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IL36RN Mutations in Generalized Pustular Psoriasis: Just the Tip of the Iceberg?

2013; Elsevier BV; Volume: 133; Issue: 11 Linguagem: Inglês

10.1038/jid.2013.361

1523-1747

Francesca Capon,

Immunodeficiency and Autoimmune Disorders

As IL36RN mutations are a cause of generalized pustular psoriasis (GPP), three recent investigations attempted to correlate the IL36RN genotype with GPP clinical presentations. These studies found that IL36RN mutations account for only a fraction of GPP cases presenting with concomitant psoriasis vulgaris (PV; common or typical psoriasis). Pathogenic alleles were also found in control populations, indicating that environmental triggers and/or modifier genes may contribute to the disease. As IL36RN mutations are a cause of generalized pustular psoriasis (GPP), three recent investigations attempted to correlate the IL36RN genotype with GPP clinical presentations. These studies found that IL36RN mutations account for only a fraction of GPP cases presenting with concomitant psoriasis vulgaris (PV; common or typical psoriasis). Pathogenic alleles were also found in control populations, indicating that environmental triggers and/or modifier genes may contribute to the disease. The analysis of monogenic autoinflammatory diseases has unique power to uncover key molecules and signaling pathways that are essential to immune homeostasis. The identification of IL36RN as a gene for generalized pustular psoriasis (GPP) is a case in point, which demonstrated the importance of IL-36 cytokines in the establishment of cutaneous inflammation (Marrakchi et al., 2011Marrakchi S. Guigue P. Renshaw B.R. et al.Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis.N Engl J Med. 2011; 365: 620-628Crossref PubMed Scopus (698) Google Scholar; Onoufriadis et al., 2011Onoufriadis A. Simpson M.A. Pink A.E. et al.Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis.Am J Hum Genet. 2011; 89: 432-437Abstract Full Text Full Text PDF PubMed Scopus (388) Google Scholar). IL36RN encodes the IL-36 receptor antagonist (IL-36Ra), a soluble molecule that counteracts the inflammatory effect of IL-36 cytokines (IL-36α, IL-36β, and IL-36γ) by binding their receptor (IL-1RL2) and preventing the downstream activation of NF-κB signaling (Sims and Smith, 2010Sims J.E. Smith D.E. The IL-1 family: regulators of immunity.Nat Rev Immunol. 2010; 10: 89-102Crossref PubMed Scopus (995) Google Scholar). Pathogenic IL36RN mutations were originally identified in consanguineous GPP pedigrees of north-African origin (Marrakchi et al., 2011Marrakchi S. Guigue P. Renshaw B.R. et al.Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis.N Engl J Med. 2011; 365: 620-628Crossref PubMed Scopus (698) Google Scholar) and in isolated cases from the UK (Onoufriadis et al., 2011Onoufriadis A. Simpson M.A. Pink A.E. et al.Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis.Am J Hum Genet. 2011; 89: 432-437Abstract Full Text Full Text PDF PubMed Scopus (388) Google Scholar). In vitro and ex vivo experiments demonstrated that GPP alleles abolish the antagonistic effect of IL-36Ra, so that IL-36 stimulation of patient cells results in enhanced production of proinflammatory cytokines such as IL-1, IL-6, and IL-8 (Marrakchi et al., 2011Marrakchi S. Guigue P. Renshaw B.R. et al.Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis.N Engl J Med. 2011; 365: 620-628Crossref PubMed Scopus (698) Google Scholar; Onoufriadis et al., 2011Onoufriadis A. Simpson M.A. Pink A.E. et al.Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis.Am J Hum Genet. 2011; 89: 432-437Abstract Full Text Full Text PDF PubMed Scopus (388) Google Scholar). In this context, increased IL-1 levels are likely to account for the occurrence of systemic inflammation and peripheral neutrophilia, two cardinal features of GPP (Griffiths and Barker, 2010Griffiths C.E.M. Barker J.N. Psoriasis.in: Burns T. Breathnach S. Cox N. Griffiths C.E.M. Rook's Textbook of Dermatology. Wiley-Blackwell, Chichester2010: 20.1-60Crossref Scopus (30) Google Scholar). Thus, the identification of IL36RN mutations has sparked an interest in the therapeutic use of IL-1 antagonists, with encouraging results emerging from pilot studies (Huffmeier et al., 2013Huffmeier U. Watzold M. Mohr J. et al.Successful therapy with anakinra in a patient with generalized pustular psoriasis carrying IL36RN mutations.Br J Dermatol. 2013; (advance online publication, 6 August 2013)https://doi.org/10.111/bjd.12548Crossref Google Scholar; Rossi-Semerano et al., 2013Rossi-Semerano L. Piram M. Chiaverini C. et al.First clinical description of an infant with interleukin-36-receptor antagonist deficiency (DITRA) successfully treated with interleukin-1-receptor antagonist anakinra.Pediatrics. 2013Google Scholar). Following the identification of the first IL36RN mutation, further disease alleles were observed in other ethnic groups and in patients affected by palmar-plantar pustulosis or acrodermatitis continua of Hallopeau (Setta-Kaffetzi et al., 2013Setta-Kaffetzi N. Navarini A.A. Patel V.M. et al.Rare pathogenic variants in IL36RN underlie a spectrum of psoriasis-associated pustular phenotypes.J Invest Dermatol. 