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1.
Nat Rev Dis Primers ; 5(1): 32, 2019 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-31073128

RESUMO

Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left ventricular or biventricular dilation and impaired contraction that is not explained by abnormal loading conditions (for example, hypertension and valvular heart disease) or coronary artery disease. Mutations in several genes can cause DCM, including genes encoding structural components of the sarcomere and desmosome. Nongenetic forms of DCM can result from different aetiologies, including inflammation of the myocardium due to an infection (mostly viral); exposure to drugs, toxins or allergens; and systemic endocrine or autoimmune diseases. The heterogeneous aetiology and clinical presentation of DCM make a correct and timely diagnosis challenging. Echocardiography and other imaging techniques are required to assess ventricular dysfunction and adverse myocardial remodelling, and immunological and histological analyses of an endomyocardial biopsy sample are indicated when inflammation or infection is suspected. As DCM eventually leads to impaired contractility, standard approaches to prevent or treat heart failure are the first-line treatment for patients with DCM. Cardiac resynchronization therapy and implantable cardioverter-defibrillators may be required to prevent life-threatening arrhythmias. In addition, identifying the probable cause of DCM helps tailor specific therapies to improve prognosis. An improved aetiology-driven personalized approach to clinical care will benefit patients with DCM, as will new diagnostic tools, such as serum biomarkers, that enable early diagnosis and treatment.

2.
Hepatology ; 2019 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-30924946

RESUMO

In spite of tremendous research advancements in nonalcoholic fatty liver disease (NAFLD), our understanding of sex-differences in NAFLD remains insufficient. This review summarizes current knowledge on sex differences in NAFLD, identifies current gaps, and discusses important considerations for future research. The prevalence and severity of NAFLD are higher in men than in women during the reproductive age. However, after menopause, NAFLD occurs at a higher rate in women suggesting that estrogen is protective. Sex differences also exist for the major risk factors of NAFLD. In general, animal models of NAFLD recapitulate sex differences observed in patients with more severe steatosis and steatohepatitis, more pro-inflammatory/pro-fibrotic cytokines, and a higher incidence of hepatic tumors in males than females. Based on computer modeling, female and male livers are metabolically distinct with unique regulators modulating sex-specific metabolic outcomes. Analysis of the literature reveals that most published clinical and epidemiological studies fail to examine sex differences appropriately. Considering the paucity of data on sex differences and the knowledge that regulators of pathways relevant to current therapeutic targets for NAFLD differ by sex, clinical trials should be designed to test drug efficacy and safety according to sex, age, reproductive stage (i.e., menopause) and synthetic hormone use. CONCLUSION: Sex differences do exist in the prevalence, risk factors, fibrosis, and clinical outcomes of NAFLD suggesting that, while not yet incorporated, sex will probably be considered in future practice guidelines. Adequate consideration of sex differences, sex hormones/menopause status, age, and other reproductive information in clinical investigation and gene association studies of NAFLD are needed to fill current gaps and implement precision medicine for patients with NAFLD. This article is protected by copyright. All rights reserved.

3.
J Am Heart Assoc ; 8(2): e008968, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30638108

RESUMO

Background Myocarditis is an important cause of acute and chronic heart failure. Men with myocarditis have worse recovery and an increased need for transplantation compared with women, but the reason for the sex difference remains unclear. Elevated sera soluble (s) ST2 predicts mortality from acute and chronic heart failure, but has not been studied in myocarditis patients. Methods and Results Adults with a diagnosis of clinically suspected myocarditis (n=303, 78% male) were identified according to the 2013 European Society of Cardiology position statement. Sera sST2 levels were examined by ELISA in humans and mice and correlated with heart function according to sex and age. Sera sST2 levels were higher in healthy men ( P=8×10-6) and men with myocarditis ( P=0.004) compared with women. sST2 levels were elevated in patients with myocarditis and New York Heart Association class III - IV heart failure ( P=0.002), predominantly in men ( P=0.0003). Sera sST2 levels were associated with New York Heart Association class in men with myocarditis who were ≤50 years old ( r=0.231, P=0.0006), but not in women ( r=0.172, P=0.57). Sera sST2 levels were also significantly higher in male mice with myocarditis ( P=0.005) where levels were associated with cardiac inflammation. Gonadectomy with hormone replacement showed that testosterone ( P<0.001), but not estradiol ( P=0.32), increased sera sST2 levels in male mice with myocarditis. Conclusions We show in a well-characterized subset of heart failure patients with clinically suspected and biopsy-confirmed myocarditis that elevated sera sST2 is associated with an increased risk of heart failure based on New York Heart Association class in men ≤50 years old.

