Autoinflammatory keratinization diseases

Among the genetic causes/predisposing factors for inflammatory keratinization disorders, several factors are associated with autoinflammatory mechanisms. Here we review these inflammatory keratinization disorders with autoinflammatory pathogenic mechanisms and advocate the novel and unique concept of autoinflammatory keratinization diseases (AIKDs). We propose the following definition of AIKD. First, the primary and main inflammation sites are the epidermis and the upper dermis. Second, inflammation in the epidermis and upper dermis leads to hyperkeratosis, which is the main and characteristic phenotype of AIKDs. Third, AIKDs have primary genetic causative factors associated with the hyperactivation of innate immunity (autoinflammation), mainly in the epidermis and upper dermis. Finally, the concept of AIKDs encompasses diseases with mixed pathomechanisms of autoinflammation and autoimmunity. AIKDs have genetic abnormalities as causative factors, and hyperactivation of the innate immune system resulting from those genetic defects plays an important role in the pathogenesis. Recently, a number of CARD14 gain-of-function variants/mutations have been reported as predisposing factors for psoriasis vulgaris (plaque-type psoriasis) and psoriatic arthritis.1Jordan C.T. Cao L. Roberson E.D. Pierson K.C. Yang C.F. Joyce C.E. et al.PSORS2 is due to mutations in CARD14.Am J Hum Genet. 2012; 90: 784-795Abstract Full Text Full Text PDF PubMed Scopus (302) Google Scholar, 2Jordan C.T. Cao L. Roberson E.D. Duan S. Helms C.A. Nair R.P. et al.Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis.Am J Hum Genet. 2012; 90: 796-808Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar Jordan et al1Jordan C.T. Cao L. Roberson E.D. Pierson K.C. Yang C.F. Joyce C.E. et al.PSORS2 is due to mutations in CARD14.Am J Hum Genet. 2012; 90: 784-795Abstract Full Text Full Text PDF PubMed Scopus (302) Google Scholar found a rare de novo gain-of-function variant in CARD14, p.Glu138Ala, in a sporadic case of severe early-onset generalized pustular psoriasis (GPP). Sugiura et al3Sugiura K. Muto M. Akiyama M. CARD14 c.526G>C (p.Asp176His) is a significant risk factor for generalized pustular psoriasis with psoriasis vulgaris in the Japanese cohort.J Invest Dermatol. 2014; 134: 1755-1757Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar reported a rare variant in CARD14, p.Asp176His, to be a significant predisposing factor for GPP with preceding or concurrent psoriasis vulgaris lesions, and this variant underlies approximately 20% of patients with GPP with psoriasis vulgaris in the Japanese population. CARD14 variants are also disease susceptibility factors for European palmoplantar pustular psoriasis (palmoplantar pustulosis).4Mössner R. Frambach Y. Wilsmann-Theis D. Löhr S. Jacobi A. Weyergraf A. et al.Palmoplantar pustular psoriasis is associated with missense variants in CARD14, but not with loss-of-function mutations in IL36RN in European patients.J Invest Dermatol. 2015; 135: 2538-2541Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar Caspase recruitment domain-containing protein 14 (CARD14) encoded by CARD14 is expressed and localized mainly in the skin, especially in keratinocytes.1Jordan C.T. Cao L. Roberson E.D. Pierson K.C. Yang C.F. Joyce C.E. et al.PSORS2 is due to mutations in CARD14.Am J Hum Genet. 2012; 90: 784-795Abstract Full Text Full Text PDF PubMed Scopus (302) Google Scholar Psoriasis-causative CARD14 mutations enhance nuclear factor κB activation and upregulate a subset of psoriasis-associated genes in keratinocytes (Fig 1).1Jordan C.T. Cao L. Roberson E.D. Pierson K.C. Yang C.F. Joyce C.E. et al.PSORS2 is due to mutations in CARD14.Am J Hum Genet. 2012; 90: 784-795Abstract Full Text Full Text PDF PubMed Scopus (302) Google Scholar, 2Jordan C.T. Cao L. Roberson E.D. Duan S. Helms C.A. Nair R.P. et al.Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis.Am J Hum Genet. 2012; 90: 796-808Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar CARD14 mutations in the keratinocytes are thought to be responsible for the disease pathology and clinical manifestations of inflammatory keratinization diseases with CARD14 mutations. However, we cannot rule out the possibility that CARD14 mutations in immune cells other than keratinocytes might be involved in the pathogenesis. Deficiency in IL-36 receptor antagonist (IL-36Ra) because of mutations in IL36RN has been reported as a genetic cause of familial GPP with recessive inheritance in the Tunisian population.5Marrakchi S. Guigue P. Renshaw B.R. Puel A. Pei X.Y. Fraitag S. et al.Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis.N Engl J Med. 2011; 365: 620-628Crossref PubMed Scopus (701) Google Scholar Onoufriadis et al6Onoufriadis A. Simpson M.A. Pink A.E. Di Meglio P. Smith C.H. Pullabhatla V. 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 (393) Google Scholar reported that IL36RN mutations underlie 3 European patients with sporadic GPP. Later, it was elucidated that most patients with sporadic GPP without psoriasis vulgaris skin symptoms have IL36RN mutations as a cause of the disease.7Sugiura K. Takemoto A. Yamaguchi M. Takahashi H. Shoda Y. Mitsuma T. 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 (225) Google Scholar Hussain et al8Hussain S. Berki D.M. Choon S.E. Burden A.D. Allen M.H. Arostegui J.I. et al.IL36RN mutations define a severe autoinflammatory phenotype of generalized pustular psoriasis.J Allergy Clin Immunol. 2015; 135: 1067-1070.e9Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar recommended that patients with GPP with the clinical triad of early-onset systemic inflammation and absence of concurrent psoriasis vulgaris should be screened for IL36RN mutations based on the results of their GPP cohort study. Mutations in IL36RN have been reported in patients with certain other psoriasis-related diseases, such as acrodermatitis continua of Hallopeau, severe acute generalized exanthematous pustulosis, and impetigo herpetiformis. IL-36Ra expression is seen primarily in the skin. IL-36Ra works as an antagonist to the IL-1 family members IL-36 α, β, and γ (Fig 1). Thus deficiency of IL-36Ra caused by IL36RN loss-of-function mutations is thought to result in acceleration of IL-36–driven skin inflammation. These facts clearly demonstrate that, among psoriasis and its related disorders, the rare subtypes, GPP, impetigo herpetiformis, and acrodermatitis continua with IL36RN mutations and GPP and palmoplantar pustular psoriasis (palmoplantar pustulosis) with CARD14 variants, are thought to be able to be categorized as AIKDs. Pityriasis rubra pilaris (PRP) is an inflammatory erythematous keratinization disorder showing perifollicular erythema, often with confluent configurations, follicular plugging, pityriasis capitis, and palmoplantar hyperkeratosis. Most PRP cases are regarded as sporadic cases, although familial occurrence is also seen, particularly in one subtype, type V (atypical juvenile type). Notably, the skin eruptions in patients with type V PRP first appear in infancy or early childhood and tend to run a chronic course with no sustained clearance of the skin. Gain-of-function mutations in CARD14 were identified in some autosomal dominant familial cases of PRP. In our recent study of 22 patients with PRP, all 3 patients with type V PRP were found to have CARD14 mutations.9Takeichi T. Sugiura K. Nomura T. Sakamoto T. Ogawa Y. Oiso N. et al.Pityriasis rubra pilaris type V as an autoinflammatory disease by CARD14 mutations.JAMA Dermatol. 2017; 153: 66-70Crossref PubMed Scopus (54) Google Scholar In addition, detailed clinical features of the reported PRP cases with CARD14 mutations in the literature were reviewed, and it was confirmed that all the PRP cases with CARD14 mutations in the literature were affected with type V PRP.9Takeichi T. Sugiura K. Nomura T. Sakamoto T. Ogawa Y. Oiso N. et al.Pityriasis rubra pilaris type V as an autoinflammatory disease by CARD14 mutations.JAMA Dermatol. 2017; 153: 66-70Crossref PubMed Scopus (54) Google Scholar To date, 8 heterozygous mutations in CARD14 have been reported in patients with type V PRP. We propose that PRP type V, the atypical juvenile type, is a distinct variant of PRP caused by CARD14 mutations9Takeichi T. Sugiura K. Nomura T. Sakamoto T. Ogawa Y. Oiso N. et al.Pityriasis rubra pilaris type V as an autoinflammatory disease by CARD14 mutations.JAMA Dermatol. 