Rare Pathogenic Variants in IL36RN Underlie a Spectrum of Psoriasis-Associated Pustular Phenotypes

Setta-Kaffetzi, Niovi; Navarini, Alexander A.; Patel, Varsha M.; Pullabhatla, Venu; Pink, Andrew E.; Choon, Siew Eng; Allen, Michael; Burden, A. David; Griffiths, C.E.M.; Seyger, M.M.B.; Kirby, Brian; Trembath, Richard C.; Simpson, Michael A.; Smith, Catherine; Capon, Francesca; Barker, Jonathan

doi:10.1038/jid.2012.490

Cited by 158 publications

(134 citation statements)

References 7 publications

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“…After the initial reports of missense mutations in IL36RN (the gene coding for IL-36Ra) leading to generalized pustular psoriasis (17,18), several other missense mutations have been identified (38)(39)(40)(41)(42)(43). Altogether, 11 missense mutations of nine different residues have been reported to date (Table I).…”

Section: Il-36ra Mutations Associated With Generalized Pustular Psorimentioning

confidence: 99%

Molecular Determinants of Agonist and Antagonist Signaling through the IL-36 Receptor

Guenther

Sundberg

2014

The Journal of Immunology

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The IL-1 family consists of 11 cytokines that control a complex network of proinflammatory signals critical for regulating immune responses to infections. They also play a central role in numerous chronic inflammatory disorders. Accordingly, inhibiting the activities of these cytokines is an important therapeutic strategy for treating autoimmune diseases and lymphomas. Agonist cytokines in the IL-1 family activate signaling by binding their cognate receptor and then recruiting a receptor accessory protein. Conversely, antagonist cytokines bind their cognate receptor but prohibit recruitment of receptor accessory protein, which precludes functional signaling complexes. The IL-36 subfamily of cytokines is the most diverse, including three agonists and at least one antagonist, and is the least well-characterized group within this family. Signaling through the IL-36 receptor directly stimulates dendritic cells and primes naive CD4 T cells for Th1 responses. Appropriately balanced IL-36 signaling is a critical determinant of skin and lung health. IL-36 signaling has been presumed to function analogously to IL-1 signaling. In this study, we have defined molecular determinants of agonist and antagonist signaling through the IL-36 receptor. We present the crystal structure of IL-36γ, which, to our knowledge, is the first reported structure of an IL-36 agonist. Using this structure as a guide, we designed a comprehensive series of IL-36 agonist/antagonist chimeric proteins for which we measured binding to the IL-36 receptor/IL-1 receptor accessory protein complex and functional activation and inhibition of signaling. Our data reveal how the fine specificity of IL-36 signaling is distinct from that of IL-1.

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Section: Il-36ra Mutations Associated With Generalized Pustular Psorimentioning

confidence: 99%

Molecular Determinants of Agonist and Antagonist Signaling through the IL-36 Receptor

Guenther

Sundberg

2014

The Journal of Immunology

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“…IL-36Ra blocks the proinflammatory cytokines IL-36a/b/g; when IL36RN is mutated, IL-36 signaling is uncontrolled with enhanced production of further proinflammatory cytokines (Onoufriadis et al 2011). However, IL36RN mutations only occur in a minority of patients (Setta-Kaffetzi et al 2013), thus, more genes are likely involved. Interestingly, a de novo mutation in the epidermal NF-kB activator CARD14 (Jordan et al 2012b) has been described to underlay a sporadic case of severe GPP, suggesting that KCs dysfunction is likely to play a predominant role in this disease phenotype.…”

Section: Generalized Pustular Psoriasismentioning

confidence: 99%

Psoriasis

Meglio

Villanova

Nestle

2014

Cold Spring Harbor Perspectives in Medicine

267

202

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Psoriasis is a common chronic inflammatory skin disease with a spectrum of clinical phenotypes and results from the interplay of genetic, environmental, and immunological factors. Four decades of clinical and basic research on psoriasis have elucidated many of the pathogenic mechanisms underlying disease and paved the way to effective targeted therapies. Here, we review this progress and identify future directions of study that are supported by a more integrative research approach and aim at further improving the patients' life.This skin is me, I can't get out.

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“…All rights reserved. [10].These disease alleles are found in both European and Asian populations, and account for approximately 25% of GPP [11], 20% of ACH and 2% of PPP cases [12]. The latter, however, is somewhat controversial, as some studies found no association at all with PPP [13].…”

Section: Accepted Articlementioning

confidence: 99%

“…Another gene involved in GPP, PPP and ACH is AP1S3 [21]. It encodes a subunit of the adaptor protein complex 1 (AP-1), which is an evolutionary conserved heterotetramer that promotes vesicular trafficking between the trans-Golgi network and the endosomes.…”

Section: Accepted Articlementioning

confidence: 99%

442 European consensus statement on phenotypes of pustular psoriasis

Navarini¹,

Burden²,

Capon³

et al. 2016

Journal of Investigative Dermatology

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Pustular psoriasis (PP) is a group of inflammatory skin conditions characterized by infiltration of neutrophil granulocytes in the epidermis to such an extent that clinically visible sterile pustules develop. Because of clinical co-incidence, PP is currently grouped with psoriasis vulgaris (PV). However, PP and PV are phenotypically different, respond differently to treatments, and seem to be distinct on the genetic level. In contrast to PV, the phenotypes of PP are not well defined. Descriptions of each form of PP are discordant among standard dermatology textbooks [1][2][3][4][5], encumbering the collection of phenotypically well-matched groups of patients as well as clinical trials.

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Rare Pathogenic Variants in IL36RN Underlie a Spectrum of Psoriasis-Associated Pustular Phenotypes

Cited by 158 publications

References 7 publications

Molecular Determinants of Agonist and Antagonist Signaling through the IL-36 Receptor

Molecular Determinants of Agonist and Antagonist Signaling through the IL-36 Receptor

Psoriasis

442 European consensus statement on phenotypes of pustular psoriasis

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