Search

Aims: CD8 + T cells are important in mediating protective responses to intracellular pathogens. However, an uncontrolled response may lead to pathology. The role of CD8 + T cells in different clinical manifestations of human leishmaniasis is controversial and poorly understood. We aim to study the response of CD8 + T cells to the first exposure to different strains of Leishmania, seeking to correlate these findings with clinical manifestations of disease., Methods and Results: We have evaluated the expression of granzyme A, inflammatory and anti-inflammatory cytokines, as well as CTLA-4 by human naïve CD8 + T cells exposed to Leishmania braziliensis and two different strains of Leishmania infantum in vitro. We observed that while exposure to L braziliensis induced an inflammatory profile, as measured by the expression of granzyme A, IFN-gamma and IL-17, as well as a higher IFN/IL-10 ratio, exposure to L infantum led to a regulatory profile, as measured by lower IFN/IL-10 ratio and higher expression of CTLA-4., Conclusion: These results may help explain why patients with the visceral clinical form present a weaker cellular response and, consequently, a worse outcome of the disease. The use of CTLA-4 checkpoint inhibitors may emerge as a potential immunotherapy to ameliorate the immune response in visceral leishmaniasis patients., (© 2019 John Wiley & Sons Ltd.)

Recent publications by Zaph et al. have highlighted the distinct requirements for generating and maintaining different subpopulations of CD4(+) memory T cells after infection with Leishmania major in mice. These studies have advanced the understanding of the nature of long-lasting immunity to Leishmania and, when considered within the context of previous work on both murine and human leishmaniasis, will aid the design of effective vaccines.

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]

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]

Abstract: Leishmaniasis is an important parasitic disease affecting millions worldwide. In attempts to understand the clinical relevance of immunological measurements as determined using flow cytometry, several immunological phenotypes were determined for a group of well defined human leishmaniasis patients and correlated with clinical measurements of the disease (Montenegro skin test (MST) and lesion area). The analysis demonstrated a positive correlation between the MST size and the frequency of ex vivo recent activated CD4+ T cells. In contrast, higher frequencies of recent activated CD8+ T cells were correlated with a smaller MST size. Moreover, a positive correlation was observed between the lesion total area and the frequency of activated CD69+ (ex vivo) and CD40L+ (cultured with Leishmania soluble antigen (SLA)) T lymphocytes. Finally, larger lesions were also correlated with a higher frequency of SLA specific inflammatory cytokine (IFN-γ or TNF-α) producing lymphocytes. These studies demonstrate that immunological markers are correlated with clinical indicators of human leishmaniasis and serve to better understand the evolution of this important parasitic disease. [Copyright &y& Elsevier]

Aims: CD8+ T cells are important in mediating protective responses to intracellular pathogens. However, an uncontrolled response may lead to pathology. The role of CD8+ T cells in different clinical manifestations of human leishmaniasis is controversial and poorly understood. We aim to study the response of CD8+ T cells to the first exposure to different strains of Leishmania, seeking to correlate these findings with clinical manifestations of disease. Methods and results: We have evaluated the expression of granzyme A, inflammatory and anti‐inflammatory cytokines, as well as CTLA‐4 by human naïve CD8+ T cells exposed to Leishmania braziliensis and two different strains of Leishmania infantum in vitro. We observed that while exposure to L braziliensis induced an inflammatory profile, as measured by the expression of granzyme A, IFN‐gamma and IL‐17, as well as a higher IFN/IL‐10 ratio, exposure to L infantum led to a regulatory profile, as measured by lower IFN/IL‐10 ratio and higher expression of CTLA‐4. Conclusion: These results may help explain why patients with the visceral clinical form present a weaker cellular response and, consequently, a worse outcome of the disease. The use of CTLA‐4 checkpoint inhibitors may emerge as a potential immunotherapy to ameliorate the immune response in visceral leishmaniasis patients. [ABSTRACT FROM AUTHOR]

Recent publications by Zaph et al. have highlighted the distinct requirements for generating and maintaining different subpopulations of CD4+ memory T cells after infection with Leishmania major in mice. These studies have advanced the understanding of the nature of long-lasting immunity to Leishmania and, when considered within the context of previous work on both murine and human leishmaniasis, will aid the design of effective vaccines. [Copyright &y& Elsevier]

Adhesion molecules play a crucial role in cell migration and recruitment. Expression of adhesion molecules that preferentially address cells to inflammatory sites is a critical event in the formation and maintenance of leishmaniasis lesions. In this work, we analyzed the expression of CD11a, CD11b and CD62L, adhesion molecules involved in cell activation and circulation, in CD4+ and CD8+ T cells from peripheral blood and lymph nodes of patients with early cutaneous leishmaniasis. The percentage of expression of CD62L, CD11a and CD11b in total lymphocytes was lower in lymph nodes as compared to peripheral blood. Moreover, differences in adhesion molecule expression between blood and lymph nodes were more striking in CD4+ than CD8+ T cells. Stimulation of PBMC from leishmaniasis patients with soluble Leishmania antigens (SLA) lead to the expansion of CD4+CD62Lhigh cells, CD4+CD11b+ cells and to an increase in the intensity of expression of CD11a in CD4+, but not CD8+ T cells. Our data suggest that early activation events that occur in the lymph nodes of patients recently infected with Leishmania lead to changes in T cell adhesion molecule expression, favoring migration to the periphery and increasing the likelihood of further recruitment to lesion sites. [Copyright &y& Elsevier]