in young patients. We here show that interleukin (IL)-1 receptor type 1–deficient (IL-1R1−/−) mice are protected from development of autoimmune myocarditis after immunization with α-myosin-peptide(614–629). CD4+ T cells from immunized IL-1R1−/− mice proliferated poorly and failed to transfer disease after injection into naive severe combined immunodeficiency (SCID) mice. In vitro stimulation experiments suggested that the function of IL-1R1−/−CD4+ T cells was not intrinsically defect, but their activation by dendritic cells was impaired in IL-1R1−/− mice. Accordingly, production of tumor necrosis factor (TNF)-α, IL-1, IL-6, and IL-12p70 was reduced in dendritic cells lacking the IL-1 receptor type 1. In fact, injection of immature, antigen-loaded IL-1R1+/+ but not IL-1R1−/− dendritic cells into IL-1R1−/− mice fully restored disease susceptibility by rendering IL-1R1−/− CD4+ T cells pathogenic. Thus, IL-1R1 triggering is required for efficient activation of dendritic cells, which is in turn a prerequisite for induction of autoreactive CD4+ T cells and autoimmunity.

Dual role of the IL-12/IFN-gamma axis in the development of autoimmune myocarditis: induction by IL-12 and protection by IFN-gamma.

IL-12 and IFN-gamma positively regulate each other and type 1 inflammatory responses, which are believed to cause tissue damage in autoimmune diseases. We investigated the role of the IL-12/IFN-gamma (Th1) axis in the development of autoimmune myocarditis. IL-12p40-deficient mice on a susceptible background resisted myocarditis. In the absence of IL-12, autospecific CD4(+) T cells proliferated poorly and showed increased Th2 cytokine responses. However, IFN-gamma-deficient mice developed fatal autoimmune disease, and blockade of IL-4R signaling did not confer susceptibility to myocarditis in IL-12p40-deficient mice, demonstrating that IL-12 triggers autoimmunity by a mechanism independent of the effector cytokines IFN-gamma and IL-4. In conclusion, our results suggest that the IL-12/IFN-gamma axis is a double-edged sword for the development of autoimmune myocarditis. Although IL-12 mediates disease by induction/expansion of Th1-type cells, IFN-gamma production from these cells limits disease progression.

An age‐related γδ T cell suppressor activity correlates with the outcome of autoimmunity in experimental Trypanosoma cruzi infection

In this work the suppressive activity of splenic T cells from young and aged BALB/c mice infected with Trypanosoma cruzi were compared and correlated with the development of autoimmune myocarditis. The T cells from young adult BALB/c mice with acute T. cruzi infection exhibit suppressor activity when added to full allogeneic or Mls-disparate mixed lymphocyte cultures. This suppression could not be reverted by exogenous interleukin (IL)-2 and was not directly dependent on the presence of IL-4, IL-10 or transforming growth factor-beta. Further characterization of the T cell lineage responsible for the suppressor activity by in vitro and/or in vivo depletion with monoclonal antibody to alpha beta or gamma delta T cell receptor revealed that splenic gamma delta T cells function as suppressor lymphocytes in young T. cruzi-infected mice. In addition, these young adult BALB/c mice do not develop autoimmune myocarditis and showed a low incidence of syngeneic heart graft rejection in the early chronic phase of the infection. In contrast, T cells from acutely infected aged BALB/c mice lacked demonstrable T suppressor activity. Furthermore, these mice developed a severe autoimmune myocarditis as early as 2 months after the onset of the infection, when the majority of them reject syngeneic heart grafts. These findings suggest that a gamma delta T cell-mediated suppressor mechanism may operate in the avoidance of the breaking of tissue-specific tolerance during the acute infection. Moreover, such a mechanism is likely related to the immune system chronobiology.

Role of IL-1 and tumor necrosis factor in coxsackie virus-induced autoimmune myocarditis.

We have previously reported that B10.A (H-2a) mice, which are resistant to the induction of postcoxsackievirus autoimmune myocarditis, become susceptible upon treatment with LPS, IL-1, or TNF. In this study, we show that the development of autoimmune myocarditis is associated with infiltration of the heart by inflammatory cells that secrete the cytokines IL-1 and TNF. Local secretion of these cytokines contributes to increased levels of IL-1 and TNF in the serum. Thus, local production of cytokines promotes the induction of this postinfectious autoimmune disease.