Urinary Peptides As a Novel Source of T Cell Allergen Epitopes.
Urinary Peptides As a Novel Source of T Cell Allergen Epitopes.
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DOI：
10.3389/fimmu.2018.00886
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发表时间：
2018
影响因子：
7.3
通讯作者：
Sette A
中科院分区：
文献类型：
--
作者：
da Silva Antunes R;Pham J;McMurtrey C;Hildebrand WH;Phillips E;Mallal S;Sidney J;Busse P;Peters B;Schulten V;Sette A
实验室工作人员和市中心儿童的老鼠过敏与过敏性鼻炎和哮喘有关，引起了严重的公共卫生问题。尿液是老鼠过敏原的主要来源，因为老鼠把尿液喷到周围的环境中，蛋白质在那里干涸，随着灰尘颗粒在空气中传播。在这里，我们测试了小鼠尿液中丰富的寡肽是否可能有助于小鼠过敏性T细胞反应。通过对小鼠尿液低分子量滤液（LoMo）的质谱分析，检测到1300多种不同的寡肽。翻译后修饰肽是常见的，几乎占总肽的一半。在小鼠过敏供体中鉴定了由225个不同寡肽组成的13个残基或更多大小的库，以测试其引发T细胞反应的能力。在体外刺激PBMCs 14天后，我们在95%的供体中检测到针对116种不同肽的反应，这些肽主要与Th2细胞因子（IL-5）相关。来自非尿相关蛋白（如表皮生长因子、胶原蛋白和β -珠蛋白）的肽反应最高（分别占总反应的15.9%、9.1和8.1%）。来自主要尿蛋白（MUPs）、肾雄激素调节蛋白（KAP）和尿调蛋白的肽是来自肾脏或尿液相关来源的主要T细胞靶点。对4-1BB表达细胞的进一步体外富集分析表明，LoMo池特异性T细胞的反应性可以在小鼠过敏体中直接检测到，而在非过敏供体中则无法检测到。进一步的细胞分析显示，应答细胞具有骨记忆T细胞表型，并证实了它们的Th2极化。总之，这些数据表明，小鼠尿源性寡肽是小鼠过敏相关T细胞反应的新靶点，这可能有助于小鼠过敏的免疫病理机制。
Mouse allergy in both laboratory workers and in inner-city children is associated with allergic rhinitis and asthma, posing a serious public health concern. Urine is a major source of mouse allergens, as mice spray urine onto their surroundings, where the proteins dry up and become airborne on dust particles. Here, we tested whether oligopeptides that are abundant in mouse urine may contribute to mouse allergic T cell response. Over 1,300 distinct oligopeptides were detected by mass spectrometry analysis of the low molecular weight filtrate fraction of mouse urine (LoMo). Posttranslationally modified peptides were common, accounting for almost half of total peptides. A pool consisting of 225 unique oligopeptides of 13 residues or more in size identified within was tested for its capacity to elicit T cell reactivity in mouse allergic donors. Following 14-day in vitro stimulation of PBMCs, we detected responses in about 95% of donors tested, directed against 116 distinct peptides, predominantly associated with Th2 cytokines (IL-5). Peptides from non-urine related proteins such as epidermal growth factor, collagen, and Beta-globin accounted for the highest response (15.9, 9.1, and 8.1% of the total response, respectively). Peptides derived from major urinary proteins (MUPs), kidney androgen-regulated protein (KAP), and uromodulin were the main T cell targets from kidney or urine related sources. Further ex vivo analysis of enrichment of 4-1BB expressing cells demonstrated that LoMo pool-specific T cell reactivity can be detected directly ex vivo in mouse allergic but not in non-allergic donors. Further cytometric analysis of responding cells revealed a bone fide memory T cell phenotype and confirmed their Th2 polarization. Overall, these data suggest that mouse urine-derived oligopeptides are a novel target for mouse allergy-associated T cell responses, which may contribute to immunopathological mechanisms in mouse allergy.