4.
J Exp Med ; 216(2): 369-383, 2019 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-30670465

RESUMO

Acquisition of self-reactive effector CD4+ T cells is a major component of the autoimmune response that can occur during myocarditis, an inflammatory form of cardiomyopathy. Although the processes by which self-reactive T cells gain effector function have received considerable attention, how these T cells contribute to effector organ inflammation and damage is less clear. Here, we identified an IL-3-dependent amplification loop that exacerbates autoimmune inflammation. In experimental myocarditis, we show that effector organ-accumulating autoreactive IL-3+ CD4+ T cells stimulate IL-3R+ tissue macrophages to produce monocyte-attracting chemokines. The newly recruited monocytes differentiate into antigen-presenting cells that stimulate local IL-3+ CD4+ T cell proliferation, thereby amplifying organ inflammation. Consequently, Il3 -/- mice resist developing robust autoimmune inflammation and myocardial dysfunction, whereas therapeutic IL-3 targeting ameliorates disease. This study defines a mechanism that orchestrates inflammation in myocarditis, describes a previously unknown function for IL-3, and identifies IL-3 as a potential therapeutic target in patients with myocarditis.

5.
Artigo em Inglês | MEDLINE | ID: mdl-29934885

RESUMO

Early detection of mild pulmonary arterial hypertension (PAH) based on clinical evaluation and echocardiography remains quite challenging. In addition to enhanced right ventricular (RV) assessment, cardiac magnetic resonance (CMR) imaging may accurately reflect deleterious remodeling and increased stiffness of the central pulmonary arteries based on pulsatility, or percent change of the PA during the cardiac cycle. The purpose of this study is to assess the utility of measuring PA pulsatility by CMR as a potential early maker in PAH. We hypothesize that pulsatility may help discriminate mild PAH from normal control subjects. Consecutive patients with PAH (n = 51) were prospectively enrolled to receive same day CMR and right heart catheterization (RHC). PA stiffness indices including pulsatility, distensibility, compliance, and capacitance were calculated. Comparisons were made between patients with varying severities of PAH and normal controls (n = 18). Of the 51 subjects, 20 had mild PAH, and 31 moderate-severe based on hemodynamic criteria. PA pulsatility demonstrated a progressive decline from normal controls (53%), mild PAH (22%), to moderate-severe PAH (17%; p < 0.001). There was no difference in RV size, function or mass between mild PAH and normal controls. PA pulsatility below 40% had an excellent ability to discriminate between mild PAH and normal controls with a sensitivity of 95% and specificity of 94%. CMR assessment of PA stiffness may noninvasively detect adverse pulmonary vascular remodeling and mild PAH, and thus be a valuable tool for early detection of PAH. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01451255; https://clinicaltrials.gov/ct2/show/NCT01451255 .

6.
Biol Sex Differ ; 9(1): 15, 2018 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-29669571

RESUMO

Registry data worldwide indicate an overall female predominance for pulmonary arterial hypertension (PAH) of 2-4 over men. Genetic predisposition accounts for only 1-5% of PAH cases, while autoimmune diseases and infections are closely linked to PAH. Idiopathic PAH may include patients with undiagnosed autoimmune diseases based on the relatively high presence of autoantibodies in this group. The two largest PAH registries to date report a sex ratio for autoimmune connective tissue disease-associated PAH of 9:1 female to male, highlighting the need for future studies to analyze subgroup data according to sex. Autoimmune diseases that have been associated with PAH include female-dominant systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, and thyroiditis as well as male-dominant autoimmune diseases like myocarditis which has been linked to HIV-associated PAH. The sex-specific association of PAH to certain infections and autoimmune diseases suggests that sex hormones and inflammation may play an important role in driving the pathogenesis of disease. However, there is a paucity of data on sex differences in inflammation in PAH, and more research is needed to better understand the pathogenesis underlying PAH in men and women. This review uses data on sex differences in PAH and PAH-associated autoimmune diseases from registries to provide insight into the pathogenesis of disease.

