Filaggrin inhibits generation of CD1a neolipid antigens by house dust mite-derived phospholipase.
Filaggrin inhibits generation of CD1a neolipid antigens by house dust mite-derived phospholipase.
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DOI：
10.1126/scitranslmed.aad6833
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发表时间：
2016-02-10
影响因子：
17.1
通讯作者：
Ogg G
中科院分区：
文献类型：
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作者：
Jarrett R;Salio M;Lloyd-Lavery A;Subramaniam S;Bourgeois E;Archer C;Cheung KL;Hardman C;Chandler D;Salimi M;Gutowska-Owsiak D;de la Serna JB;Fallon PG;Jolin H;Mckenzie A;Dziembowski A;Podobas EI;Bal W;Johnson D;Moody DB;Cerundolo V;Ogg G
特应性皮炎是一种常见的皮炎性皮肤病，其发病机制与屏障功能障碍和皮肤炎症有关。相关炎症的潜在机制尚未完全了解，虽然已知表达CD1a的朗格汉斯细胞在病变内富集，但尚未研究其在临床疾病发病机制中的作用。在这里，我们观察到，屋尘螨（HDM）产生新脂质抗原，由CD1a呈递给受影响个体的血液和皮肤病变中的T细胞。HDM反应性CD1a反应性T细胞在出生后频率增加，并显示出快速的效应功能，与抗原驱动的成熟一致。为了确定潜在的机制，我们分析了HDM激发的人皮肤，并观察了体内变应原衍生的磷脂酶（PLA2）活性。CD1a反应性T细胞活化依赖于HDM衍生的PLA2，并且这些细胞在过敏原激发后浸润皮肤。聚丝蛋白不足与特应性皮炎有关，我们观察到聚丝蛋白抑制PLA2活性，并抑制皮肤和血液中CD1a反应性PLA2产生的新脂质特异性T细胞活性。最广泛使用的超敏反应分类方案，如Gell和Coombs，是基于T细胞的非肽刺激物作为修饰肽或蛋白质的半抗原的想法。然而，我们的结果指出了一个更广泛的模型，该模型不抑制半抗原化，而是显示HDM蛋白产生直接激活T细胞的新脂质抗原。具体而言，这些数据确定了特应性皮肤炎症的途径，其中屋尘螨衍生的磷脂酶A2产生抗原性新脂质以呈递给CD 1a反应性T细胞，并将PLA2抑制定义为丝聚蛋白的函数，支持PLA2抑制作为治疗方法。
Atopic dermatitis is a common pruritic skin disease in which barrier dysfunction and cutaneous inflammation play a role in pathogenesis. Mechanisms underlying the associated inflammation are not fully understood, and while CD1a-expressing Langerhans cells are known to be enriched within lesions, their role in clinical disease pathogenesis has not been studied. Here we observed that house dust mite (HDM) generates neolipid antigens for presentation by CD1a to T cells in the blood and skin lesions of affected individuals. HDM-responsive CD1a-reactive T cells increased in frequency after birth and showed rapid effector function, consistent with antigen-driven maturation. To define the underlying mechanisms, we analyzed HDM-challenged human skin and observed allergen-derived phospholipase (PLA2) activity in vivo. CD1a-reactive T cell activation was dependent on HDM-derived PLA2 and such cells infiltrated the skin after allergen challenge. Filaggrin insufficiency is associated with atopic dermatitis, and we observed that filaggrin inhibits PLA2 activity and inhibits CD1a-reactive PLA2-generated neolipid-specific T cell activity from skin and blood. The most widely used classification schemes of hypersensitivity, such as Gell and Coombs are predicated on the idea that non-peptide stimulants of T cells act as haptens that modify peptides or proteins. However our results point to a broader model that does not posit haptenation, but instead shows that HDM proteins generate neolipid antigens which directly activate T cells. Specifically, the data identify a pathway of atopic skin inflammation, in which house dust mite-derived phospholipase A2 generates antigenic neolipids for presentation to CD1a-reactive T cells, and define PLA2 inhibition as a function of filaggrin, supporting PLA2 inhibition as a therapeutic approach.