ABSTRACT
The outcome of Leishmania infections varies substantially, depending on the host and the parasite strain; infection may be asymptomatic or cause mild or severe skin ulcers (cutaneous leishmaniasis [CL]), limited or disseminated lesions, or lethal visceral disease. We previously reported an association between IL-2R mutations and susceptibility to visceral leishmaniasis in children infected with Leishmania donovani. In the present study, we evaluated the possible role of IL-2 signaling in human CL. We first showed that the transcripts of several genes of the IL-2 pathway were abundant in skin lesions caused by Leishmania braziliensis. We then carried out a genetic analysis, focusing on major genes of the IL-2 pathway. We used a family-based approach and found that polymorphisms of several genes appeared to be associated with CL in a Brazilian population. Moreover, two polymorphisms of the IL2RA gene were significantly and independently associated with CL. We confirmed this result in a second Brazilian sample (also exposed to L. braziliensis) and in Iranians infected with Leishmania tropica: IL2RA rs10905669 T (Pcombined = 6 × 10(-7)) and IL2RA rs706778 T (Pcombined = 2 × 10(-9)) were associated with greater susceptibility to lesion development. These alleles were also correlated with a poor IFN-γ response and poor FOXP3(+) regulatory T cell activation. Thus, IL-2 plays a crucial role in protection against the cutaneous ulcers caused by Leishmania, and the IL-2 pathway is a potential target for strategies aiming to control Leishmania-related diseases.
Subject(s)
Interleukin-2 Receptor alpha Subunit/immunology , Interleukin-2/immunology , Leishmania braziliensis/immunology , Leishmaniasis, Cutaneous/immunology , Polymorphism, Single Nucleotide/immunology , Adolescent , Adult , Child , Female , Forkhead Transcription Factors/immunology , Forkhead Transcription Factors/metabolism , Gene Expression Profiling , Gene Frequency , Genetic Predisposition to Disease/genetics , Genotype , Host-Parasite Interactions/immunology , Humans , Interferon-gamma/immunology , Interleukin-2/genetics , Interleukin-2 Receptor alpha Subunit/genetics , Leishmania braziliensis/physiology , Leishmaniasis, Cutaneous/genetics , Leishmaniasis, Cutaneous/parasitology , Linkage Disequilibrium , Male , Middle Aged , Oligonucleotide Array Sequence Analysis , Polymorphism, Single Nucleotide/genetics , Signal Transduction/genetics , Signal Transduction/immunology , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Young AdultABSTRACT
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-gamma, 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.