2013; 133: 1366-1369Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar). At the same time, the presence of genetic heterogeneity and the small size of many data sets prevented the investigation of genotype–phenotype correlations. In recent issues of the Journal of Investigative Dermatology, three groups have independently sought to address this question through the genetic analysis of sizeable patient resources. A common theme discussed in all studies was the correlation between IL36RN alleles and the occurrence of psoriasis vulgaris (PV). On the basis of the well-established association between GPP and PV (Griffiths and Barker, 2010Griffiths C.E.M. Barker J.N. Psoriasis.in: Burns T. Breathnach S. Cox N. Griffiths C.E.M. Rook's Textbook of Dermatology. Wiley-Blackwell, Chichester2010: 20.1-60Crossref Scopus (30) Google Scholar), Li et al., 2013Li M. Han J. Lu Z. et al.Prevalent and rare mutations in il-36RN gene in chinese patients with generalized pustular psoriasis and psoriasis vulgaris.J Invest Dermatol. 2013; 133: 2637-2639Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar investigated the possibility that IL36RN mutations may also be found in PV patients. Although their study detected disease alleles in 33 of 68 GPP patients, it did not identify recessive changes in PV cases (n=113) and found no evidence of association between IL36RN variation and PV susceptibility (Li et al., 2013Li M. Han J. Lu Z. et al.Prevalent and rare mutations in il-36RN gene in chinese patients with generalized pustular psoriasis and psoriasis vulgaris.J Invest Dermatol. 2013; 133: 2637-2639Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar). Of note, similar results were obtained by our group, in a recent analysis of 349 patients with familial PV (Berki et al., 2013Berki D. Mahil S.K. David Burden A. et al.Loss of IL36RN function does not confer susceptibility to psoriasis vulgaris.J Invest Dermatol. 2013; (advance online publication, 25 June 2013)https://doi.org/10.1038/jid.2013.285Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar). Sugiura et al., 2013Sugiura K. Takemoto A. Yamaguchi M. et al.The majority of generalized pustular psoriasis without psoriasis vulgaris is caused by deficiency of interleukin-36 receptor antagonist.J Invest Dermatol. 2013; 133: 2514-2521Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar addressed the same question from a slightly different perspective and compared the prevalence of IL36RN mutations in two groups of patients: those suffering from GPP and PV (n=20) versus those with GPP alone (n=11). The study uncovered IL36RN disease alleles in the majority (82%) of patients with GPP alone and in a very small number of individuals affected by GPP with concomitant PV (10%) (Sugiura et al., 2013Sugiura K. Takemoto A. Yamaguchi M. et al.The majority of generalized pustular psoriasis without psoriasis vulgaris is caused by deficiency of interleukin-36 receptor antagonist.J Invest Dermatol. 2013; 133: 2514-2521Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar). Interestingly, a similar trend was observed in the study by Korber et al., 2013Korber A. Mossner R. Renner R. et al.Mutations in IL36RN in patients with generalized pustular psoriasis.J Invest Dermatol. 2013; 133: 2634-2637Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar, who found recessive IL36RN mutations in 6/13 patients with GPP alone (46%) but only in one of the six individuals who also suffered from PV (17%). Taken together, the findings of these papers indicate that loss of IL36RN function does not contribute to the pathogenesis of PV. Importantly, HLA-Cw6, the major susceptibility determinant for PV, is not associated with GPP (Griffiths and Barker, 2010Griffiths C.E.M. Barker J.N. Psoriasis.in: Burns T. Breathnach S. Cox N. Griffiths C.E.M. Rook's Textbook of Dermatology. Wiley-Blackwell, Chichester2010: 20.1-60Crossref Scopus (30) Google Scholar). Thus, genetic studies indicate that GPP and PV are etiologically distinct clinical entities, rather than variants of the same disease. This notion has important therapeutic implications, as it may account for the limited efficacy of tumor necrosis factor blockers in the treatment of GPP (Griffiths and Barker, 2010Griffiths C.E.M. Barker J.N. Psoriasis.in: Burns T. Breathnach S. Cox N. Griffiths C.E.M. Rook's Textbook of Dermatology. Wiley-Blackwell, Chichester2010: 20.1-60Crossref Scopus (30) Google Scholar). The paradigm for autosomal recessive disease inheritance requires that all individuals harboring two mutant alleles show disease symptoms. Thus, it is remarkable that Li et al., 2013Li M. Han J. Lu Z. et al.Prevalent and rare mutations in il-36RN gene in chinese patients with generalized pustular psoriasis and psoriasis vulgaris.J Invest Dermatol. 