Twenty-four out of 25 patients with Chagas' heart disease have circulating immunoglobulins which react by indirect immunofluorescence technique with endocardium, interstitium and blood vessels of the heart. With skeletal muscle the reaction was observed in interstitium and vascular structures, but with other organs it was limited to vascular structures. This endocardial-vascular-interstitial factor (EVI) fixed complement. Some evidence indicated that this reaction could be obtained using the serum and tissues from the same patient: for instance, in one positive case a right atrium biopsy was performed. When this substrate was used for indirect immunofluorescence, employing the patient's own serum, positive results were obtained. Specificity is not related to AB blood group systems, or to Forssman or Wassermann antigens. The reacting factor was effectively absorbed from sera with organ homogenates, and with guinea pig red blood cells although it was independent of heterophil antibodies. In almost all cases studied, the EVI factor of the serum, when absorbed with epimastigotes of T. cruzi, results in a negative reaction, suggesting that the genesis of the reacting gamma globulin is related to antigens of T. cruzi.The EVI factor was also observed in 19 of 47 asymptomatic controls from an endemic area with positive serology for T. cruzi and in 3 of 27 with negative serology. These 3 cases had anti-T. cruzi antibodies in titers just below those considered of clinical value. The EVI factor was not observed in 119 normal individuals and 286 patients with selected cardiovascular diseases or another pathology from a nonendemic area. These findings and those mentioned above were statistically significant (P < 0.001). These results indicate the possibility of a more accurate diagnosis of chagasic myocardiopathy based on the study of the EVI factor, because in an individual case the diagnosis of chronic chagasic cardiopathy can be considered with a low probability in the absence of this factor.

Chagasic Cardiopathy Demonstration of a Serum Gamma Globulin Factor Which Reacts with Endocardium and Vascular Structures

Publisher Summary Trypanosoma cruzi (T. cruzi), the causative agent of Chagas disease, is a digenetic trypanosomatid, which circulates in the bloodstream of the vertebrate host as trypomastigotes and has an obligatory intracellular phase in which the parasite multiplies as amastigotes, which differentiate into trypomastigotes. From an immunological point of view, therefore, the parasite presents stages that are directly exposed to the effector elements of the immune response, such as antibodies and macrophages, as well as stages that are sequestrated within host cells. T. cruzi infection is characterized by an acute phase with large numbers of parasites and by a sub-patent chronic phase in which circulating and tissue stages are difficult to detect. The mechanisms involved in the resistance to the parasite and in the control of parasitism during the chronic phase are not known. Chagas disease is life-long and spontaneous cures do not occur. There is increasing evidence that auto-immune processes participate in the pathogenesis of the cardiac and digestive forms of the disease. These many obscure aspects and challenging problems explain the increasing use of T. cruzi as a model for the study of humoral and cellular immunity in both basic and applied immunology.

Immunity to Trypanosoma cruzi.

The role of CD4+ and CD8+ T cells in the surveillance of Trypanosoma cruzi or Trypanosoma brucei brucei was studied in mice which lacked CD4 or CD8 molecules and which were generated by embryonic stem cell technology. Whereas wild-type mice infected with T. cruzi (Tulahuen strain) displayed low levels of parasitemia and no mortality, striking increases in parasite growth and mortality occurred in both CD8- and CD4- mice. On the contrary, CD8- and, to a lesser degree, CD4- mice showed enhanced resistance to T. b. brucei. T-cell-dependent immunoglobulin G-specific responses were produced in CD8- but not CD4- mice. Normal T-cell proliferative responses were measured in both CD4- and CD8- mice. Interleukin-4 production after concanavalin A or anti-CD3 monoclonal antibody stimulation was strikingly enhanced in CD8- but not CD4- spleen cells, whereas gamma interferon production was normal in both CD4- and CD8- spleen cells. Spleen and lymph node cells from CD8- (but not CD4-) mice at 20 days postinfection with T. cruzi had higher levels of interleukin-4 mRNA than the wild-type controls, as shown in a competitive polymerase chain reaction assay. On the other hand, CD4- (but not CD8-) mice at 20 days postinfection with T. cruzi had lower levels of gamma interferon mRNA than the wild-type mice.

