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IL36RN Mutations in Generalized Pustular Psoriasis: Just the Tip of the Iceberg?
See related articles on pg 2514, 2634 and 2637
IL36RN Mutations in Generalized Pustular Psoriasis: Just the Tip of the Iceberg? Francesca Capon1 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. Journal of Investigative Dermatology (2013) 133, 2503–2504. doi:10.1038/jid.2013.361
IL36RN mutations in the pathogenesis of GPP
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., 2011; Onoufriadis et al., 2011). IL36RN encodes the IL-36 receptor antagonist (IL-36Ra), a soluble molecule that counteracts the inflammatory effect of IL-36 cytokines (IL-36a, IL-36b, and IL-36g) by binding their receptor (IL-1RL2) and preventing the downstream activation of NF-kB signaling (Sims and Smith, 2010). Pathogenic IL36RN mutations were originally identified in consanguineous GPP pedigrees of north-African origin (Marrakchi et al., 2011) and in isolated cases from the UK (Onoufriadis et al., 2011). 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 IL1, IL-6, and IL-8 (Marrakchi et al., 2011; Onoufriadis et al., 2011). 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, 2010). 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., 2013; Rossi-Semerano et al., 2013). Genotype–phenotype correlations
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., 2013). 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
1
Division of Genetics and Molecular Medicine, King’s College London, London, UK
Correspondence: Francesca Capon, Division of Genetics and Molecular Medicine, King’s College London, 9th Floor Tower Wing, Guy’s Hospital, Great Maze Pond, London SE1 9RT, UK. E-mail: [email protected]
& 2013 The Society for Investigative Dermatology
COMMENTARY
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, 2010), Li et al. (2013) 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 ¼ 113) and found no evidence of association between IL36RN variation and PV susceptibility (Li et al., 2013). Of note, similar results were obtained by our group, in a recent analysis of 349 patients with familial PV (Berki et al., 2013). Sugiura et al. (2013) 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 ¼ 20) versus those with GPP alone (n ¼ 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., 2013). Interestingly, a similar trend was observed in the study by Korber et al. (2013), 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, 2010). 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, 2010). www.jidonline.org 2503
COMMENTARY
Clinical Implications
The results of genetic studies indicate that GPP is etiologically distinct from PV. This may account for the limited efficiency of tumor necrosis factor blocking agents in GPP.
Reports of IL36RN mutations in control individuals suggest that exposure to specific environmental agents or mutations in additional predisposing genes may be required for disease onset. The identification of environmental triggers may help develop strategies that prevent recurrent GPP flares.
The identification of IL36RN mutations in a significant proportion of GPP cases has encouraged the therapeutic use of IL-1 antagonists, on the basis of the assumption that IL-1 overproduction is a disease driver in these patients. Thus, it will be important to determine whether IL36RN-negative cases are also associated with mutations that affect IL-1 signaling.
Are IL36RN mutations sufficient to cause disease?
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. (2013) identified two unrelated control subjects carrying a homozygous frameshift mutation (c.115 þ 6 T4C). Of note, the frequency of the c.115 þ 6 T4C 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 þ 6C/c.115 þ 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., 2013; Sugiura et al., 2013). 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., 2013), a finding confirmed by Korber et al. (2013) and Sugiura et al. (2013). The need for mutations at a second gene locus would also account for the low recurrence rate of GPP within sibships (Griffiths and Barker, 2010). Future directions: moving beyond IL36RN
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 IL36RNnegative patients ranging from 51% (Li et al., 2013) to 84% (Setta-Kaffetzi et al., 2013). 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/IL1 axis and has promoted the therapeutic use of IL-1 antagonists (Huffmeier et al., 2013; Rossi-Semerano et al., 2013). In this context, it will be important to
2504 Journal of Investigative Dermatology (2013), Volume 133
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. CONFLICT OF INTEREST
The authors state no conflict of interest.