8.
Pharmacogenet Genomics ; 27(10): 378-385, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28763429

RESUMO

OBJECTIVES: The major clinical side effect of the ERBB2-targeted breast cancer therapy, trastuzumab, is a decline in the left ventricular ejection fraction (LVEF). Improved markers are needed to better identify patients susceptible to cardiotoxicity. METHODS: The NCCTG N9831 trial compared adjuvant doxorubicin and cyclophosphamide followed by either weekly paclitaxel (arm A); paclitaxel then trastuzumab (arm B); or concurrent paclitaxel and trastuzumab (arm C) in patients with HER2-positive breast cancer. A genome-wide association study was performed on all patients with available DNA (N=1446). We used linear regression to identify single nucleotide polymorphisms (SNPs) associated with decline in LVEF, adjusting for age, baseline LVEF, antihypertensive medications, and the first two principle components. RESULTS: In total, 618 863 SNPs passed quality control and DNA from 1191 patients passed genotyping quality control and were identified as Whites of non-Hispanic origin. SNPs at six loci were associated with a decline in LVEF (P=7.73×10 to 8.93×10), LDB2, BRINP1, chr6 intergenic, RAB22A, TRPC6, and LINC01060, in patients who received chemotherapy plus trastuzumab (arms BC, N=800). None of these loci were significant in patients who received chemotherapy only (arm A, N=391) and did not increase in significance in the combined analysis of all patients. We did not observe association, P<0.05, with SNPs previously associated with trastuzumab-induced cardiotoxicity at ERBB2, I655V, and P1170A. We replicated association, P<0.05, with SNPs previously associated with anthracycline-induced cardiotoxicity at CBR3 and ABCB1. CONCLUSION: Our study identified six putative novel cardiotoxicity loci in patients treated with combination chemotherapy and trastuzumab that require further investigation and confirmed known associations of anthracycline-induced cardiotoxicity.


Assuntos
Antineoplásicos Imunológicos/toxicidade , Neoplasias da Mama/tratamento farmacológico , Estudo de Associação Genômica Ampla , Coração/efeitos dos fármacos , Trastuzumab/toxicidade , Neoplasias da Mama/patologia , Feminino , Humanos , Receptor ErbB-2/antagonistas & inibidores
9.
JCI Insight ; 1(9)2016 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-27366791

RESUMO

In human myocarditis and its sequela dilated cardiomyopathy (DCM), the mechanisms and immune phenotype governing disease and subsequent heart failure are not known. Here, we identified a Th17 cell immunophenotype of human myocarditis/DCM with elevated CD4+IL17+ T cells and Th17-promoting cytokines IL-6, TGF-ß, and IL-23 as well as GM-CSF-secreting CD4+ T cells. The Th17 phenotype was linked with the effects of cardiac myosin on CD14+ monocytes, TLR2, and heart failure. Persistent heart failure was associated with high percentages of IL-17-producing T cells and IL-17-promoting cytokines, and the myocarditis/DCM phenotype included significantly low percentages of FOXP3+ Tregs, which may contribute to disease severity. We demonstrate a potentially novel mechanism in human myocarditis/DCM in which TLR2 peptide ligands from human cardiac myosin stimulated exaggerated Th17-related cytokines including TGF-ß, IL-6, and IL-23 from myocarditic CD14+ monocytes in vitro, and an anti-TLR2 antibody abrogated the cytokine response. Our translational study explains how an immune phenotype may be initiated by cardiac myosin TLR ligand stimulation of monocytes to generate Th17-promoting cytokines and development of pathogenic Th17 cells in human myocarditis and heart failure, and provides a rationale for targeting IL-17A as a therapeutic option.

10.
Biol Sex Differ ; 6: 19, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26535108

RESUMO

Autoimmune diseases (ADs) are estimated to affect between 5 and 8 % of the US population, and approximately 80 % of these patients are women. Sjögren's syndrome (SS) is an AD that occurs predominately in women over men (16:1). The hallmark characteristic of SS is diminished secretory production from the primary exocrine gland and the lacrimal or salivary glands resulting in symptoms of dry eye and mouth. The disease is believed to be mediated by an inflammatory and autoantibody response directed against salivary and lacrimal gland tissues. This review will examine the literature on sex differences in the immune response of patients and animal models of Sjögren's syndrome in order to gain a better understanding of disease pathogenesis.

