ABSTRACT
While the role of cytokine genes has been well documented in the context of Leishmania (Viannia) braziliensis infection, no studies have addressed the influence of human leukocyte antigen-G (HLA-G) in susceptibility/resistance to American Tegumentary Leishmaniasis (ATL). Here, we evaluated the influences of HLA-G, IL-10, TNF-A and IFN-G in the susceptibility and clinical manifestations of ATL. DNA of 114 ATL patients and 346 healthy individuals were sequenced for well-documented polymorphisms in HLA-G 3' untranslated region (UTR), in IL-10 and TNF-A promoters and in IFN-G intron 1. Soluble HLA-G (sHLA-G) and cytokine levels were evaluated by ELISA and flow cytometry, respectively. Analyses were performed using GraphPad and R-package software. Individuals bearing HLA-G +3142G/G showed an association with increased risk for ATL, whereas those carrying the HLA-G +3142C/G and one copy of UTR6 haplotype, showed an association with decreased risk for ATL. sHLA-G was overexpressed in "susceptible" patients compared to the "resistant'' one, and also in patients bearing +3142G/G genotype. From these results, HLA-G +3142G/G may be considered as genotype of susceptibility and UTR6 as marker of protection to ATL. Our findings showed a participation of HLA-G in the pathogenesis of the ATL.
Subject(s)
3' Flanking Region/genetics , Genotype , HLA-G Antigens/genetics , Leishmaniasis/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Brazil , Child , Female , Gene Frequency , Genetic Association Studies , Genetic Predisposition to Disease , Haplotypes , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide , Young AdultABSTRACT
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
BACKGROUND: It is uncertain whether Leishmania parasites ever disappear after clinical cure of American cutaneous leishmaniasis (ACL). Recently, sensitive molecular techniques have allowed the identification of Leishmania parasites directly in specimens from patients' scars. METHODS: Scars of 32 patients from northeastern Brazil who were treated and clinically cured of ACL were analyzed by use of polymerase chain reaction (PCR), culture, and histopathologic examination. RESULTS: DNA specific for Leishmania (Viannia) was detected in scars of 30 (93.7%) of 32 patients. In specimens from 3 of the scars, Leishmania parasites could be isolated by culture; PCR results also were positive for those 3 specimens. No parasites were found by histopathologic examination, and fibrotic alterations were present in all cases, with slight inflammatory foci observed in 4 of the cases studied. CONCLUSIONS: The results suggest that clinical cure of ACL is rarely associated with sterile cure. The implications of persistence of parasites for the clinical evolution, relapse, and transmission of leishmaniasis deserves further studies, particularly with the increasing incidence of coinfection with leishmaniasis and acquired immunodeficiency syndrome.
