The fundamental nature of Chagas' disease:A view provided by immune responses and idiotypes.

Abstract

Chagas' disease is caused by the protozoan Trypanosoma cruzi which infects 10-15 million people in endemic areas throughout Latin America and is naturally transmitted by insect vectors of the family Reduviidae. Infection can also occur by congenital passage, oral ingestion, laboratory accident, and in organ transplants and blood transfusions. There are 3 life-cycle forms of T. cruzi. Epimastigotes multiply in the midgut of the insect vector, differentiate in the hind-gut into infectious trypomastigotes, and are excreted with the feces or urine after a blood meal. They enter the body by mucous membranes or abraded skin, enter mammalian host cells, escape the phagolysosomal vacuole, and differentiate into amastigotes. Intracellular amastigotes multiply in host cells, redifferentiate to trypomastigotes, and are released upon cell rupture.Acute Chagas' disease can be asymptomatic, or a mild to severe illness. Morbidity can be localized and/or systemic and is usually accompanied by general immunosuppression with blood and tissue parasitemia. It can be fatal. Usually, symptoms and parasitemia decrease within months, followed by a life-long, chronic infection with little morbidity and few apparent parasites. Serologically-positive, chronic asymptomatic patients are termed indeterminate (I). Morbidity develops in 20-30% of chronic patients after 10-30 years and often involves myocardiopathy (Cardiac disease; C), ranging from minor electrocardiographic changes to sudden death by heart failure. Severe “digestive” megasyndromes can also develop. Chagasic myocardial inflammatory infiltrates are associated with cardiac muscle and neuron destruction, followed by progressive fibrotic replacement. Asymptomatic Ipatients who die of unrelated causes have identical (but less intense) lesions.Responses against T. cruzi antigens, their immunoregulation, and responses against related idiotypes (Ids) correlate with the presence of the different clinical forms of the infection. Although there are numerous findings of autoimmune lymphocyte and antibody reactivities in chagasic patients, a causal relationship is always difficult to prove. Chagasic patients' peripheral blood mononuclear cells (PBMC) respond to T. cruzi epimastigote antigens (EPI) with varying vigor. Almost all low responders are Cpatients, and their responses are usually augmented by removal of adherent macrophage suppressor cells or the addition of indomethacin. Chronic I-patients are medium or high responders, and exhibit little adherent cell-mediated immunoregulation. Western blotting studies indicate patients' Ab and cell-mediated responses to EPI show differences between C-and I-patients. PBMC from I-patients responded more often to high molecular weight components (100-150 kD), while both I-and C-patients responded well to moieties between 28-32 and 48-57 kD. All chagasic patients' sera had Abs and PBMC responses to T. cruzi GP57/51 antigen.Chronic Chagas' patients have peripheral blood anti-Id T cells that respond to anti-EPI Abs purified from patients' sera. Some patients' PBMC anti-Id responses to anti-EPI Ids from C-patients (Id-C) are inhibited by chloroquine (Group 1), but some are not inhibited by chloroquine, anti-HLA Class II antigens, or sodium azide (Group 2). Most patients in Group 1 are asymptomatic, but all Group 2 patients have severe disease. Direct (non-processed; non-MHC-presented) stimulation of anti-Id T cells from C-patients by Ids expressed on anti-EPI Abs from C-patients could be immunopathogenic. Anti-Id specific rabbit sera detect Id differences in the anti-EPI Abs from pooled or individual C vs. I-cases. Competitive ELISA assays and Western blot analyses of Abs show that Ids on I-patients' anti-EPI Abs are primary structure expressions, while Ids on C-patients' anti-EPI Abs are defined by intact Ab molecules.