Chagas' Disease

Laranja, F. S.; Dias, Emmanuel; Nobrega, G.; Miranda, Alice

doi:10.1161/01.cir.14.6.1035

Cited by 416 publications

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“…Interestingly, Okumura et al reported necrotizing arteritis in small arteries beneath the peritoneal lining of the bowel and, occasionally, of the aorta and coronary arteries of T. cruzi-infected mice, which was at that time interpreted as "allergic necrotizing angiitis" (10). Dias et al reported obliterative changes of the small and medium-sized branches of coronary arteries, with reductions of the vascular lumens, present in younger age groups of autopsied cases of Chagas' disease patients (11).…”

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confidence: 99%

Trypanosoma cruzi Causes Paralyzing Systemic Necrotizing Vasculitis Driven by Pathogen-Specific Type I Immunity in Mice

et al. 2016

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dInfectious agents are often considered potential triggers of chronic inflammatory disease, including autoimmunity; however, direct evidence is usually lacking. Here we show that following control of acute infection of mice with the myotropic Colombiana strain of Trypanosoma cruzi, parasites persisted in tissue at low levels associated with development of systemic necrotizing vasculitis. Lesions occurred in many but not all organs and tissues, with skeletal muscle arteries being the most severely affected, and were associated with myositis, atrophy, paresis/paralysis, and death. Histopathology showed fibrinoid vascular necrosis, rare amastigote nests within skeletal muscle myocytes, and massive leukocyte infiltrates composed mainly of inflammatory monocytes, F4/80 ؉ macrophages, and T. cruzi tetramer-specific CD8 ؉ T lymphocytes capable of producing gamma interferon (IFN-␥) and tumor necrosis factor alpha (TNF-␣) but not interleukin-17 (IL-17). T. cruzi-specific IgG was detected in sera from infected mice, but antibody deposits and neutrophilic inflammation were not features of the lesions. Thus, T. cruzi infection of mice may be a specific infectious trigger of paralyzing systemic necrotizing vasculitis most severely affecting skeletal muscle, driven by pathogen-specific type I immune responses. Vasculitis is a general term for a spectrum of diseases involving leukocyte infiltration of the blood vessel wall. Many subtypes of vasculitis are recognized based on the types of blood vessels involved and the nature of the underlying immunopathology. In some cases, an association of vasculitis with specific infectious agents has been reported; for example, polyarteritis nodosa (PAN) has been associated with hepatitis B virus (HBV), hepatitis C virus (HCV), and HIV infections (1). However, it has been difficult to establish either causality or pathogenetic mechanisms, in part because of the low prevalence of vasculitis and the lack of good animal models (2). In this regard, while studying the chronic phase of C57BL/6J mice infected with the myotropic Colombiana strain of Trypanosoma cruzi, the infectious cause of Chagas' disease in humans, we noticed that the majority of animals developed hind limb paralysis associated with severe systemic necrotizing vasculitis affecting arteries and arterioles in skeletal muscle. Lesions were also present in many other tissues. A review of the literature identified several studies from 1970 to 2000 that described perivascular inflammation and frank arteritis in chronically T. cruzi-infected mouse skeletal muscle, aorta, nerves, and heart (3-9); however, the underlying immunologic mechanisms of disease were not defined. Interestingly, Okumura et al. reported necrotizing arteritis in small arteries beneath the peritoneal lining of the bowel and, occasionally, of the aorta and coronary arteries of T. cruzi-infected mice, which was at that time interpreted as "allergic necrotizing angiitis" (10). Dias et al. reported obliterative changes of the small and medium-sized branches of coronary...

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confidence: 99%

Trypanosoma cruzi Causes Paralyzing Systemic Necrotizing Vasculitis Driven by Pathogen-Specific Type I Immunity in Mice

et al. 2016

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“…There is no specific or pathognomonic electrocardiographic feature of CHD. But, a detached right bundlebranch block or its connection with the left anterior hemiblock in patients with positive serology indicates chronic CHD [27,28]. CHD clinically often shows up as dilated cardiomyopathy having a tendency towards the development of apical aneurysms.…”

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confidence: 99%

“…CHD clinically often shows up as dilated cardiomyopathy having a tendency towards the development of apical aneurysms. It is a fibrotic disease that is normally situated in the posteroinferior and apical region of the left ventricle, the sinus node, and the conduction system below the bundle branch [27]. It has probable arrhythmogenic tendency that may lead to ventricular arrhythmias and SCD.…”

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confidence: 99%

Fibrosis-Induced Abnormalities of the Cardiac Conduction System and Malignant Arrhythmias in Patients with Chagas Disease

Oa¹,

Lb²

2017

J Bioequiv Availab

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“…Most patients survive the acute phase of the disease asymptomatically; the chronic stage of the disease develops over 20 -30 years and is manifested by cardiovascular, digestive, and autonomic nervous system disorders (3)(4)(5)(6). Several studies have focused on the disease-related loss of function of the autonomic receptors, the ␤-adrenergic and muscarinic cholinergic receptors (mAChR) 1 (5)(6)(7)(8)(9)(10)(11).…”

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Desensitization and Sequestration of Human m2 Muscarinic Acetylcholine Receptors by Autoantibodies from Patients with Chagas' Disease

Leirós

Sterin‐Borda

Borda

et al. 1997

Journal of Biological Chemistry

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Chronic Chagas' disease is associated with pathologic changes of the cardiovascular, digestive, and autonomic nervous system, culminating in autonomic denervation and congestive heart failure. Previously, circulating autoantibodies that activate signaling by cardiac muscarinic acetylcholine receptors (mAChRs) have been described. However, it remains unclear whether the chagasic IgGs directly interact with the m2 mAChRs (predominant cardiac subtype), and, if so, whether chronic exposure of the mAChRs to such activating IgGs would result in receptor desensitization. Here we performed studies with purified and reconstituted hm2 mAChRs and demonstrate that IgGs from chagasic serum immunoprecipitated the mAChRs in a manner similar to an anti-m2 mAChR monoclonal antibody tested in parallel. The chagasic antibodies did not directly interact with the ligand binding site, because the binding of radiolabeled antagonist was unchanged by the addition of the chagasic IgG. In intact cells stably expressing the hm2 mAChR, the chagasic IgGs, but not normal IgGs, mimicked the ability of the agonist acetylcholine to induce two effects associated with agonist-induced receptor desensitization: a decrease in affinity for agonist binding to m2 mAChR and sequestration of the hm2 mAChRs from the cell surface. The results demonstrate that the chagasic IgGs can directly interact with and desensitize m2 mAChRs and provide support for the hypothesis of autoimmune mechanisms having a role in the pathogenesis of Chagas' cardioneuromyopathy.

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Chagas' Disease

Cited by 416 publications

References 0 publications

Trypanosoma cruzi Causes Paralyzing Systemic Necrotizing Vasculitis Driven by Pathogen-Specific Type I Immunity in Mice

Trypanosoma cruzi Causes Paralyzing Systemic Necrotizing Vasculitis Driven by Pathogen-Specific Type I Immunity in Mice

Fibrosis-Induced Abnormalities of the Cardiac Conduction System and Malignant Arrhythmias in Patients with Chagas Disease

Desensitization and Sequestration of Human m2 Muscarinic Acetylcholine Receptors by Autoantibodies from Patients with Chagas' Disease

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