2017; 153: 66-70Crossref PubMed Scopus (54) Google Scholar and should be regarded as an AIKD. Keratosis lichenoides chronica (KLC) is a rare inflammatory keratinization disorder of unknown pathobiology. Characteristic clinical features of KLC include tiny papules on the trunk and extremities that become confluent, resulting in linear and reticulate patterns, and seborrheic dermatitis–like eruptions on the face. The lesions have a chronic and often progressive course. Recently, a distinct gain-of-function mutation in the inflammasome sensor protein, NLR family, pyrin domain containing protein 1 (NLRP1) was found to be the cause in a family with KLC.10Zhong F.L. Mamaï O. Sborgi L. Boussofara L. Hopkins R. Robinson K. et al.Germline NLRP1 mutations cause skin inflammatory and cancer susceptibility syndromes via inflammasome activation.Cell. 2016; 167: 187-202.e17Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar NLRP1 is considered the most prominently expressed inflammasome sensor in human skin, and keratinocytes express all other inflammasome components, including caspase-1, apoptosis-associated speck-like protein containing a CARD (ASC), IL-1β, and IL-18.10Zhong F.L. Mamaï O. Sborgi L. Boussofara L. Hopkins R. Robinson K. et al.Germline NLRP1 mutations cause skin inflammatory and cancer susceptibility syndromes via inflammasome activation.Cell. 2016; 167: 187-202.e17Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar Evidence for spontaneous inflammasome activation by the KLC-causing NLRP1 mutation in patients' keratinocytes has been demonstrated, and inflammasome-dependent IL-1 cytokines have been shown to cause familial KLC.10Zhong F.L. Mamaï O. Sborgi L. Boussofara L. Hopkins R. Robinson K. et al.Germline NLRP1 mutations cause skin inflammatory and cancer susceptibility syndromes via inflammasome activation.Cell. 2016; 167: 187-202.e17Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar In this context we now consider that autoinflammatory mechanisms play an important role in the pathogenesis of KLC, at least in that of familial KLC. Here we advocate for the new disease category AIKD, which describes inflammatory keratinization disorders with autoinflammatory mechanisms as their predominant cause, including minor subsets of psoriasis and related diseases, PRP type V and KLC, as mentioned above (Table I). Inflammatory hyperkeratotic skin lesions are not common in patients with conventional autoinflammatory diseases. Thus although AIKDs are thought to have autoinflammatory pathogenic mechanisms, unique pathomechanisms with inflammation that involves epidermal keratinocytes and results in hyperkeratosis are assumed in patients with AIKDs. As the causes/predisposing factors for inflammatory keratinization disorders come to be elucidated, a larger number of disorders will be categorized as AIKDs.Table IInflammatory keratinization disorders included in AIKDs and their pathogenesesDiseaseGenetic causative factor (frequency)Pathogenic inflammatory mechanisms and pathways in keratinocytesIL36Ra-related pustulosis GPP without PVIL36RN mutations (prevalent)IL-36 → MyD88 → NF-κB/MAPK → TNF, IL-1, IL-8, IL-17, IL-36, CXCL1, CXCL2, CCL20 Impetigo herpetiformisIL36RN mutations (prevalent) Acrodermatitis continuaIL36RN mutations (not rare)CARD14-mediated pustular psoriasis GPP with PVCARD14 variants (not rare) Palmoplantar pustular psoriasis (palmoplantar pustulosis)CARD14 variants (not rare)CARD14 → NF-κB → IL-36, IL-8, CXCL1, CXCL2, CCL20PRP PRP type VCARD14 mutations (prevalent) PRP other typesCARD14 variants (rare)KLC (familial)NLRP1 mutation (unknown)NLRP1 → inflammasome→ caspase-1 → IL-1→ TNF, GM-CSF, IL-36MAPK, Mitogen-activated protein kinase; NF-κB, nuclear factor κB; PV, psoriasis vulgaris. Open table in a new tab MAPK, Mitogen-activated protein kinase; NF-κB, nuclear factor κB; PV, psoriasis vulgaris. Hidradenitis suppurativa as an autoinflammatory keratinization diseaseJournal of Allergy and Clinical ImmunologyVol. 141Issue 5PreviewWe have read with great interest the article titled "Autoinflammatory keratinization diseases" by Akiyama et al.1 The authors advocate the definition of autoinflammatory keratinization diseases (AIKDs) to indicate the keratinization disorders with an autoinflammatory pathogenesis. In these disorders, the primary and main inflammation sites are the epidermis and the upper dermis. The authors hope that a larger number of disorders will be categorized as AIKDs, and we acknowledge that stratification of diseases on the basis of proven keratinocyte involvement is a noble pursuit. Full-Text PDF