ファイル公開：2018-12-01journal articl

Akiyama, Masashi

McGrath, John A.

Sugiura, Kazumitsu

Takeichi, Takuya

Journal of Allergy and Clinical Immunology

English

Nagoya Repository

 1 The Journal of Allergy and Clinical Immunology 1 Manuscript ID: JACI-D-16-01828 2nd Revised Version 2  3 Paradigms and perspectives 4  5 Autoinflammatory keratinization diseases 6  7 Masashi Akiyama, MD, PhD,a Takuya Takeichi, MD, PhD,a John A. McGrath, MD, 8 FRCPb and Kazumitsu Sugiura, MD, PhDc 9  10 aDepartment of Dermatology, Nagoya University Graduate School of Medicine, 11 Nagoya, Japan, bSt John’s Institute of Dermatology, King’s College London, Guy’s 12 Hospital, London, UK and cDepartment of Dermatology, Fujita Health University 13 School of Medicine, Toyoake, Japan 14  15 Key words: autoinflammation, CARD14, IL-36 receptor antagonist, keratinization, 16 keratosis lichenoides chronica, NLRP1, pityriasis rubra pylaris, psoriasis, psoriatic 17 arthritis, pustular psoriasis 18  19 Corresponding Author: 20 Masashi Akiyama M.D., Ph.D. 21 Department of Dermatology 22 Nagoya University Graduate School of Medicine 23 65 Tsurumai-cho, Showa-ku, Nagoya 24 Aichi 466-8550, Japan 25 Tel: +81-52-744-2318, Fax: +81-52-744-2318 26 E-mail: makiyama@med.nagoya-u.ac.jp 27  28 Funding sources: No external funding 29  30 Conflicts of interest: None declared 31  32 Word, reference, table and figure counts: 996 words, 10 references, 1 table, 1 figure 33   34  2 Among the genetic causes/predisposing factors for inflammatory keratinization disorders, several 35 factors are associated with autoinflammatory mechanisms. Here we review these inflammatory 36 keratinization disorders with autoinflammatory pathogenic mechanisms and advocate the novel, 37 unique concept of “autoinflammatory keratinization diseases” (AIKD). We propose the following 38 definition of AIKD. (1) The primary and main inflammation sites are the epidermis and the upper 39 dermis. (2) The inflammation in the epidermis and the upper dermis leads to hyperkeratosis, 40 which is the main and characteristic phenotype of AIKD. (3) AIKD have primary genetic 41 causative factors associated with the hyperactivation of innate immunity (autoinflammation), 42 mainly in the epidermis and the upper dermis. (4) The concept of AIKD subsumes diseases with 43 mixed pathomechanisms of autoinflammation and autoimmunity. AIKD have genetic 44 abnormalities as causative factors, and hyperactivation of the innate immune system resulting 45 from those genetic defects plays an important role in the pathogenesis. 46  47 Recently, a number of CARD14 gain-of-function variants/mutations have been reported as 48 predisposing factors for psoriasis vulgaris (plaque-type psoriasis) and psoriatic arthritis.1, 2 49 Jordan et al.1 found a rare de novo gain-of-function variant in CARD14, p.Glu138Ala, in a 50 sporadic case of severe early-onset generalized pustular psoriasis (GPP). Sugiura et al.3 reported 51 a rare variant in CARD14, p.Asp176His, to be a significant predisposing factor for GPP with 52 preceding or concurrent psoriasis vulgaris lesions, and this variant underlies approximately 20% 53 of GPP cases with psoriasis vulgaris in the Japanese population. CARD14 variants are also 54 disease susceptibility factors of European palmoplantar pustular psoriasis (palmoplantar 55 pustulosis).4  56  57 CARD14 encodes the CARD family member “caspase recruitment domain family, member 14” 58 (CARD14). CARD14 is expressed and localized