Immunological and Genetic Evidence for a Crucial Role of IL-10 in Cutaneous Lesions in Humans Infected with Leishmania braziliensis

Abstract

In populations exposed to Leishmania braziliensis, certain subjects develop skin ulcers, whereas others are naturally protected against cutaneous leishmaniasis. We have evaluated which cytokines are most crucial in the development of skin lesions. We found that active lesions occur in subjects with polarized Th2 or mixed Th1/Th2 responses, both associated with elevated IL-10 production. IL-10 was strongly associated (p = 0.004, odd ratio (OR) = 6.8, confidence interval = 1.9–25) with lesions, excluding IFN-γ, IL-12, TNF, IL-13, and IL-4 from the regression model. IL-10 was produced by blood monocytes and CD4+CD25+ T lymphocytes (mostly Foxp3+). However, we did not observe any difference between the number of these cells present in the blood of subjects with active lesions and those present in resistant subjects. Genetic analysis of the IL10−819C/T polymorphism, located in the IL10 promoter, showed that the C allele increased the risk of lesions (OR = 2.5 (1.12–5.7), p = 0.003). Functional analysis of these variants showed allele-specific binding of nuclear factors. The IL10-819C/C genotype was associated with higher levels of IL-10 than C/T and T/T genotypes. These observations demonstrate an important role for IL-10 in skin lesions in humans infected with L. braziliensis, and identify circulating monocytes and Tregs as principal sources of IL-10 in these patients.

Intralesional Regulatory T-Cell Suppressive Function during Human Acute and Chronic Cutaneous Leishmaniasis Due to Leishmania guyanensis

“…Interestingly, levels of Treg cells were identical in healed subjects, those with active leishmaniasis, and resistant subjects. However, in these experiments, the level of Treg cells was not evaluated in control subjects, and the number of Treg cells within lesions was not determined (28). In another study, the accumulation of Treg cells with suppressive activity was described for lesions of patients suffering from leishmaniasis due to L. braziliensis (10), confirming that Treg cells are present predominantly at the site of infection during infection with Leishmania.…”

“…Treg cells with immunosuppressive functions have been identified clearly in skin lesions from patients infected with L. braziliensis, but their exact role in pathogenesis has not been evaluated (10). More recently, Treg cells have also been identified in peripheral blood mononuclear cells (PBMC) from acute and cured localized cutaneous leishmaniasis patients infected with L. braziliensis (28).…”

Immunophenotyping of circulating T cells in a mucosal leishmaniasis patient coinfected with HIV

“…Human protection against localized cutaneous leishmaniasis (LCL) due to Leishmania (Viannia) braziliensis (Lb) is dependent on an efficient T helper lymphocyte 1 (Th1) response, whereas susceptibility is associated with an increased Th2 and T regulatory (Treg) profile 1,2 . Mucosal leishmaniasis (ML) is defined as an uncontrolled Th1-type inflammation of the oropharyngeal region, presenting a disfiguring facial lesion and can occur after unsuccessful healing of a previous LCL 3 .…”

Genetic risk factors for human susceptibility to infections of relevance in dermatology

“…In leishmaniasis, a previously known functional polymorphism (-819) of the IL10 gene, associated with regulation of IL-10 serum levels, was also associated with the development of leishmaniasis skin lesions in a Brazilian population sample from the northeastern state of Bahia. 76 Again, the same polymorphism is widely described in association with leprosy. 14 Allele frequencies of a polymorphism in the promoter region of IL6 gene were differentially distributed among ML patients compared to CL cases.…”