Differential susceptibilities of mice genomically deleted of CD4 and CD8 to infections with Trypanosoma cruzi or Trypanosoma brucei.

Chagas' disease is a major health problem in Latin America, where it constitutes one of the leading causes of heart failure. About one fourth of Trypanosoma cruzi-infected individuals develop chronic chagasic cardiomyopathy (CChC), the most severe form of the disease. CChC is histologically characterized by the presence of multifocal inflammatory infiltrates in the heart, composed mainly by mononuclear cells, usually adhered to myocytes and leading to myocytolysis, and frequently by interstitial fibrosis. The pathogenesis of CChC is still unclear, despite intense investigations both in human beings and in animal models of the disease. Although tissue parasitism is rare in the chronic phase of infection, an immune response targeted to persistent parasites or parasite antigens is suggested, by some authors, as the pathogenic mechanism of CChC. Other researchers affirm that the lack of correlation between tissue parasitism and intensity of inflammation suggests, along with the presence of autoreactive immune responses, that CChC results from the action of an autoimmune response. Herein we review reports from the literature and our own data, which together indicate, on one hand, the participation of parasite-specific immune responses and, on the other hand, clearly demonstrate the participation of heart-specific immune responses in the pathogenesis of CChC. Moreover, multiple factors may determine whether an individual in the indeterminate form of the disease will develop CChC. The mechanisms by which T. cruzi breaks immunological tolerance to heart antigens are also discussed.

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The pathogenesis of Chagas' disease: when autoimmune and parasite-specific immune responses meet

Immunity to blood parasites of animals and man.

Neonatally thymectomized C3H or Rockland mice infected with trypanomastigotes of Trypanosoma cruzi had higher parasitaemia and shorter survival than their non-thymectomized counterparts. The appearance of antibodies detectable by IFT, IHA or DAT was delayed in neonatally thymectomized mice infected with epimastigotes of T. cruzi. Less thymectomized than non-thymectomized mice survived infection with epimastigotes. Our findings suggest that thymus-dependent, immune mechanisms are involved in controlling infection with T. cruzi in mice.

The effect of immuno-depression due to neonatal thymectomy on infections with trypanosoma cruzi in mice

Summary
The action of pressure on antigenic materials obtained from culture forms of Trypanosoma cruzi was investigated. The antigens were prepared in a Ribi Refrigerated Cell Fractionator-RF-1 (Ivan Sorvall, Inc.), with temperature control and in an atmosphere of inert gas. The complement-fixation (CF) test, skin test, and the resistance of Rockland strain mice after vaccination were used to study these antigens. The most typical CF curves were obtained with soluble extracts of T. cruzi prepared at less than 10,000 PSI (pounds per square inch). The best skin reactions were obtained with the insoluble portion of an extract of T. cruzi prepared at 20,000 PSI. The antigen used for immunization was not toxic for rabbits, mice, or human beings. The immunizing capacity of this antigen was more effective when it was prepared at less than 10,000 PSI. The survival of mice immunized with this antigen and challenged with a killing dose of T. cruzi varied from 88% to 100% and depended on the number of doses and the quantity of antigen injected. Some of the immunized mice showed transient, low parasitemia after the challenge infection.

O. C. Traversa

Papers

The effect of immuno-depression due to neonatal thymectomy on infections with trypanosoma cruzi in mice

Complement-fixation tests, skin tests, and experimental immunization with antigens of Trypanosoma cruzi prepared under pressure.

Trypanosoma cruzi: experimental immunization of mice.

Histopathology in Rockland mice immunized against American trypanosomiasis (Chagas' disease).