REFERENCES Berki D, Mahil SK, David Burden A et al. (2013) Loss of IL36RN function does not confer susceptibility to psoriasis vulgaris. J Invest Dermatol. advance online publication, 25 June 2013, doi: 10.1038/jid.2013.285 Griffiths CEM, Barker JN (2010) Psoriasis. In: Burns T, Breathnach S, Cox N, Griffiths CEM (eds) Rook’s Textbook of Dermatology Wiley-Blackwell: Chichester, pp 20.1–60 Huffmeier U, Watzold M, Mohr J et al. (2013) Successful therapy with anakinra in a patient with generalized pustular psoriasis carrying IL36RN mutations. Br J Dermatol. advance online publication, 6 August 2013, doi: 10.111/bjd.12548 Korber A, Mossner R, Renner R et al. (2013) Mutations in IL36RN in patients with generalized pustular psoriasis. J Invest Dermatol 133:2634–7 Li M, Han J, Lu Z et al. (2013) Prevalent and rare mutations in il-36RN gene in chinese patients with generalized pustular psoriasis and psoriasis vulgaris. J Invest Dermatol 133:2637–9 Marrakchi S, Guigue P, Renshaw BR et al. (2011) Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis. N Engl J Med 365:620–8 Onoufriadis A, Simpson MA, Pink AE et al. (2011) Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis. Am J Hum Genet 89:432–7 Rossi-Semerano L, Piram M, Chiaverini C et al. (2013) First clinical description of an infant with interleukin-36-receptor antagonist deficiency (DITRA) successfully treated with interleukin-1-receptor antagonist anakinra. Pediatrics (e-pub ahead of print 9 September 2013, doi:10.1542/peds.2012-3935) Setta-Kaffetzi N, Navarini AA, Patel VM et al. (2013) Rare pathogenic variants in IL36RN underlie a spectrum of psoriasis-associated pustular phenotypes. J Invest Dermatol 133:1366–9 Sims JE, Smith DE (2010) The IL-1 family: regulators of immunity. Nat Rev Immunol 10:89–102 Sugiura K, Takemoto A, Yamaguchi M et al. (2013) The majority of generalized pustular psoriasis without psoriasis vulgaris is caused by deficiency of interleukin-36 receptor antagonist. J Invest Dermatol 133:2514–21
IL36RN Mutations in Generalized Pustular Psoriasis: Just the Tip of the Iceberg? Francesca Capon1 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. Journal of Investigative Dermatology (2013) 133, 2503–2504. doi:10.1038/jid.2013.361
IL36RN mutations in the pathogenesis of GPP
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., 2011; Onoufriadis et al., 2011). IL36RN encodes the IL-36 receptor antagonist (IL-36Ra), a soluble molecule that counteracts the inflammatory effect of IL-36 cytokines (IL-36a, IL-36b, and IL-36g) by binding their receptor (IL-1RL2) and preventing the downstream activation of NF-kB signaling (Sims and Smith, 2010). Pathogenic IL36RN mutations were originally identified in consanguineous GPP pedigrees of north-African origin (Marrakchi et al., 2011) and in isolated cases from the UK (Onoufriadis et al., 2011). 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 IL1, IL-6, and IL-8 (Marrakchi et al., 2011; Onoufriadis et al., 2011). 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, 2010). 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., 2013; Rossi-Semerano et al., 2013). Genotype–phenotype correlations
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., 2013). 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
1
Division of Genetics and Molecular Medicine, King’s College London, London, UK
Correspondence: Francesca Capon, Division of Genetics and Molecular Medicine, King’s College London, 9th Floor Tower Wing, Guy’s Hospital, Great Maze Pond, London SE1 9RT, UK. E-mail: [email protected]
& 2013 The Society for Investigative Dermatology
COMMENTARY
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, 2010), Li et al. (2013) 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 ¼ 113) and found no evidence of association between IL36RN variation and PV susceptibility (Li et al., 2013). Of note, similar results were obtained by our group, in a recent analysis of 349 patients with familial PV (Berki et al., 2013). Sugiura et al. (2013) 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 ¼ 20) versus those with GPP alone (n ¼ 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., 2013). Interestingly, a similar trend was observed in the study by Korber et al. (2013), 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, 2010). 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, 2010). www.jidonline.org 2503
COMMENTARY
Clinical Implications
The results of genetic studies indicate that GPP is etiologically distinct from PV. This may account for the limited efficiency of tumor necrosis factor blocking agents in GPP.
