SummaryRecent studies have shown that mucocutaneous leishmaniasis (MCL), a severe and debilitating form of American cutaneous leishmaniasis (ACL) caused by Leishmania braziliensis infection, is accompanied by high circulating levels of tumor necrosis factor (TNF)-oL. Analysis of TNF polymorphisms in Venezuelan ACL patients and endemic unaffected controls demonstrates a high relative risk (RR) of 7.5 (P <0.001) of MCL disease in homozygotes for allele 2 of a polymorphism in intron 2 of the TNF-[3 gene, especially in females (RR = 9.5; P <0.001) compared with males (RR = 4; P <0.05). A significantly higher frequency (P <0.05) of allele 2 at the -308-basepair TNF-c~ gene polymorphism was also observed in MCL patients (0.18) compared with endemic control subjects (0.069), again associated with a high relative risk of disease (RR = 3.5; P <0.05) even in the heterozygous condition. Because both the TNF-c~ and TNF-[3 polymorphisms have previously been linked with functional differences in TNF-oL levels, these data suggest that susceptibility to the mucocutaneous form of disease may be directly associated with regulatory polymorphisms affecting TNF-~x production.

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It is well established that malnutrition affects the immune response and increases the susceptibility to parasitic infection. In the present study we evaluated some aspects of the cellular and cytokine network that regulate the IgE responses, which are important components of host defence mechanisms against helminthic parasites in children infected with the intestinal helminth Ascaris lumbricoides, and with differing degrees of malnutrition. We found a defective T cell response in malnourished children, as indicated by diminished levels of circulating total (CD3+), helper (CD4+), IL-2-receptor-bearing (CD4+CD25+) and memory helper T cell responses (CD4+CD45RO+) in keeping with the decreased specific IgE levels against Ascaris lumbricoides. In contrast, the proportions of total B cells (CD20+), and those bearing the low-affinity IgE receptor (CD23+) were increased in the moderated malnourished children. Moreover, serum IL-4 levels and total IgE were also increased in these children. We suggest that malnutrition can cause an imbalance in T cell subpopulations that may lead to a defective T cell maturation and a decreased specific anti-Ascaris IgE response thus increasing the susceptibility to such infections. The high levels of total IgE observed may be related to a non-specific stimulation of the proliferation of activated B cells, probably caused by helminthic parasites and other infectious agents that are frequent in malnourished children.

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Leukocyte subpopulations, the expression of the interleukin-2 (IL-2) receptor, and the production of IL-2 and gamma interferon (IFN-gamma) were studied in the peripheral blood mononuclear cells of American cutaneous leishmaniasis patients that had been stimulated in vitro with either leishmanial antigen or mitogen (phytohemagglutinin M). The 75 patients examined were classified as having either the localized (LCL; 66 patients), mucocutaneous (MCL; 5 patients), or the rare diffuse (DCL; 4 patients) form of the disease. Patients with DCL, who are characterized by their defective cell-mediated immune response to leishmanial antigen, failed to express the IL-2 receptor and did not produce IFN-gamma when exposed to the antigen but did so when stimulated by phytohemagglutinin M. Both LCL and MCL patients showed strong proliferative responses to leishmanial antigen; these were by far the greatest in MCL patients. Both groups had significantly increased IL-2 receptor expression and IFN-gamma production after exposure to either antigen or mitogen, and these were highest in the MCL patients. Concerning the leukocyte subpopulations evaluated (CD2, CD4, CD8, CD20, MO2), the most significant findings were a decrease of both CD4+ cells and the CD4/CD8 ratio in MCL patients compared with the other groups. Considering IL-2 production, in response to phytohemagglutinin M both MCL and LCL patients showed amounts of IL-2 comparable to those of the controls. Our results help explain the anergy of T cells from DCL patients to leishmanial antigen, which could lead to a defective production of IFN-gamma and possibly contribute to their incapacity to kill the Leishmania parasite. Concerning MCL patients, the significantly increased expression of IL-2 receptor, decreased expression of the CD4 (helper-inducer of suppression) phenotype, and elevated IFV-gamma production might partially explains the state of hypersensitivity and mucosal damage exhibited by these patients.

Previous work has shown that American cutaneous leishmaniasis (ACL) patients treated with viable BCG plus heat killed promastigotes of Leishmania amazonensis show the same rate of cure as patients receiving conventional chemotherapy. The treatment is safe and economical, but the immunological correlates of cure have not been examined. In the present study, T cell responses have been analysed in 43 ACL patients, including patient groups sampled before and after therapy, and in 10 endemic controls. Lymphocyte proliferation, interferon (IFN)-gamma and interleukin (IL)-5 responses to crude antigen (L. amazonensis, MEL; Mycobacterium tuberculosis PPD; M. bovis BCG) stimulation, and serum IL-5 levels, were analysed. In endemic volunteers, proliferative responses to BCG were high and IFN-gamma responses low. In contrast, localized cutaneous (LCL) and mucocutaneous (MCL) patients showed low proliferative and high IFN-gamma responses to BCG. Treatment enhanced the IFN-gamma response and further decreased the proliferative response to BCG, especially in MCL patients. LCL and MCL patients showed an increase in proliferative and IFN-gamma responses to MEL with treatment, but the response was not exaggerated in MCL patients, either before or after treatment, compared to LCL patients. IL-5 production was low in T cell assays, and > 62% of untreated patients had very low serum IL-5 levels. There were no significant changes in serum IL-5 with treatment. Overall results show enhanced antigen-specific IFN-gamma responses to the two components of the immunotherapy, live M. bovis BCG and heat killed L. amazonensis, which is consistent with a shift in balance of T cell response towards a T helper 1 response and clinical cure mediated by IFN-gamma.

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