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* Institut National de la Santé et de la Recherche Médicale, U399 INSERM, Marseille;
Laboratory of Parasitology Mycology, Faculty of Medicine la Timone, University of Aix-Marseille, Marseille;
Institut National de la Santé et de la Recherche Médicale, U550, Laboratory of Human Genetics of Infectious Diseases, University of Paris René Descartes, Necker Medical School, Paris, France;
Laboratory of Immunology and Infectious Diseases, Triangulo Mineiro Federal University, Uberaba, Brazil; and
¶ Laboratory of Immunology, Pasteur Institute, Tehran, Iran
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-
, 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.
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1 This work was supported by the Institut National de la Santé et de la Recherche Médicale, an Institut National de la Santé et de la Recherche Médicale-Conselho Nacional de Pesquisas Collaborative Grant, the World Health Organization (ID096546), the European Economic Community (TS3 CT940296, IC18CT970212), the Scientific and Technical Cooperation with Developing Countries (IC18CT980373), the French Ministere de la Recherche et des Techniques (PRFMMIP), the Conseil Général Provence Alpes Côte d’Azur, and the Conseil Régional Provence Alpes Côte d’Azur. A.S. was supported by the French ministere de l’enseignement et de la recherche and by the Fondation pour la recherche Medicale.
2 A.S. and V.R. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Alain Dessein, Institut National de la Santé et de la Recherche Médicale, U399, Faculty of Medicine, 27 Boulevard Jean Moulin 13385, Marseille cedex 05, France. E-mail address: alain.dessein{at}medecine.univ-mrs.fr
4 Abbreviations used in this paper: CL, cutaneous leishmaniasis; LCL, localized CL; rCL, subjects resistant to CL; Lb, Leishmania braziliensis; EMSA, electrophoretic mobility shift assay; MCL, mucocutaneous leishmaniasis; MAF, minor allele frequeny; aCL, subjects with active CL; hCL, subjects with healed CL lesions.
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