11.
Environ Res ; 142: 273-80, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26186135

RESUMO

BACKGROUND: Arsenic has immunomodulatory properties and may have the potential to alter susceptibility to infection in humans. OBJECTIVES: We aimed to assess the relation of arsenic exposure during pregnancy with immune function and hepatitis E virus (HEV) infection, defined as seroconversion during pregnancy and postpartum. METHODS: We assessed IgG seroconversion to HEV between 1st and 3rd trimester (TM) and 3 months postpartum (PP) among 1100 pregnancies in a multiple micronutrient supplementation trial in rural Bangladesh. Forty women seroconverted to HEV and were matched with 40 non-seroconverting women (controls) by age, parity and intervention. We assessed urinary inorganic arsenic plus methylated species (∑As) (µg/L) at 1st and 3rd TM and plasma cytokines (pg/mL) at 1st and 3rd TM and 3 months PP. RESULTS: HEV seroconverters' urinary ∑As was elevated throughout pregnancy. Non-seroconverters' urinary ∑As was similar to HEV seroconverters at 1st TM but declined at 3rd TM. The adjusted odds ratio (95% confidence interval) of HEV seroconversion was 2.17 (1.07, 4.39) per interquartile range (IQR) increase in average-pregnancy urinary ∑As. Increased urinary ∑As was associated with increased concentrations of IL-2 during the 1st and 3rd TM and 3 months PP among HEV seroconverters but not non-seroconverters. CONCLUSIONS: The relation of urinary arsenic during pregnancy with incident HEV seroconversion and with IL-2 levels among HEV-seroconverting pregnant women suggests arsenic exposure during pregnancy may enhance susceptibility to HEV infection.


Assuntos
Arsênico/urina , Poluentes Ambientais/urina , Hepatite E/epidemiologia , Adolescente , Adulto , Anticorpos Antivirais/sangue , Bangladesh/epidemiologia , Estudos de Casos e Controles , Citocinas/sangue , Suscetibilidade a Doenças , Exposição Ambiental/análise , Feminino , Hepatite E/sangue , Hepatite E/imunologia , Hepatite E/urina , Vírus da Hepatite E/imunologia , Humanos , Imunoglobulina G/sangue , Gravidez/sangue , Gravidez/urina , Primeiro Trimestre da Gravidez/sangue , Primeiro Trimestre da Gravidez/urina , Terceiro Trimestre da Gravidez/sangue , Terceiro Trimestre da Gravidez/urina , Soroconversão , Adulto Jovem
12.
Inflamm Res ; 64(1): 31-40, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25376339

RESUMO

OBJECTIVE: Mercury is a ubiquitous environmental contaminant with toxic outcomes over a range of exposures. In this study, we investigated the effects of mercury exposure on early immune responses to coxsackievirus B3 (CVB3) infection in a murine model of autoimmune heart disease. MATERIALS AND METHODS: Female BALB/c mice, susceptible to CVB3-induced autoimmune myocarditis, were treated with mercuric chloride (200 µg/kg body weight every other day for 2 weeks) prior to infection with CVB3. Six hours post-infection, immune cells were isolated from the spleen and peritoneum for flow cytometry, gene expression, and cytokine profiling. Thirty-five days post-infection, hearts were collected for histological examination of immune cell infiltration. RESULTS: As for male mice, mercury exposure significantly increased autoimmune myocarditis and immune infiltration into the heart. During the innate response 6 h post-infection, mercury increased expression of co-stimulatory molecules and innate immune receptors on peritoneal macrophages. At the same time point, the alternatively activated macrophage gene, arginase, was increased while the classically activated macrophage gene, inducible nitric oxide synthase, was unaffected. Expression of activation markers were decreased on peritoneal B cells with mercury exposure while T cells were unaffected. Mercury increased production of pro-inflammatory mediators in the spleen. Macrophage-recruiting chemokines and activating cytokines, such as CCL2, CCL4, and IL-6, were increased with mercury following CVB3 infection. CONCLUSIONS: Thus, mercury treatment exacerbates autoimmune myocarditis in female mice and alters early innate signaling on peritoneal macrophages. Mercury also modulates the cytokine profile in the spleen toward a macrophage-activating milieu, and upregulates alternatively activated macrophage genes, providing evidence that mercury exposure promotes inflammation in the context of infection.