Reports of IL36RN mutations in control individuals suggest that exposure to specific environmental agents or mutations in additional predisposing genes may be required for disease onset. The identification of environmental triggers may help develop strategies that prevent recurrent GPP flares.
The identification of IL36RN mutations in a significant proportion of GPP cases has encouraged the therapeutic use of IL-1 antagonists, on the basis of the assumption that IL-1 overproduction is a disease driver in these patients. Thus, it will be important to determine whether IL36RN-negative cases are also associated with mutations that affect IL-1 signaling.
Are IL36RN mutations sufficient to cause disease?
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. (2013) identified two unrelated control subjects carrying a homozygous frameshift mutation (c.115 þ 6 T4C). Of note, the frequency of the c.115 þ 6 T4C 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 þ 6C/c.115 þ 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., 2013; Sugiura et al., 2013). 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., 2013), a finding confirmed by Korber et al. (2013) and Sugiura et al. (2013). The need for mutations at a second gene locus would also account for the low recurrence rate of GPP within sibships (Griffiths and Barker, 2010). Future directions: moving beyond IL36RN
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 IL36RNnegative patients ranging from 51% (Li et al., 2013) to 84% (Setta-Kaffetzi et al., 2013). 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/IL1 axis and has promoted the therapeutic use of IL-1 antagonists (Huffmeier et al., 2013; Rossi-Semerano et al., 2013). In this context, it will be important to
2504 Journal of Investigative Dermatology (2013), Volume 133
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. CONFLICT OF INTEREST
The authors state no conflict of interest.
REFERENCES Berki D, Mahil SK, David Burden A et al. (2013) Loss of IL36RN function does not confer susceptibility to psoriasis vulgaris. J Invest Dermatol. advance online publication, 25 June 2013, doi: 10.1038/jid.2013.285 Griffiths CEM, Barker JN (2010) Psoriasis. In: Burns T, Breathnach S, Cox N, Griffiths CEM (eds) Rook’s Textbook of Dermatology Wiley-Blackwell: Chichester, pp 20.1–60 Huffmeier U, Watzold M, Mohr J et al. (2013) Successful therapy with anakinra in a patient with generalized pustular psoriasis carrying IL36RN mutations. Br J Dermatol. advance online publication, 6 August 2013, doi: 10.111/bjd.12548 Korber A, Mossner R, Renner R et al. (2013) Mutations in IL36RN in patients with generalized pustular psoriasis. J Invest Dermatol 133:2634–7 Li M, Han J, Lu Z et al. (2013) Prevalent and rare mutations in il-36RN gene in chinese patients with generalized pustular psoriasis and psoriasis vulgaris. J Invest Dermatol 133:2637–9 Marrakchi S, Guigue P, Renshaw BR et al. (2011) Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis. N Engl J Med 365:620–8 Onoufriadis A, Simpson MA, Pink AE et al. (2011) Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis. Am J Hum Genet 89:432–7 Rossi-Semerano L, Piram M, Chiaverini C et al. (2013) First clinical description of an infant with interleukin-36-receptor antagonist deficiency (DITRA) successfully treated with interleukin-1-receptor antagonist anakinra. Pediatrics (e-pub ahead of print 9 September 2013, doi:10.1542/peds.2012-3935) Setta-Kaffetzi N, Navarini AA, Patel VM et al. (2013) Rare pathogenic variants in IL36RN underlie a spectrum of psoriasis-associated pustular phenotypes. J Invest Dermatol 133:1366–9 Sims JE, Smith DE (2010) The IL-1 family: regulators of immunity. Nat Rev Immunol 10:89–102 Sugiura K, Takemoto A, Yamaguchi M et al. (2013) The majority of generalized pustular psoriasis without psoriasis vulgaris is caused by deficiency of interleukin-36 receptor antagonist. J Invest Dermatol 133:2514–21