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Broken Skin Barrier Is a Key Driver of Atopic Eczema, Asthma and Allergy

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Broken Skin Barrier Is a Key Driver of Atopic Eczema, Asthma and Allergy Broken skin barrier is a key driver of atopic eczema, asthma and allergy Irwin McLean Centre for Dermatology & Genetic Medicine Division of Molecular Medicine University of Dundee Scotland Skin – the largest organ The epidermis – a super-tough, self-renewing tissue Stratum corneum Epidermis Dermis Keratinocytes Skin barrier function Pathogens Allergens Irritants Skin barrier Stratum corneum H2O The Filaggrin gene 38: 337-342, March 2006 From Ichthyosis Vulgaris… 38:441-446, April 2006 …to Atopic Eczema, Asthma etc 39:650-654, April 2007 Ichthyosis vulgaris • Most common monogenic skin disorder • Dry, scaly skin, worse in winter/dry climate • Hyperlinearity of palms/soles; keratosis pilaris • ~1% of the UK population have full form • >10% have a sub-clinical form • Evidence for defect involving filaggrin – Biochemistry – Genetic mapping • Large repetitive gene • Difficult to sequence • Many IV patients have eczema! Atopic dermatitis • Atopic dermatitis (= “eczema”) • Affects >20% of children in developed nations • Incidence has increased in recent decades • Often accompanied by other allergic diseases (atopic disease, atopy) – Eczema – Food allergies (30%) – Asthma (50%) – Rhinitis (hay fever; 70%) • “Atopic march” • Healthcare burden US$ billlions Filaggrin protein Profilaggrin 10-12 full filaggrin repeats N C 2x partial filaggrin repeats S100 domain B domain Unique C-terminus Filaggrin - filament aggregating protein Epidermal filaggrin staining Keratin aggregation Processed Filaggrin (37 kDa) Proteolysis Profilaggrin (>400 kDa) Keratin filaments “Natural moisturizing factor” Epidermal filaggrin staining Hygroscopic amino acids Further proteolysis Chemically modified filaggrin Peptidyl arginine deiminases Keratin aggregation Filaggrin – a multi-functional skin barrier protein H2O RETENTION NMF pH UV PROTECTION Natural Moisturising Factor ANTI-MICROBIAL BARRIER FORMATION Filaggrin INERT Profilaggrin FLG is a large, highly repetitive gene on 1q21.3 FLG gene 15 bp 153 bp 13 kb (or variant sizes of 14 kb or 15 kb) FLG Protein domains encoded 10-12 near-perfect 324 amino acid repeats 2 imperfect repeats Irvine, McLean,Aileen Leung Sandilands, NEJM Frances 2011 Smith, Toshifumi Nomura, Huijia Chen Irvine, McLean, Leung NEJM 2011 Alan Irvine, Irwin McLean, Donald Leung, NEJM (2011) Filaggrin function and inherited deficiency “Normal” ~89% UK population 1x filaggrin mutation ~10% UK population ~8x risk eczema 2x filaggrin mutations ~1% UK population ~150x risk eczema 10 repeats 2x copies = 1.7x risk of AD 11 repeats 12 repeats2x copies = 0.6x risk of AD Filaggrin upregulation therapy Most filaggrin-related eczema patients carry a single null mutation FLG FLG Drug Discovery in Dundee Cutaneous Drug Discovery Portfolio: CDDP Alan Mike Paul Irwin Fairlamb Ferguson Wyatt McLean Target Discovery Validation Drug Lead Partnering selection Potential Informatics Proof of Fully Industrial Clinically Drug Target and concept validated partners and useable functional Genetic/chemi molecular PPP partners therapeutics genomics cal/animal data model package Filaggrin expression in keratinocytes treated with chemical library Robyn Hickerson, Pam Robertson Human filaggrin–luciferase transgenic mice Xenogen IVIS 200 live animal imaging Luciferase IMF footpad Human filaggrin–luciferase transgenic mice Untreated Treated Vehicle only Vehicle plus Compound Skin barrier function Pathogens Allergens Irritants Skin barrier Stratum corneum H2O Impaired skin barrier function Pathogens Allergens Irritants Stratum corneum H2O Allergic immune response Eczema Thanks Alan Irvine MD Thanks .
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