IL2RA Genetic Variants Reduce IL-2–Dependent Responses and Aggravate Human Cutaneous Leishmaniasis
| Autor: | Sima Rafati, Hélia Dessein, Valéria Rêgo Alves Pereira, Lain Pontes-de-Carvalho, Pablo Oliveira, Virmondes Rodrigues, Maira G. R. Pitta, Maria Edileuza Felinto de Brito, Sandrine Cabantous, Audrey Romano, Alain Dessein, Ferrucio Santoro, Laurent Argiro |
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| Rok vydání: | 2015 |
| Předmět: |
Adult
Male Leishmania tropica Adolescent Genotype Immunology Leishmania donovani Leishmaniasis Cutaneous Polymorphism Single Nucleotide T-Lymphocytes Regulatory Leishmania braziliensis Linkage Disequilibrium Host-Parasite Interactions Interferon-gamma Young Adult Gene Frequency Cutaneous leishmaniasis parasitic diseases medicine Humans Immunology and Allergy Genetic Predisposition to Disease Child Oligonucleotide Array Sequence Analysis biology Gene Expression Profiling Interleukin-2 Receptor alpha Subunit FOXP3 Forkhead Transcription Factors Leishmaniasis Middle Aged medicine.disease Leishmania biology.organism_classification Visceral leishmaniasis Interleukin-2 Female Signal Transduction |
| Zdroj: | The Journal of Immunology. 194:2664-2672 |
| ISSN: | 1550-6606 0022-1767 1090-5669 |
| DOI: | 10.4049/jimmunol.1402047 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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