Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis
Alexandros Onoufriadis,Michael A. Simpson,Andrew Pink,Paola Di Meglio,Catherine H. Smith,Venu Pullabhatla,Jo Knight,Sarah L. Spain,Frank O. Nestle,A. David Burden,Francesca Capon,Richard C. Trembath,Jonathan Barker +12 more
TLDR
Findings suggest loss of function of IL36RN as the genetic basis of GPP and implicate innate immune dysregulation in this severe episodic inflammatory disease, thereby highlighting IL-1 signaling as a potential target for therapeutic intervention.Abstract:
Generalized pustular psoriasis (GPP) is a rare and yet potentially lethal clinical variant of psoriasis, characterized by the formation of sterile cutaneous pustules, neutrophilia, fever and features of systemic inflammation. We sequenced the exomes of five unrelated individuals diagnosed with GPP. Nonsynonymous, splice-site, insertion, and deletion variants with an estimated population frequency of T (p.Ser113Leu) missense substitution of IL36RN was identified in two individuals, with a third subject found to be a compound heterozygote for c.338C>T (p.Ser113Leu) and a c.142C>T (p.Arg48Trp) missense substitution. IL36RN (previously known as IL1F5) encodes an IL-1 family receptor antagonist, which opposes the activity of the IL-36A and IL-36G innate cytokines. Homology searches revealed that GPP mutations alter evolutionarily conserved residues. Homozygosity for the c.338C>T (p.Ser113Leu) variant is associated with an elevated proinflammatory response following ex vivo stimulation with IL36A. These findings suggest loss of function of IL36RN as the genetic basis of GPP and implicate innate immune dysregulation in this severe episodic inflammatory disease, thereby highlighting IL-1 signaling as a potential target for therapeutic intervention.read more
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Journal ArticleDOI
Immunology of Psoriasis
TL;DR: The genetic background of psoriasis and its relationship to immune function, specifically genetic mutations, key PSORS loci, single nucleotide polymorphisms, and the skin transcriptome are discussed.
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Overview of the IL-1 family in innate inflammation and acquired immunity.
TL;DR: Although the inflammatory properties of the IL‐1 family dominate in innate immunity, IL‐2 family member can play a role in acquired immunity and this overview is a condensed update.
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Psoriasis Pathogenesis and Treatment.
Adriana Rendon,Knut Schäkel +1 more
TL;DR: The role of genetics, associated epigenetic mechanisms, and the interaction of the skin flora in the pathophysiology of psoriasis is described, which includes a comprehensive review of well-established widely available therapies and novel targeted drugs.
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Francisco A. Bonilla,David A. Khan,Zuhair K. Ballas,Javier Chinen,Michael M. Frank,Joyce T. Hsu,Michael D. Keller,Lisa Kobrynski,Hirsh D. Komarow,Bruce Mazer,Robert P. Nelson,Jordan S. Orange,John M. Routes,William T. Shearer,Ricardo U. Sorensen,James W. Verbsky,David I. Bernstein,Joann Blessing-Moore,David Lang,Richard A. Nicklas,John Oppenheimer,Jay M Portnoy,Christopher Randolph,Diane E. Schuller,Sheldon L. Spector,S. Tilles,Dana V. Wallace,D.A. Khan +27 more
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The immunogenetics of Psoriasis: A comprehensive review.
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