Molecular mimicry between the immunodominant ribosomal protein P0 of Trypanosoma cruzi and a functional epitope on the human beta 1-adrenergic receptor.

Ferrari, Inés; Levìn, Mariano J.; Wallukat, Gerd; Elies, R; Lebesgue, Diane; Chiale, Pablo A.; Elizari, Marcelo V.; Rosenbaum, Mauricio B.; Hoebeke, Johan

doi:10.1084/jem.182.1.59

Cited by 138 publications

(83 citation statements)

References 38 publications

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“…3B). The size of this antigen is different from the sizes of other published cross-reactive antigens, including B13 (8), ribosomal proteins (12,29), Cha (15), cruzipain (13), and Fl-160 (41). We have attempted to do searches for A/J mouse alpha heavychain cardiac myosin homologs in T. cruzi DB but have found only unknown-clone sequences with low scores (smallest sum probability, Ͻ10 Ϫ7 ).…”

Section: Discussionmentioning

confidence: 88%

A Cardiac Myosin-Specific Autoimmune Response Is Induced by Immunization withTrypanosoma cruziProteins

et al. 2004

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Trypanosoma cruzi is the protozoan parasite that causes Chagas' heart disease, a potentially fatal cardiomyopathy prevalent in Central and South America. Infection with T. cruzi induces cardiac myosin autoimmunity in susceptible humans and mice, and this autoimmunity has been suggested to contribute to cardiac inflammation. To address how T. cruzi induces cardiac myosin autoimmunity, we investigated whether immunity to T. cruzi antigens could induce cardiac myosin-specific autoimmunity in the absence of live parasites. We immunized A/J mice with a T. cruzi Brazil-derived protein extract emulsified in complete Freund's adjuvant and found that these mice developed cardiac myosin-specific delayed-type hypersensitivity (DTH) and autoantibodies in the absence of detectable cardiac damage. The induction of autoimmunity was specific since immunization with extracts of the related protozoan parasite Leishmania amazonensis did not induce myosin autoimmunity. The immunogenetic makeup of the host was important for this response, since C57BL/6 mice did not develop cardiac myosin DTH upon immunization with T. cruzi extract. Perhaps more interesting, mice immunized with cardiac myosin developed T. cruzi-specific DTH and antibodies. This DTH was also antigen specific, since immunization with skeletal myosin and myoglobin did not induce T. cruzi-specific immunity. These results suggest that immunization with cardiac myosin or T. cruzi antigen can induce specific, bidirectionally cross-reactive immune responses in the absence of detectable cardiac damage.Trypanosoma cruzi is the protozoan parasite that causes Chagas' heart disease (CHD), a potentially fatal cardiomyopathy resulting in dilated tissue. Approximately 16 million people are infected with this protozoan parasite, and 120 million are at risk of infection in Central and South America (28). CHD develops in roughly one-third of T. cruzi-infected individuals as an acute or chronic myocarditis of variable degree (reviewed in reference 39). Among the various mechanisms invoked to explain the pathogenesis of CHD, autoimmunity is one that both has been supported by much experimental evidence and has received much criticism. There is no doubt that autoimmunity results from chronic T. cruzi infection of humans and experimental animals. The questions are (i) whether this autoimmunity is pathogenic and (ii) by what mechanism(s) autoimmunity is induced. The debate surrounding this issue is long-standing (reviewed in references 17, 22, 39, and 40).T. cruzi infection induces humoral and cellular autoimmunity to a diverse set of autoantigens (reviewed in references 17 and 22), including cardiac myosin. Myosin-specific autoimmunity is induced in both humans (8) and experimental models (24) upon T. cruzi infection. In previous work (24), it was found that within weeks of infection, A/J mice acutely infected with T. cruzi developed severe myocarditis accompanied by myosinspecific delayed-type hypersensitivity (DTH) and antibody production. Autoimmunity to cardiac myosin has also been rep...

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Section: Discussionmentioning

confidence: 88%

A Cardiac Myosin-Specific Autoimmune Response Is Induced by Immunization withTrypanosoma cruziProteins

et al. 2004

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“…Thus, cross-reactive antibodies between T cruzi and human ribosomal P proteins or the ␤1-adrenergic receptor have been detected in chagasic patients. 139 Moreover, antibodies cross-reactive between cardiac myosin heavy chain and the T cruzi protein B13 are more frequently found in sera from patients with definite Chagas heart disease than in patients with the indeterminate form of the disease. 140 Also, CD4ϩ T cell clones derived from an endomyocardial biopsy sample from a patient with Chagas cardiomyopathy crossreactively recognized cardiac myosin and T cruzi protein B13.…”

Section: Autoimmunity In Human Chagas Cardiomyopathymentioning

confidence: 99%

Pathogenesis of Chronic Chagas Heart Disease

Marin-Neto

Cunha-Neto²,

Maciel³

et al. 2007

Circulation

718

640

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Background-Chagas disease remains a significant public health issue and a major cause of morbidity and mortality in Latin America. Despite nearly 1 century of research, the pathogenesis of chronic Chagas cardiomyopathy is incompletely understood, the most intriguing challenge of which is the complex host-parasite interaction. Methods and Results-A systematic review of the literature found in MEDLINE, EMBASE, BIREME, LILACS, and SCIELO was performed to search for relevant references on pathogenesis and pathophysiology of Chagas disease. Evidence from studies in animal models and in anima nobile points to 4 main pathogenetic mechanisms to explain the development of chronic Chagas heart disease: autonomic nervous system derangements, microvascular disturbances, parasite-dependent myocardial aggression, and immune-mediated myocardial injury. Despite its prominent peculiarities, the role of autonomic derangements and microcirculatory disturbances is probably ancillary among causes of chronic myocardial damage. The pathogenesis of chronic Chagas heart disease is dependent on a low-grade but incessant systemic infection with documented immune-adverse reaction. Parasite persistence and immunological mechanisms are inextricably related in the myocardial aggression in the chronic phase of Chagas heart disease. Conclusions-Most clinical studies have been performed in very small number of patients. Future research should explore the clinical potential implications and therapeutic opportunities of these 2 fundamental underlying pathogenetic mechanisms.

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“…Some cardiac alterations such as extrasystoles or atria ventricular blocks are observed with a relatively high frequency, but none is totally specific of chagasic cardiomyopathy. 9,10,[12][13][14] Autoimmune reactions have been implicated in the progression of the disease, due to the presence of cross-reactive antigens shared by heart tissues and T. cruzi, [15][16][17] but their relevance to the development of the disease is still debated. 18,19 This chronic phase of the disease is highly incapacitating, and may ultimately lead to cardiac failure and death.…”

Section: Overview Of the Diseasementioning

confidence: 99%

Update on Chagas' disease in Mexico

Dumonteil

1999

Salud pública Méx

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Molecular mimicry between the immunodominant ribosomal protein P0 of Trypanosoma cruzi and a functional epitope on the human beta 1-adrenergic receptor.

Cited by 138 publications

References 38 publications

A Cardiac Myosin-Specific Autoimmune Response Is Induced by Immunization withTrypanosoma cruziProteins

A Cardiac Myosin-Specific Autoimmune Response Is Induced by Immunization withTrypanosoma cruziProteins

Pathogenesis of Chronic Chagas Heart Disease

Update on Chagas' disease in Mexico

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