mainly in the skin, especially in keratinocytes.1 59 Psoriasis-causative CARD14 mutations enhance NF-κB activation and upregulate a subset of 60 psoriasis-associated genes in keratinocytes (Fig 1).1, 2 The CARD14 mutations in the 61  3 keratinocytes are thought to be responsible for pathogeneses and clinical manifestations of 62 inflammatory keratinization diseases with CARD14 mutations. However, we cannot rule out the 63 possibility that CARD14 mutations in immune cells other than keratinocytes may be involved in 64 the pathogenesis. 65  66 Deficiency in interleukin 36 receptor antagonist (IL-36Ra) due to mutations in IL36RN has been 67 reported as a genetic cause of familial GPP with recessive inheritance in the Tunisian 68 population.5 Onoufriadis et al.6 reported that IL36RN mutations underlie three sporadic European 69 GPP patients. Later, it was elucidated that most sporadic GPP patients without psoriasis vulgaris 70 skin symptoms have IL36RN mutations as a cause of the disease.7 Hussain et al.8 recommended 71 that GPP patients with the clinical triad of early onset, systemic inflammation and absence of 72 concurrent psoriasis vulgaris be screened for IL36RN mutations, based on the results of their 73 GPP cohort study. Mutations in IL36RN have been reported in patients with certain other 74 psoriasis-related diseases, acrodermatitis continua of Hallopeau, severe acute generalized 75 exanthematous pustulosis and impetigo herpetiformis. 76  77 IL-36Ra expression is seen primarily in the skin. IL-36Ra works as an antagonist to the 78 interleukin-1 family members IL-36 α, β and γ (Fig 1). Thus, deficiency of IL-36Ra due to 79 IL36RN loss-of-function mutations is thought to result in the acceleration of IL-36-driven skin 80 inflammation. 81  82 These facts clearly demonstrate that, among psoriasis and its related disorders, rare subtypes, 83 GPP, impetigo herpetiformis and acrodermatitis continua with IL36RN mutations, and GPP and 84 palmoplantar pustular psoriasis (palmoplantar pustulosis) with CARD14 variants are thought to 85 be catagorizable as AIKD. 86  87 Pityriasis rubra pilaris (PRP) is an inflammatory erythematous keratinization disorder showing 88  4 perifollicular erythema often with confluent configurations, follicular plugging, pityriasis capitis 89 and palmoplantar hyperkeratosis. Most PRP cases are regarded as sporadic cases, although 90 familial occurrence is also seen, particularly in one subtype, type V (atypical juvenile type). 91 Notably, the skin eruptions in type V PRP first appear in infancy or early childhood and tend to 92 run a chronic course with no sustained clearance of the skin. Gain-of-function mutations in 93 CARD14 were identified in some autosomal dominant familial cases of PRP. In our recent study 94 of 22 patients with PRP, all three patients with PRP type V were found to have CARD14 95 mutations.9 In addition, detailed clinical features of the reported PRP cases with CARD14 96 mutations in the literature were reviewed and it was confirmed that all the PRP cases with 97 CARD14 mutations in the literature were affected with type V PRP.9 To date, eight heterozygous 98 mutations in CARD14 have been reported in patients with type V PRP. We propose that PRP type 99 V, the atypical juvenile type, is a distinct variant of PRP that is caused by CARD14 mutations9 100 and should be regarded as an AIKD. 101  102 Keratosis lichenoides chronica (KLC) is a rare inflammatory keratinization disorder of unknown 103 pathomechanism. Characteristic clinical features of KLC are tiny papules on the trunk and 104 extremities, which become confluent, resulting in linear and reticulate patterns, and seborrheic 105 dermatitis-like eruptions on the face. The lesions have a chronic and often progressive course. 