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Filaggrin inhibits generation of CD1a neolipid antigens by house dust mite-derived phospholipase.

Jarrett, Rachael and Salio, Mariolina and Lloyd-Lavery, Antonia and Subramaniam, Sumithra and Bourgeois, Elvire and Archer, Charles and Cheung, Ka Lun and Hardman, Clare and Chandler, David and Salimi, Mariam and Gutowska-Owsiak, Danuta and Bernardino de la Serna, Jorge and Fallon, Padraic G and Jolin, Helen and Mckenzie, Andrew and Podobas, Ewa Izabela and Dziembowski, Andrzej and Bal, Wojciech and Johnson, David and Moody, D Branch and Cerundolo, Vincenzo and Ogg, Graham (2016) Filaggrin inhibits generation of CD1a neolipid antigens by house dust mite-derived phospholipase. Science Translational Medicine, 8 (325). pp. 1-12. ISSN 1946-6242


Official URL: http://stm.sciencemag.org/content/8/325/325ra18.sh...


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.

Item Type:Article
Subjects:R Medicine > RL Dermatology
Divisions:Department of Biophysics
ID Code:1285
Deposited By: PhD EI Podobas
Deposited On:02 Jan 2017 15:48
Last Modified:02 Jan 2017 15:48

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