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Background Our goal was to identify genetic risk factors for cutaneous leishmaniasis (CL) caused by Leishmania braziliensis. Methods Genotyping 2066 CL cases and 2046 controls using Illumina HumanCoreExomeBeadChips provided data for 4 498 586 imputed single-nucleotide variants (SNVs). A genome-wide association study (GWAS) using linear mixed models took account of genetic diversity/ethnicity/admixture. Post-GWAS positional, expression quantitative trait locus (eQTL) and chromatin interaction mapping was performed in Functional Mapping and Annotation (FUMA). Transcriptional data were compared between lesions and normal skin, and cytokines measured using flow cytometry and Bioplex assay. Results Positional mapping identified 32 genomic loci associated with CL, none achieving genome-wide significance (P < 5 × 10−8). Lead SNVs at 23 loci occurred at protein coding or noncoding RNA genes, 15 with eQTLs for functionally relevant cells/tissues and/or showing differential expression in lesions. Of these, the 6 most plausible genetic risk loci were SERPINB10 (P imputed_1000G = 2.67 × 10−6), CRLF3 (P imputed_1000G = 5.12 × 10−6), STX7 (P imputed_1000G = 6.06 × 10−6), KRT80 (P imputed_1000G = 6.58 × 10−6), LAMP3 (P imputed_1000G = 6.54 × 10−6), and IFNG-AS1 (P imputed_1000G = 1.32 × 10−5). LAMP3 (P adjusted = 9.25 × 10−12; +6-fold), STX7 (P adjusted = 7.62 × 10−3; +1.3-fold), and CRLF3 (P adjusted = 9.19 × 10−9; +1.97-fold) were expressed more highly in CL biopsies compared to normal skin; KRT80 (P adjusted = 3.07 × 10−8; −3-fold) was lower. Multiple cis-eQTLs across SERPINB10 mapped to chromatin interaction regions of transcriptional/enhancer activity in neutrophils, monocytes, B cells, and hematopoietic stem cells. Those at IFNG-AS1 mapped to transcriptional/enhancer regions in T, natural killer, and B cells. The percentage of peripheral blood CD3+ T cells making antigen-specific interferon-γ differed significantly by IFNG-AS1 genotype. Conclusions This first GWAS for CL identified multiple genetic risk loci including a novel lead to understanding CL pathogenesis through regulation of interferon-γ by IFNG antisense RNA 1. [ABSTRACT FROM AUTHOR]

Background: Cutaneous leishmaniasis (CL) is characterized by an exaggerated inflammatory response. During pregnancy there is a decreased inflammatory response, and we have shown that pregnant women with CL develop exuberant lesions.Methods: Cytokine production by peripheral blood mononuclear cells and the frequency of cells expressing cytokines in lesions from pregnant and nonpregnant women with CL were evaluated.Results: We observed that CL lesions from pregnant women displayed a more intense cellular infiltrate, associated with an increase in neutrophils and CD4+ cells. While no difference was observed regarding the number of interferon-gamma (IFN-γ)+ cells in lesions from pregnant compared to nonpregnant women with CL, interleukin-10 (IL-10) and IL-4 expression were approximately 3-times higher in lesions in pregnant women. Main sources of IL-4 and IL-10 were CD4+ and CD68+ cells, respectively. Expression of IL-4, but not IFN-γ or IL-10, was positively correlated with the intensity of inflammatory infiltrate in lesions from pregnant women.Conclusions: These results provide evidence of an IL-4-mediated pathology in Leishmania braziliensis-infected pregnant women. These differences in lesion pathogenesis in pregnant and nonpregnant women may open possibilities for new therapies for CL treatment during pregnancy, which are currently lacking. [ABSTRACT FROM AUTHOR]

This study was designed to investigate whether the expression of interleukin 17 (IL-17) is associated with the indeterminate or cardiac clinical forms of Chagas disease and whether IL-17 expression can be correlated with patients' cardiac function. Our results demonstrated that cardiac Chagas patients have a lower intensity of expression of IL-17 by total lymphocytes and lower frequency of circulating T helper 17 cells. Correlative analysis showed that high IL-17 expression was associated with better cardiac function, as determined by left ventricular ejection fraction and left ventricular diastolic diameter values. Therefore, IL-17 expression can be a protective factor to prevent myocardial damage in human Chagas disease. [ABSTRACT FROM AUTHOR]