106 Recently, a distinct gain-of-function mutation in the inflammasome sensor protein, NLR family, 107 pyrin domain containing protein 1 (NLRP1) was found as the cause in a family with KLC.10 108  109 NLRP1 is considered to be the most prominently expressed inflammasome sensor in human skin, 110 and keratinocytes express all other inflammasome components, including CASP1, ASC, IL-1β 111 and IL-18.10 Evidence for spontaneous inflammasome activation by the KLC-causing NLRP1 112 mutation in patients’ keratinocytes has been provided, and inflammasome-dependent IL-1 113 cytokines have been demonstrated to cause familial KLC.10 In this context, we now consider that 114 autoinflammatory mechanisms play an important role in the pathogenesis of KLC, at least in that 115  5 of familial KLC. 116  117 Here we advocate for the new disease category AIKD, which describes inflammatory 118 keratinization disorders with autoinflammatory mechanisms as their predominant etiology, 119 including minor subsets of psoriasis and related diseases, PRP type V and KLC, as mentioned 120 above (Table I). Inflammatory hyperkeratotic skin lesions are not common in conventional 121 autoinflammatory diseases. Thus, although AIKD is thought to have autoinflammatory 122 pathogenic mechanisms, unique pathomechanisms with inflammation that involves epidermal 123 keratinocytes and results in hyperkeratosis are assumed in AIKD. As the causes/predisposing 124 factors for inflammatory keratinization disorders come to be successively elucidated, a larger 125 number of disorders will be categorized into AIKD. 126  127   128  6 REFERENCES 129  130 1. Jordan CT, Cao L, Roberson ED, Pierson KC, Yang CF, Joyce CE, et al. PSORS2 is due to 131 mutations in CARD14. Am J Hum Genet 2012; 90: 784-95. 132  133 2. Jordan CT, Cao L, Roberson ED, Duan S, Helms CA, Nair RP, et al. Rare and common 134 variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis. Am J Hum 135 Genet 2012; 90: 796-808. 136  137 3. Sugiura K, Muto M, Akiyama M. CARD14 c.526G>C (p.Asp176His) is a significant risk 138 factor for generalized pustular psoriasis with psoriasis vulgaris in the Japanese cohort. J Invest 139 Dermatol 2014; 134: 1755-7. 140  141 4. Mössner R, Frambach Y, Wilsmann-Theis D, Löhr S, Jacobi A, Weyergraf A, et al. 142 Palmoplantar pustular psoriasis is associated with missense variants in CARD14, but not with 143 loss-of-function mutations in IL36RN in European patients. J Invest Dermatol 2015; 135: 144 2538-41. 145  146 5. Marrakchi S, Guigue P, Renshaw BR, Puel A, Pei XY, Fraitag S, et al. Interleukin-36-receptor 147 antagonist deficiency and generalized pustular psoriasis. N Engl J Med 2011; 365: 620-8. 148  149 6. Onoufriadis A, Simpson MA, Pink AE, Di Meglio P, Smith CH, Pullabhatla V, et al. 150 Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease 151 known as generalized pustular psoriasis. Am J Hum Genet 2011; 89: 432-7. 152  153 7. Sugiura K, Takemoto A, Yamaguchi M, Takahashi H, Shoda Y, Mitsuma T, et al. The majority 154 of generalized pustular psoriasis without psoriasis vulgaris is caused by deficiency of 155 interleukin-36 receptor antagonist. J Invest Dermatol 2013; 133: 2514-21. 