Assuntos
Doenças Autoimunes/etiologia , Infecções por Coxsackievirus/complicações , Infecções por Coxsackievirus/imunologia , Imunidade Inata/efeitos dos fármacos , Cloreto de Mercúrio/farmacologia , Miocardite/etiologia , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/patologia , Quimiocinas/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Relação Dose-Resposta a Droga , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Miocardite/imunologia , Miocardite/patologia , Baço/efeitos dos fármacos , Baço/metabolismo , Baço/patologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/patologia
13.
J Theor Biol ; 375: 101-123, 2015 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-25484004

RESUMO

Many theories of autoimmune disease have been proposed since the discovery that the immune system can attack the body. These theories include the hidden or cryptic antigen theory, modified antigen theory, T cell bypass, T cell-B cell mismatch, epitope spread or drift, the bystander effect, molecular mimicry, anti-idiotype theory, antigenic complementarity, and dual-affinity T cell receptors. We critically review these theories and relevant mathematical models as they apply to autoimmune myocarditis. All theories share the common assumption that autoimmune diseases are triggered by environmental factors such as infections or chemical exposure. Most, but not all, theories and mathematical models are unifactorial assuming single-agent causation of disease. Experimental and clinical evidence and mathematical models exist to support some aspects of most theories, but evidence/models that support one theory almost invariably supports other theories as well. More importantly, every theory (and every model) lacks the ability to account for some key autoimmune disease phenomena such as the fundamental roles of innate immunity, sex differences in disease susceptibility, the necessity for adjuvants in experimental animal models, and the often paradoxical effect of exposure timing and dose on disease induction. We argue that a more comprehensive and integrated theory of autoimmunity associated with new mathematical models is needed and suggest specific experimental and clinical tests for each major theory that might help to clarify how they relate to clinical disease and reveal how theories are related.


Assuntos
Doenças Autoimunes/imunologia , Miocardite/imunologia , Imunidade Adaptativa , Sequência de Aminoácidos , Animais , Antígenos/química , Modelos Animais de Doenças , Enterovirus , Epitopos/química , Feminino , Humanos , Imunidade Inata , Masculino , Camundongos , Modelos Biológicos , Dados de Sequência Molecular , Miocardite/microbiologia , Miocardite/virologia , Miosinas/química , Ratos , Homologia de Sequência de Aminoácidos , Fatores Sexuais
16.
J Cardiovasc Transl Res ; 7(2): 192-202, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24402571

RESUMO

Myocarditis is more severe in men than in women and difficult to diagnose due to a lack of imaging modalities that directly detect myocardial inflammation. Translocator protein 18 kDa (TSPO) is used extensively to image brain inflammation due to its presence in CD11b(+) brain microglia. In this study, we examined expression of TSPO and CD11b in mice with coxsackievirus B3 (CVB3) myocarditis and biopsy sections from myocarditis patients in order to determine if it could be used to image myocarditis. We found that male mice with CVB3 myocarditis upregulated more genes associated with TSPO activation than female mice. TSPO expression was increased in the heart of male mice and men with myocarditis compared with female subjects due to testosterone, where it was expressed predominantly in CD11b(+) immune cells. We show that TSPO ligands detect myocardial inflammation using microSPECT, with increased uptake of [(125)I]-IodoDPA-713 in male mice with CVB3 myocarditis compared with undiseased controls.


Assuntos
Enterovirus Humano B/patogenicidade , Infecções por Enterovirus/diagnóstico por imagem , Imagem Molecular/métodos , Miocardite/diagnóstico por imagem , Miocárdio/metabolismo , Receptores de GABA/metabolismo , Tomografia Computadorizada de Emissão de Fóton Único , Acetamidas , Animais , Biomarcadores/metabolismo , Biópsia , Antígeno CD11b/metabolismo , Modelos Animais de Doenças , Infecções por Enterovirus/genética , Infecções por Enterovirus/metabolismo , Infecções por Enterovirus/patologia , Feminino , Regulação da Expressão Gênica , Terapia de Reposição Hormonal , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Imagem Multimodal , Miocardite/genética , Miocardite/metabolismo , Miocardite/patologia , Miocárdio/patologia , Orquiectomia , Valor Preditivo dos Testes , Pirimidinas , Receptores de GABA/genética , Índice de Gravidade de Doença , Fatores Sexuais , Testosterona/administração & dosagem , Testosterona/metabolismo , Tomografia Computadorizada por Raios X
18.
Curr Allergy Asthma Rep ; 14(1): 407, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24352912