Interleukin 17 (IL-17) plays a critical role in inflammation and autoimmunity. Very little is known about IL- 17 in protozoa infection. Here, we show that lymphocytes obtained from patients with mucosal leishmaniasis and cutaneous leishmaniasis produce higher levels of IL-17 than do lymphocytes obtained from uninfected control subjects (P < .01). There was a tendency for tissue obtained from patients with mucosal leishmaniasis to contain a higher number of cells expressing IL-17, compared with tissue obtained from patients with cutaneous leishmaniasis, and there was a direct correlation between the number of cells expressing IL-17 and the presence of cellular inflammation at the lesion site (r² = 0.86; P < .001). These data support the role of IL-17 in the pathogenesis of the inflammatory reaction in leishmaniasis. [ABSTRACT FROM AUTHOR]

This study was designed to determine whether the functional IL-10 gene polymorphism -1082G/A is associated with the development of cardiomyopathy in individuals infected with Trypanosoma cruzi and whether interleukin (IL)-10 expression can be correlated with patients' cardiac function. Our results demonstrated that the polymorphic allele, which correlates with lower expression of IL-10, was associated with the development of Chagas disease cardiomyopathy. Accordingly, correlative analysis showed that low IL-10 expression was associated with worse cardiac function, as determined by leftventricular ejection fraction values. Therefore, the IL-10 gene polymorphism and IL-10 expression are important in determining susceptibility to chagasic cardiomyopathy. [ABSTRACT FROM AUTHOR]

Cutaneous leishmaniasis affects millions of people worldwide. After observations of atypical lesions in pregnant women at the health centers of Corte de Pedra, Brazil, 9 years of records were reviewed, and 26 pregnant patients were identified. A retrospective case-control study revealed that lesions in pregnant women were much larger than those in nonpregnant patients in an age- and sex-matched group (mean area, 6.08 cm² vs. 1.46 cm²;P = .008), and many lesions had an exophytic nature. Despite foregoing treatment until after delivery, response to pentavalent antimony therapy was favorable (rate of cure with 1 course of treatment, 85%). High rates of preterm births (10.5%) and stillbirths (10.5%) were reported. Cutaneous leishmaniasis during pregnancy produces distinct lesions and may have adverse fetal effects. [ABSTRACT FROM AUTHOR]

Human T cell lymphotropic virus type 1 (HTLV-1) infection is associated with an exacerbated type 1 immune response and secretion of high levels of proinflammatory cytokines. In contrast, helminthic infection induces a type 2 immune response. In the present study, the cytokine profile in HTLV-1 carriers coinfected with helminths (Strongyloides stercoralis and/or Schistosoma mansoni) was compared with that in HTLV-1 carriers not coinfected with helminths. Levels of interferon (IFN)-γ were higher in HTLV-1 carriers not coinfected with helminths than in HTLV-1 carriers coinfected with helminths (p<.05). The overall frequency of IFN-γ-P<.05 expressing CD8+ and CD4+ cells was decreased in HTLV-1 carriers coinfected with helminths (p<.05). The P<.05 percentage of interleukin (IL)-5- and IL-10-expressing T cells in HTLV-1 carriers coinfected with helminths was higher than that in HTLV-1 carriers not coinfected with helminths (p<.05). Moreover, we found that the prevalence of helminthic infection was 7-fold higher in HTLV-1 carriers than in patients with HTLV-1- associated myelopathy/tropical spastic paraparesis (p<.05). These data show that helminthic infection decreases activation of type 1 cells, which may influence the clinical outcome of HTLV-1 infection. [ABSTRACT FROM AUTHOR]

Whole blood preparations from patients with either the indeterminate (asymptomatic) or cardiac clinical forms of chronic infection were analyzed by flow cytometry using double-labeling to identify subsets of circulating lymphocytes. Several significant differences were demonstrated between the blood lymphocyte profiles of chagaslc patients and non-chagaslc controls. Clear increase in the percentages and actual numbers of double-positive cells of the phenotype CD3/HLA-DR, as well as decrease in the percentage of CD45RA/CD4 and CD45RA/CD8 T cells, Indicate greater numbers of activated T cells circulating in the blood of infected patients. Consistent parallel increases were seen also in the B lymphocyte subset which stained double-positive for CD19/CD5. There were no significant differences in the circulation of these chronic chagaslc patients in the CD4:CD8 ratios. Also, no substantive phenotyplc differences were observed in the lymphocyte populations between the two ends of the clinical spectrum (Indeterminate versus cardiac) in chronic human Chagas' disease. These observations demonstrate that increased levels of activated T cells and CD5 B cells are present in the circulation of people with chronic Chagas' disease. These are cell phenotypes that have been associated in other conditions with autoimmune, polyclonal, and hyperlmmune responses. The specificities of these activated cells and the roles they may play in resistance or pathogenesis during chronic Chagas' disease need now to be determined. [ABSTRACT FROM PUBLISHER]