title: IL2RA genetic variants reduce IL-2-dependent responses and aggravate human cutaneous leishmaniasis.
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.
authors: Aix Marseille Université, Génétique et Immunologie des Maladies Parasitaires, Unité Mixte de Recherche S906, 13385 Marseille, France; INSERM, Unité 906, 13385 Marseille, France; Laboratory of Pathology and Bio-Intervention, Gonçalo Moniz Research Center, Oswaldo Cruz Foundation, Salvador, Bahia 40296, Brazil;
authors: Pablo R S
authors: PR
authors: Oliveira
authors: Aix Marseille Université, Génétique et Immunologie des Maladies Parasitaires, Unité Mixte de Recherche S906, 13385 Marseille, France; INSERM, Unité 906, 13385 Marseille, France;
authors: Hélia
authors: H
authors: Dessein
authors: Aix Marseille Université, Génétique et Immunologie des Maladies Parasitaires, Unité Mixte de Recherche S906, 13385 Marseille, France; INSERM, Unité 906, 13385 Marseille, France;
authors: Audrey
authors: A
authors: Romano
authors: Aix Marseille Université, Génétique et Immunologie des Maladies Parasitaires, Unité Mixte de Recherche S906, 13385 Marseille, France; INSERM, Unité 906, 13385 Marseille, France;
authors: Sandrine
authors: S
authors: Cabantous
authors: Laboratory of Immunogenetics, Department of Immunology, Aggeu Magalhães Research Center, Oswaldo Cruz Foundation, Recife, Pernambuco 50670 420, Brazil;
authors: Maria E F
authors: ME
authors: de Brito
authors: Aix Marseille Université, Génétique et Immunologie des Maladies Parasitaires, Unité Mixte de Recherche S906, 13385 Marseille, France; INSERM, Unité 906, 13385 Marseille, France;
authors: Ferrucio
authors: F
authors: Santoro
authors: Aix Marseille Université, Génétique et Immunologie des Maladies Parasitaires, Unité Mixte de Recherche S906, 13385 Marseille, France; INSERM, Unité 906, 13385 Marseille, France;
authors: Maira G R
authors: MG
authors: Pitta
authors: Laboratory of Immunogenetics, Department of Immunology, Aggeu Magalhães Research Center, Oswaldo Cruz Foundation, Recife, Pernambuco 50670 420, Brazil;
authors: Valéria
authors: V
authors: Pereira
authors: Laboratory of Pathology and Bio-Intervention, Gonçalo Moniz Research Center, Oswaldo Cruz Foundation, Salvador, Bahia 40296, Brazil;
authors: Lain C
authors: LC
authors: Pontes-de-Carvalho
authors: Laboratory of Immunology, Department of Biological Sciences, Federal University of the Triângulo Mineiro, Uberaba, Mina Gerais 38015 050, Brazil; and.
authors: Virmondes
authors: V
authors: Rodrigues
authors: Laboratory of Immunology, Pasteur Institute of Tehran, Tehran 1316943551, Iran.
authors: Sima
authors: S
authors: Rafati
authors: Aix Marseille Université, Génétique et Immunologie des Maladies Parasitaires, Unité Mixte de Recherche S906, 13385 Marseille, France; INSERM, Unité 906, 13385 Marseille, France;
authors: Laurent
authors: L
authors: Argiro
authors: Aix Marseille Université, Génétique et Immunologie des Maladies Parasitaires, Unité Mixte de Recherche S906, 13385 Marseille, France; INSERM, Unité 906, 13385 Marseille, France; alain.dessein@univ-amu.fr.
authors: Alain J
authors: AJ
authors: Dessein
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D020869:Gene Expression Profiling; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006790:Host-Parasite Interactions / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology*; D007892:Leishmania braziliensis / Q000276:immunology* / Q000502:physiology; D016773:Leishmaniasis, Cutaneous / Q000235:genetics / Q000276:immunology* / Q000469:parasitology; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D055815:Young Adult
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D007371:Interferon-gamma