2013; 133: 2637-2639Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar identified two unrelated control subjects carrying a homozygous frameshift mutation (c.115 +6 T>C). Of note, the frequency of the c.115+6 T>C allele in the Chinese population (2.05%) predicts that approximately 1:2,400 individuals will be homozygous for this change. As this figure markedly exceeds the prevalence of GPP in Asia (approximately 1:100,000), future studies are likely to identify further asymptomatic individuals with a c.115 +6C/c.115 +6C genotype. Patients who were homozygous for alleles of proven pathogenicity but only showed disease symptoms after the age of 65 years have also been reported (Setta-Kaffetzi et al., 2013Setta-Kaffetzi N. Navarini A.A. Patel V.M. et al.Rare pathogenic variants in IL36RN underlie a spectrum of psoriasis-associated pustular phenotypes.J Invest Dermatol. 2013; 133: 1366-1369Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar; Sugiura et al., 2013Sugiura K. Takemoto A. Yamaguchi M. et al.The majority of generalized pustular psoriasis without psoriasis vulgaris is caused by deficiency of interleukin-36 receptor antagonist.J Invest Dermatol. 2013; 133: 2514-2521Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar). This further supports the notion that IL36RN mutations may only cause disease in the presence of specific environmental agents. Given the rarity of GPP, identifying such triggers through epidemiological studies will remain a challenge, until multinational patient registries are established. It is also possible that the full manifestation of disease symptoms may require mutations at a second disease locus. The involvement of a modifier gene would explain the intriguing observation that several patients carry a single IL36RN mutation (Setta-Kaffetzi et al., 2013Setta-Kaffetzi N. Navarini A.A. Patel V.M. et al.Rare pathogenic variants in IL36RN underlie a spectrum of psoriasis-associated pustular phenotypes.J Invest Dermatol. 2013; 133: 1366-1369Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar), a finding confirmed by Korber et al., 2013Korber A. Mossner R. Renner R. et al.Mutations in IL36RN in patients with generalized pustular psoriasis.J Invest Dermatol. 2013; 133: 2634-2637Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar and Sugiura et al., 2013Sugiura K. Takemoto A. Yamaguchi M. et al.The majority of generalized pustular psoriasis without psoriasis vulgaris is caused by deficiency of interleukin-36 receptor antagonist.J Invest Dermatol. 2013; 133: 2514-2521Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar. The need for mutations at a second gene locus would also account for the low recurrence rate of GPP within sibships (Griffiths and Barker, 2010Griffiths C.E.M. Barker J.N. Psoriasis.in: Burns T. Breathnach S. Cox N. Griffiths C.E.M. Rook's Textbook of Dermatology. Wiley-Blackwell, Chichester2010: 20.1-60Crossref Scopus (30) Google Scholar). Two years after IL36RN alleles were first identified as a cause of GPP, a variety of missense and nonsense changes have been described in European and Asian patients, with 13 pathogenic variants currently reported in the Infevers registry of Hereditary Auto-Inflammatory Disorder Mutations (http://fmf.igh.cnrs.fr/ISSAID/infevers/). All follow-up studies have found evidence of genetic heterogeneity, with the percentage of IL36RN-negative patients ranging from 51% (Li et al., 2013Li M. Han J. Lu Z. et al.Prevalent and rare mutations in il-36RN gene in chinese patients with generalized pustular psoriasis and psoriasis vulgaris.J Invest Dermatol. 2013; 133: 2637-2639Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar) to 84% (Setta-Kaffetzi et al., 2013Setta-Kaffetzi N. Navarini A.A. Patel V.M. et al.Rare pathogenic variants in IL36RN underlie a spectrum of psoriasis-associated pustular phenotypes.J Invest Dermatol. 2013; 133: 1366-1369Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar). Thus, it widely recognized that IL36RN mutations account for a minority of GPP cases. Of note, exome sequencing data generated by our group indicate that IL36RN-negative cases are also genetically heterogeneous, so that the identification of novel disease genes will require the recruitment of carefully phenotyped and clinically homogeneous resources. The identification of IL36RN mutations in GPP patients has highlighted the pathogenic potential of the IL-36/IL-1 axis and has promoted the therapeutic use of IL-1 antagonists (Huffmeier et al., 2013Huffmeier U. Watzold M. Mohr J. et al.Successful therapy with anakinra in a patient with generalized pustular psoriasis carrying IL36RN mutations.Br J Dermatol. 2013; (advance online publication, 6 August 2013)https://doi.org/10.111/bjd.12548Crossref Google Scholar; Rossi-Semerano et al., 2013Rossi-Semerano L. Piram M. Chiaverini C. et al.First clinical description of an infant with interleukin-36-receptor antagonist deficiency (DITRA) successfully treated with interleukin-1-receptor antagonist anakinra.Pediatrics. 2013Google Scholar). In this context, it will be important to establish whether IL36RN-negative cases are also caused by mutations that affect IL-1 signaling, as patients who harbor such defects might be good candidates for the use of IL-1 blockers. Thus, gene discovery projects hold the promise of identifying mechanistic biomarkers that could inform therapeutic decisions in the treatment of GPP.