156  157 8. Hussain S, Berki DM, Choon SE, Burden AD, Allen MH, Arostegui JI, et al. IL36RN 158 mutations define a severe autoinflammatory phenotype of generalized pustular psoriasis. J 159 Allergy Clin Immunol 2015; 135: 1067-70.e9. 160  161  7 9. Takeichi T, Sugiura K, Nomura T, Sakamoto T, Ogawa Y, Oiso N, et al. Pityriasis rubra 162 pilaris type V as an autoinflammatory disease by CARD14 mutations. JAMA Dermatol 2017; 163 153: 66-70. 164  165 10. Zhong FL, Mamaï O, Sborgi L, Boussofara L, Hopkins R, Robinson K, et al. Germline 166 NLRP1 mutations cause skin inflammatory and cancer susceptibility syndromes via 167 inflammasome activation. Cell 2016; 167: 187-202.e17. 168  169 170  8 Figure legend 171  172 FIG 1. Pathways and processes of inflammatory responses induced by CARD14 173 gain-of-function mutations and IL-36Ra deficiency. 174 Mutant CARD14 hyperactivates NFκB (red arrows with *), leading to the secretion of 175 chemokines/cytokines, IL-36, IL-8, CXCL1, CXCL2 and CCL20, from the keratinocyte and 176 resulting in the activation of neutrophils and dendritic cells in the dermis. In addition, Th1 and 177 Th17 cells are induced and Th1 cytokines and IL-17 are secreted. IL-36Ra deficiency (red 178 x-mark with *) causes up-regulation of IL-36 signaling, also leading to the secretion of 179 chemokines/cytokines from the keratinocytes. Up-regulated IL-36 signaling finally activates 180 neutrophils and dendritic cells and promotes Th1 and Th17 cell polarization. Black arrows: 181 secretion or activation; brown arrows: cell differentiation or chemotaxis; ⊥: inhibition. 182  183   184  9 TABLE I. Inflammatory keratinization disorders included in AIKD and their pathogeneses 185 Disease Genetic causative factor (frequency) Pathogenic inflammatory mechanisms and pathways in keratinocytes IL36Ra-related pustulosis   generalized pustular psoriasis (GPP) without PV IL36RN mutations (prevalent) IL-36→MyD88→NFkB/MAPK →TNF, IL-1, IL-8, IL-17, IL-36, CXCL1, CXCL2, CCL20 impetigo herpetiformis IL36RN mutations (prevalent) acrodermatitis continua IL36RN mutations (not rare) CARD14-mediated pustular psoriasis     CARD14→NFkB→IL-36, IL-8, CXCL1, CXCL2, CCL20 GPP with PV CARD14 variants (not rare) palmoplantar pustular psoriasis (palmoplantar pustulosis)  CARD14 variants (not rare) Pityriasis rubra pylaris (PRP)  PRP type V CARD14 mutations (prevalent) PRP other types CARD14 variants (rare) Keratosis lichenoides chronica (familial) NLRP1 mutation (unknown) NLRP1→inflammasome →caspase-1→IL-1 →TNF, GM-CSF, IL-36  186  187  188   189  10  190  191  192 FIG 1. Pathways and processes of inflammatory responses induced by CARD14 193 gain-of-function mutations and IL-36Ra deficiency. 194 Mutant CARD14 hyperactivates NFκB (red arrows with *), leading to the secretion of 195 chemokines/cytokines, IL-36, IL-8, CXCL1, CXCL2 and CCL20, from the keratinocyte and 196 resulting in the activation of neutrophils and dendritic cells in the dermis. In addition, Th1 and 197 Th17 cells are induced and Th1 cytokines and IL-17 are secreted. IL-36Ra deficiency (red 198 x-mark with *) causes up-regulation of IL-36 signaling, also leading to the secretion of 199 chemokines/cytokines from the keratinocytes. Up-regulated IL-36 signaling finally activates 200 neutrophils and dendritic cells and promotes Th1 and Th17 cell polarization. Black arrows: 201 secretion or activation; brown arrows: cell differentiation or chemotaxis; ⊥: inhibition. 202  203  204 

