Filaggrin inhibits generation of CD1a neolipid antigens by house dust mite-derived phospholipase.
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| Abstract |
Atopic dermatitis is a common pruritic skin disease in which barrier dysfunction and cutaneous inflammation contribute to pathogenesis. Mechanisms underlying the associated inflammation are not fully understood, and although Langerhans cells expressing the nonclassical major histocompatibility complex (MHC) family member CD1a are known to be enriched within lesions, their role in clinical disease pathogenesis has not been studied. We observed that house dust mite (HDM) allergen generates neolipid antigens presented 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 in individuals with atopic dermatitis and showed rapid effector function, consistent with antigen-driven maturation. In HDM-challenged human skin, we observed phospholipase A2 (PLA2) activity in vivo. CD1a-reactive T cell activation was dependent on HDM-derived PLA2, and such cells infiltrated the skin after allergen challenge. Moreover, we observed that the skin barrier protein filaggrin, insufficiency of which is associated with atopic skin disease, inhibited PLA2 activity and decreased CD1a-reactive PLA2-generated neolipid-specific T cell activity from skin and blood. The most widely used classification schemes of hypersensitivity suggest that nonpeptide stimulants of T cells act as haptens that modify peptides or proteins; however, our results show that HDM proteins may also generate neolipid antigens that directly activate T cells. These data define PLA2 inhibition as a function of filaggrin, supporting PLA2 inhibition as a therapeutic approach.
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| Authors | Rachael Jarrett, Mariolina Salio, Antonia Lloyd-Lavery, Sumithra Subramaniam, Elvire Bourgeois, Charles Archer, Ka Lun Cheung, Clare Hardman, David Chandler, Maryam Salimi, Danuta Gutowska-Owsiak, Jorge Bernardino de la Serna, Padraic G Fallon, Helen Jolin, Andrew Mckenzie, Andrzej Dziembowski, Ewa Izabela Podobas, Wojciech Bal, David Johnson, D Branch Moody, Vincenzo Cerundolo, Graham Ogg |
| Journal | Science translational medicine (Sci Transl Med) Vol. 8 Issue 325 Pg. 325ra18 (Feb 10 2016) ISSN: 1946-6242 [Electronic] United States |
| PMID | 26865566 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't) |
| Copyright | Copyright © 2016, American Association for the Advancement of Science. |
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