Rare Variations in IL36RN in Severe Adverse Drug Reactions Manifesting as Acute Generalized Exanthematous Pustulosis

Navarini, Alexander A.; Valeyrie‐Allanore, Laurence; Setta-Kaffetzi, Niovi; Barker, Jonathan; Capon, Francesca; Creamer, Daniel; Roujeau, Jean‐Claude; Sekula, Peggy; Simpson, Michael A.; Trembath, Richard C.; Mockenhaupt, Maja; Smith, Catherine

doi:10.1038/jid.2013.44

Cited by 120 publications

(99 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…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

View full text Add to dashboard Cite

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.

show abstract

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

View full text Add to dashboard Cite

show abstract

“…TO THE EDITOR Recessive mutations of the gene encoding the interleukin-36 receptor antagonist (IL36RN) have been associated with generalized pustular psoriasis, palmarplantar pustulosis, and acrodermatitis continua of Hallopeau (Marrakchi et al, 2011;Onoufriadis et al, 2011;Setta-Kaffetzi et al, 2013). As patients suffering from these pustular conditions often present with concomitant psoriasis vulgaris (PV), it has been proposed that IL36RN deficiency may also contribute to PV susceptibility (Marrakchi et al, 2011).…”

mentioning

confidence: 98%

Loss of IL36RN Function Does Not Confer Susceptibility to Psoriasis Vulgaris

Berki

Mahil

Burden

et al. 2014

Journal of Investigative Dermatology

Self Cite

View full text Add to dashboard Cite

“…Revision of the genetic findings reveals that some mutations seem to be enriched in mixed phenotypes not well captured by our traditional PP trinity of GPP, ACH and PPP. In addition, some other entities [18] might be added to the realm of PP. Even though interest is rekindled with the new genetic findings that promise potential new treatments, we are very far away from systematic trials as are available for PV.…”

Section: Discussion and Outlookmentioning

confidence: 99%

“…In total, more than 10 patients with GPP and heterozygous IL36RN changes have been reported, which could be explained by additional mutations at a second locus [17]. Heterozygous IL36RN alleles were also found in some cases [18,19] of the pustular drug rash AGEP, which could suggest a close relation or overlap with PP. IL-36 is close to IL-1 that has been implicated as the early pathogenetic mechanism in the model of bimodal immune activation in psoriasis [20], acting as autoinflammatory factor.…”

Section: Accepted Articlementioning

confidence: 99%

See 1 more Smart Citation

442 European consensus statement on phenotypes of pustular psoriasis

Navarini¹,

Burden²,

Capon³

et al. 2016

Journal of Investigative Dermatology

View full text Add to dashboard Cite

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.

show abstract

Rare Variations in IL36RN in Severe Adverse Drug Reactions Manifesting as Acute Generalized Exanthematous Pustulosis

Cited by 120 publications

References 13 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

Loss of IL36RN Function Does Not Confer Susceptibility to Psoriasis Vulgaris

442 European consensus statement on phenotypes of pustular psoriasis

Contact Info

Product

Resources

About