title: Filaggrin inhibits generation of CD1a neolipid antigens by house dust mite-derived phospholipase.
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.
authors: MRC Human Immunology Unit, NIHR Biomedical Research Centre, Radcliffe Department of Medicine, University of Oxford, UK.
authors: Rachael
authors: R
authors: Jarrett
authors: MRC Human Immunology Unit, NIHR Biomedical Research Centre, Radcliffe Department of Medicine, University of Oxford, UK.
authors: Mariolina
authors: M
authors: Salio
authors: MRC Human Immunology Unit, NIHR Biomedical Research Centre, Radcliffe Department of Medicine, University of Oxford, UK.
authors: Antonia
authors: A
authors: Lloyd-Lavery
authors: MRC Human Immunology Unit, NIHR Biomedical Research Centre, Radcliffe Department of Medicine, University of Oxford, UK.
authors: Sumithra
authors: S
authors: Subramaniam
authors: Division of Rheumatology, Immunology and Allergy, Department of Medicine Brigham and Women's Hospital, Harvard Medical School, 1 Jimmy Fund Way, Boston, Massachusetts, 02114, USA.
authors: Elvire
authors: E
authors: Bourgeois
authors: MRC Human Immunology Unit, NIHR Biomedical Research Centre, Radcliffe Department of Medicine, University of Oxford, UK.
authors: Charles
authors: C
authors: Archer
authors: MRC Human Immunology Unit, NIHR Biomedical Research Centre, Radcliffe Department of Medicine, University of Oxford, UK.
authors: Ka Lun
authors: KL
authors: Cheung
authors: MRC Human Immunology Unit, NIHR Biomedical Research Centre, Radcliffe Department of Medicine, University of Oxford, UK.
authors: Clare
authors: C
authors: Hardman
authors: MRC Human Immunology Unit, NIHR Biomedical Research Centre, Radcliffe Department of Medicine, University of Oxford, UK.
authors: David
authors: D
authors: Chandler
authors: MRC Human Immunology Unit, NIHR Biomedical Research Centre, Radcliffe Department of Medicine, University of Oxford, UK.
authors: Maryam
authors: M
authors: Salimi
authors: MRC Human Immunology Unit, NIHR Biomedical Research Centre, Radcliffe Department of Medicine, University of Oxford, UK.
authors: Danuta
authors: D
authors: Gutowska-Owsiak
authors: MRC Human Immunology Unit, NIHR Biomedical Research Centre, Radcliffe Department of Medicine, University of Oxford, UK.
authors: Jorge Bernardino
authors: JB
authors: de la Serna
authors: Trinity Biomedical Sciences Institute, Trinity College, Dublin, Ireland.|Institute of Molecular Medicine, St James's Hospital, Dublin, Ireland.|National Children's Research Centre, Our Lady's Childrens Hospital, Dublin, Ireland.
authors: Padraic G
authors: PG
authors: Fallon
authors: MRC Laboratory of Molecular Biology, Cambridge, UK.
authors: Helen
authors: H
authors: Jolin
authors: MRC Laboratory of Molecular Biology, Cambridge, UK.
authors: Andrew
authors: A
authors: Mckenzie
authors: Institute of Biochemistry and Biophysics Polish Academy of Sciences, Warsaw, Poland.
authors: Andrzej
authors: A
authors: Dziembowski
authors: Institute of Biochemistry and Biophysics Polish Academy of Sciences, Warsaw, Poland.
authors: Ewa Izabela
authors: EI
authors: Podobas
authors: Institute of Biochemistry and Biophysics Polish Academy of Sciences, Warsaw, Poland.
authors: Wojciech
authors: W
authors: Bal
authors: Department of Plastic and Reconstructive Surgery, John Radcliffe Hospital, Oxford University Hospitals NHS Trust, UK.
authors: David
authors: D
authors: Johnson
authors: Division of Rheumatology, Immunology and Allergy, Department of Medicine Brigham and Women's Hospital, Harvard Medical School, 1 Jimmy Fund Way, Boston, Massachusetts, 02114, USA.
authors: D Branch
authors: DB
authors: Moody
authors: MRC Human Immunology Unit, NIHR Biomedical Research Centre, Radcliffe Department of Medicine, University of Oxford, UK.
authors: Vincenzo
authors: V
authors: Cerundolo
authors: MRC Human Immunology Unit, NIHR Biomedical Research Centre, Radcliffe Department of Medicine, University of Oxford, UK.
authors: Graham
authors: G
authors: Ogg
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D018949:Antigens, CD1 / Q000378:metabolism*; D002469:Cell Separation; D016207:Cytokines / Q000378:metabolism; D003876:Dermatitis, Atopic / Q000097:blood / Q000276:immunology; D000091344:Filaggrin Proteins; D054513:Group IV Phospholipases A2 / Q000378:metabolism*; D006801:Humans; D007381:Intermediate Filament Proteins / Q000494:pharmacology*; D020014:K562 Cells; D008875:Middle Aged; D039981:Pyroglyphidae / Q000187:drug effects / Q000201:enzymology*; D012867:Skin / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D055815:Young Adult
chemical_list: D018949:Antigens, CD1; C419393:CD1a antigen; D016207:Cytokines; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; D054513:Group IV Phospholipases A2