RESUMO

The possible role of infections in driving autoimmune disease (AD) has long been debated. Many theories have emerged including release of hidden antigens, epitope spread, anti-idiotypes, molecular mimicry, the adjuvant effect, antigenic complementarity, or simply that AD could be a direct consequence of activation or subversion of the immune response by microbes. A number of issues are not adequately addressed by current theories, including why animal models of AD require adjuvants containing microbial peptides in addition to self tissue to induce disease, and why ADs occur more often in one sex than the other. Reviews published in the past 3 years have focused on the role of the innate immune response in driving AD and the possible role of persistent infections in altering immune responses. Overall, recent evidence suggests that microbes activating specific innate immune responses are critical, while antigenic cross-reactivity may perpetuate immune responses leading to chronic autoinflammatory disease.


Assuntos
Doenças Autoimunes/imunologia , Autoimunidade/imunologia , Infecção/imunologia , Animais , Antígenos/genética , Antígenos/imunologia , Autoimunidade/genética , Efeito Espectador/imunologia , Reações Cruzadas/imunologia , Epitopos/imunologia , Humanos , Imunidade Inata/imunologia , Mimetismo Molecular/imunologia
19.
Clin Med Insights Cardiol ; 8(Suppl 3): 49-59, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25983559

RESUMO

Atherosclerosis is the leading cause of death in the United States and worldwide, yet more men die from atherosclerosis than women, and at a younger age. Women, on the other hand, mainly develop atherosclerosis following menopause, and particularly if they have one or more autoimmune diseases, suggesting that the immune mechanisms that increase disease in men are different from those in women. The key processes in the pathogenesis of atherosclerosis are vascular inflammation, lipid accumulation, intimal thickening and fibrosis, remodeling, and plaque rupture or erosion leading to myocardial infarction and ischemia. Evidence indicates that sex hormones alter the immune response during atherosclerosis, resulting in different disease phenotypes according to sex. Women, for example, respond to infection and damage with increased antibody and autoantibody responses, while men have elevated innate immune activation. This review describes current knowledge regarding sex differences in the inflammatory immune response during atherosclerosis. Understanding sex differences is critical for improving individualized medicine.

20.
J Immunol ; 191(8): 4038-47, 2013 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-24048893

RESUMO

CD4(+) T cells play a central role in inflammatory heart disease, implicating a cytokine product associated with Th cell effector function as a necessary mediator of this pathophysiology. IFN-γ-deficient mice developed severe experimental autoimmune myocarditis (EAM), in which mice are immunized with cardiac myosin peptide, whereas IL-17A-deficient mice were protected from progression to dilated cardiomyopathy. We generated IFN-γ(-/-)IL-17A(-/-) mice to assess whether IL-17 signaling was responsible for the severe EAM of IFN-γ(-/-) mice. Surprisingly, IFN-γ(-/-)IL-17A(-/-) mice developed a rapidly fatal EAM. Eosinophils constituted a third of infiltrating leukocytes, qualifying this disease as eosinophilic myocarditis. We found increased cardiac production of CCL11/eotaxin, as well as Th2 deviation, among heart-infiltrating CD4(+) cells. Ablation of eosinophil development improved survival of IFN-γ(-/-)IL-17A(-/-) mice, demonstrating the necessity of eosinophils in fatal heart failure. The severe and rapidly fatal autoimmune inflammation that developed in the combined absence of IFN-γ and IL-17A constitutes a novel model of eosinophilic heart disease in humans. This is also, to our knowledge, the first demonstration that eosinophils have the capacity to act as necessary mediators of morbidity in an autoimmune process.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Eosinófilos/imunologia , Interferon gama/deficiência , Interleucina-17/deficiência , Miocardite/imunologia , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/prevenção & controle , Biomarcadores , Miosinas Cardíacas/imunologia , Cardiomiopatias/imunologia , Quimiocina CCL11/biossíntese , Inflamação , Interferon gama/genética , Interferon gama/imunologia , Interleucina-17/genética , Interleucina-17/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Miocardite/genética , Miocardite/prevenção & controle , Miocárdio/imunologia , Miosite
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