PD-L1 May Mediate T-Cell Exhaustion in a Case of Early Diffuse Leishmaniasis Caused by Leishmania (L.) amazonensis
PD-L1 May Mediate T-Cell Exhaustion in a Case of Early Diffuse Leishmaniasis Caused by Leishmania (L.) amazonensis
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DOI：
10.3389/fimmu.2018.01021
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发表时间：
2018-05-11
影响因子：
7.3
通讯作者：
Ribeiro Sampaio, Raimunda Nonata
中科院分区：
文献类型：
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作者：
Barroso, Daniel Holanda;Couto Falcao, Sarah De Athayde;Ribeiro Sampaio, Raimunda Nonata
简介：弥漫性皮肤利什曼病（DCL）是一种罕见的疾病形式与利什曼原虫（L。）产于南美洲的亚马逊河流域。它代表了美国皮肤利什曼病的“无反应性”极，其对治疗的抵抗力的解释仍然难以捉摸。我们的目的是研究一些可能的免疫学机制参与差DCL治疗反应通过评估一些细胞表面分子从患者DCL通过流式细胞仪。病例介绍：一个65岁的DCL患者谁最初没有响应的标准治疗疾病显示空泡化的巨噬细胞充满无鞭毛体病变活检，和L。（L.）经ITS 1 PCR扩增鉴定为亚马逊亚种。利什曼原虫皮肤试验和间接免疫荧光分析显示阴性结果。在治疗几个月后，当患者没有出现病变时，收集患者的外周血。用可溶性L.（L.）亚马逊抗原（SLA）。使用流式细胞术分析细胞中的细胞死亡、表面分子和细胞内分子，例如IFN-γ和颗粒酶B。表面标志物的分析显示，在用SLA再刺激的单核细胞中，抑制性分子程序性死亡配体1（PD-L1）的表达增加（约65%），而阴性对照对PD-L1呈35%阳性。相反，与阴性对照相比，我们观察到CD 4（+）IFN-γ（+）T细胞（8.32 vs 1.7%）和CD 8（+）IFN-γ（+）T细胞（14% vs 1%）减少。我们还观察到颗粒酶B水平在CD 8（+）T细胞中的相关下降，从阴性对照的31%下降到SLA再刺激后的5%.Conclusion：利什曼原虫抗原刺激后PD-L1抑制通路的功能失调激活以及IFN-γ和颗粒酶B产生细胞水平的降低可能与DCL患者对标准药物治疗的无反应性密切相关。
Introduction: Diffuse cutaneous leishmaniasis (DCL) is a rare disease form associated with Leishmania (L.) amazonensis in South America. It represents the "anergic" pole of American Tegumentary Leishmaniasis, and the explanation for its resistance to treatment remains elusive. We aimed to study some possible immunological mechanisms involved in the poor DCL treatment response by evaluating some cell surface molecules obtained from a patient with DCL by flow cytometry.Case presentation: A 65-year-old DCL patient who initially failed to respond to the standard treatment for the disease showed vacuolated macrophages filled with amastigotes in lesion biopsy, and L. (L.) amazonensis was identified through ITS1PCR amplification. The Leishmania skin test and indirect immunofluorescence analysis revealed negative results. Peripheral blood from the patient was collected after a few months of treatment, when the patient presented with no lesion. Peripheral blood mononuclear cells were analyzed ex vivo and in vitro after 48 h of stimulation with soluble L. (L.) amazonensis antigen (SLA). Cell death, surface molecules, and intracellular molecules, such as IFN-gamma and granzyme B, were analyzed in the cells using flow cytometry. Analysis of the surface markers showed an increased expression of the inhibitory molecule programmed death ligand 1 (PD-L1) in the monocytes restimulated with SLA (approximately 65%), whereas the negative controls were 35% positive for PD-L1. Conversely, compared with the negative controls, we observed a decrease in CD4(+) IFN-gamma(+) T cells (8.32 versus 1.7%) and CD8(+) IFN-gamma(+) T cells (14% versus 1%). We also observed a relevant decrease in the granzyme B levels in the CD8(+) T cells, from 31% in the negative controls to 5% after SLA restimulation.Conclusion: The dysfunctional activation of PD-L1 inhibitory pathway after Leishmania antigen stimulation and reduced levels of IFN-gamma and granzyme B-producing cells could be closely related to unresponssiveness to standard drug treatment of DCL patient.