IFN-γ/IL-10 ratios and ZCL development.

BackgroundThis study aimed to define immunological markers of exposure to L. major parasites and identify correlates of protection against infection.MethodsWe analyzed a cohort of 790 individuals at risk of developing ZCL living in endemic areas with varying L. major infection prevalence. One area had a high infection prevalence indicated by high proportions of leishmanin skin test (LST) positive subjects, while the other areas were recent foci with lower infection prevalence. Blood samples were collected before the transmission season to measure Interferon gamma (IFN-γ), Interleukin 10 (IL-10), and Granzyme B (GrB) levels in response to parasite stimulation in peripheral blood mononuclear cells.A one-year follow-up period involved active detection of new ZCL cases to estimate disease incidence after a transmission season and identify immune correlates of protection.ResultsThe study population showed heterogeneity in parasite contact, evident from specific scars and/or positive LST results, significantly higher in the old focus compared to recent foci. IFN-γ and GrB were markers of parasite exposure and reliable indicators of immunity to L. major. Positive correlations were observed between IFN-γ/IL-10 and GrB/IL-10 ratios and LST results.Unexpectedly, only 29 new ZCL cases (4%) appeared after a transmission season, with 27 cases reported in recent foci and 2 in the oldest focus. Our findings indicate that individuals in L. major endemic areas are likely to develop ZCL regardless of their LST status.We showed that high pre-transmission season levels of IFN-γ and GrB produced by PBMC, along with a high IFN-γ/IL-10 ratio, were associated with protection.ConclusionThis study on a large cohort at risk of ZCL confirmed IFN-γ and GrB as protective factors against the disease. A high IFN-γ/IL-10 ratio, but not GrB/IL-10 ratio was associated with resistance. These results are valuable for developing and evaluating of a vaccine against human leishmaniasis.**背景** 本研究旨在明确暴露于硕大利什曼原虫（L. major）的免疫学标志物，并鉴定感染防护相关关联因素。 **方法** 本研究对790名存在罹患兽源性皮肤利什曼病（ZCL）风险的个体开展队列分析，研究对象均居住在硕大利什曼原虫感染流行率存在差异的流行区域：其中一个疫源地的利什曼素皮肤试验（LST）阳性率较高，提示当地感染流行率偏高；其余区域为新发疫源地，感染流行率相对较低。于传播季开始前采集血液样本，对外周血单个核细胞（PBMC）在寄生虫刺激下产生的γ干扰素（IFN-γ）、白细胞介素10（IL-10）及颗粒酶B（GrB）水平进行检测。本研究设置为期1年的随访周期，通过主动监测新发皮肤利什曼病病例，以估算传播季结束后的疾病发病率，并明确与防护相关的免疫关联因素。 **结果** 研究人群的寄生虫接触暴露存在异质性，该异质性可通过特异性瘢痕及/或利什曼素皮肤试验阳性结果体现，且老疫源地的暴露异质性显著高于新疫源地。γ干扰素与颗粒酶B可作为寄生虫暴露标志物，同时也是硕大利什曼原虫感染免疫的可靠指标。γ干扰素/白细胞介素10比值、颗粒酶B/白细胞介素10比值均与利什曼素皮肤试验结果呈显著正相关。出乎意料的是，本轮传播季结束后仅发现29例新发皮肤利什曼病病例（占比4%），其中27例来自新疫源地，仅2例来自最古老的疫源地。本研究结果显示，无论利什曼素皮肤试验结果如何，硕大利什曼原虫流行区居民均有可能罹患皮肤利什曼病。我们发现，外周血单个核细胞在传播季前产生的高浓度γ干扰素与颗粒酶B，以及较高的γ干扰素/白细胞介素10比值，均与疾病防护效应相关。 **结论** 本针对大型皮肤利什曼病风险队列的研究证实，γ干扰素与颗粒酶B是该疾病的防护因素；较高的γ干扰素/白细胞介素10比值与疾病抵抗力相关，而颗粒酶B/白细胞介素10比值则无此关联。上述研究结果对于研发与评估人类利什曼病疫苗具有重要应用价值。