Autoinflammatory keratinization diseases

King's Research Portal

                       King’s Research Portal  DOI:10.1016/j.jaci.2017.05.019Document VersionPeer reviewed versionLink to publication record in King's Research PortalCitation for published version (APA):Akiyama, M., Takeichi, T., McGrath, J. A., & Sugiura, K. (2017). Autoinflammatory keratinization diseases.Journal of Allergy and Clinical Immunology. Advance online publication.https://doi.org/10.1016/j.jaci.2017.05.019Citing this paperPlease note that where the full-text provided on King's Research Portal is the Author Accepted Manuscript or Post-Print version this maydiffer from the final Published version. If citing, it is advised that you check and use the publisher's definitive version for pagination,volume/issue, and date of publication details. And where the final published version is provided on the Research Portal, if citing you areagain advised to check the publisher's website for any subsequent corrections.General rightsCopyright and moral rights for the publications made accessible in the Research Portal are retained by the authors and/or other copyrightowners and it is a condition of accessing publications that users recognize and abide by the legal requirements associated with these rights.•Users may download and print one copy of any publication from the Research Portal for the purpose of private study or research.•You may not further distribute the material or use it for any profit-making activity or commercial gain•You may freely distribute the URL identifying the publication in the Research PortalTake down policyIf you believe that this document breaches copyright please contact librarypure@kcl.ac.uk providing details, and we will remove access tothe work immediately and investigate your claim.Download date: 27. Dec. 2025 1 The Journal of Allergy and Clinical Immunology 1 Manuscript ID: JACI-D-16-01828 2nd Revised Version 2  3 Paradigms and perspectives 4  5 Autoinflammatory keratinization diseases 6  7 Masashi Akiyama, MD, PhD,a Takuya Takeichi, MD, PhD,a John A. McGrath, MD, 8 FRCPb and Kazumitsu Sugiura, MD, PhDc 9  10 aDepartment of Dermatology, Nagoya University Graduate School of Medicine, 11 Nagoya, Japan, bSt John’s Institute of Dermatology, King’s College London, Guy’s 12 Hospital, London, UK and cDepartment of Dermatology, Fujita Health University 13 School of Medicine, Toyoake, Japan 14  15 Key words: autoinflammation, CARD14, IL-36 receptor antagonist, keratinization, 16 keratosis lichenoides chronica, NLRP1, pityriasis rubra pylaris, psoriasis, psoriatic 17 arthritis, pustular psoriasis 18  19 Corresponding Author: 20 Masashi Akiyama M.D., Ph.D. 21 Department of Dermatology 22 Nagoya University Graduate School of Medicine 23 65 Tsurumai-cho, Showa-ku, Nagoya 24 Aichi 466-8550, Japan 25 Tel: +81-52-744-2318, Fax: +81-52-744-2318 26 E-mail: makiyama@med.nagoya-u.ac.jp 27  28 Funding sources: No external funding 29  30 Conflicts of interest: None declared 31  32 Word, reference, table and figure counts: 996 words, 10 references, 1 table, 1 figure 33   34  2 Among the genetic causes/predisposing factors for inflammatory keratinization disorders, several 35 factors are associated with autoinflammatory mechanisms. Here we review these inflammatory 36 keratinization disorders with autoinflammatory pathogenic mechanisms and advocate the novel, 37 unique concept of “autoinflammatory keratinization diseases” (AIKD). We propose the following 38 definition of AIKD. (1) The primary and main inflammation sites are the epidermis and the upper 39 dermis. (2) The inflammation in the epidermis and the upper dermis leads to hyperkeratosis, which 40 is the main and characteristic phenotype of AIKD. (3) AIKD have primary genetic causative 41 factors associated with the hyperactivation of innate immunity (autoinflammation), mainly in the 42 epidermis and the upper dermis. (4) The concept of AIKD subsumes diseases with mixed 43 pathomechanisms of autoinflammation and autoimmunity. AIKD have genetic abnormalities as 44 causative factors, and hyperactivation of the innate immune system resulting from those genetic 45 defects plays an important role in the pathogenesis. 46  47 Recently, a number of CARD14 gain-of-function variants/mutations have been reported as 48 predisposing factors for psoriasis vulgaris (plaque-type psoriasis) and psoriatic arthritis.1, 2 Jordan 49 et al.1 found a rare de novo gain-of-function variant in CARD14, p.Glu138Ala, in a sporadic case 50 of severe early-onset generalized pustular psoriasis (GPP). Sugiura et al.3 reported a rare variant in 51 CARD14, p.Asp176His, to be a significant predisposing factor for GPP with preceding or 52 concurrent psoriasis vulgaris lesions, and this variant underlies approximately 20% of GPP cases 53 with psoriasis vulgaris in the Japanese population. CARD14 variants are also disease susceptibility 54 factors of European palmoplantar pustular psoriasis (palmoplantar pustulosis).4  55  56 CARD14 encodes the CARD family member “caspase recruitment domain family, member 14” 57 (CARD14). CARD14 is expressed and localized mainly in the skin, especially in keratinocytes.1 58 Psoriasis-causative CARD14 mutations enhance NF-B activation and upregulate a subset of 59 psoriasis-associated genes in keratinocytes (Fig 1).1, 2 The CARD14 mutations in the keratinocytes 60 are thought to be responsible for pathogeneses and clinical manifestations of inflammatory 61  3 keratinization diseases with CARD14 mutations. However, we cannot rule out the possibility that 62 CARD14 mutations in immune cells other than keratinocytes may be involved in the pathogenesis. 63  64 Deficiency in interleukin 36 receptor antagonist (IL-36Ra) due to mutations in IL36RN has been 65 reported as a genetic cause of familial GPP with recessive inheritance in the Tunisian population.5 66 Onoufriadis et al.6 reported that IL36RN mutations underlie three sporadic European GPP patients. 67 Later, it was elucidated that most sporadic GPP patients without psoriasis vulgaris skin symptoms 68 have IL36RN mutations as a cause of the disease.7 Hussain et al.8 recommended that GPP patients 69 with the clinical triad of early onset, systemic inflammation and absence of concurrent psoriasis 70 vulgaris be screened for IL36RN mutations, based on the results of their GPP cohort study. 71 Mutations in IL36RN have been reported in patients with certain other psoriasis-related diseases, 72 acrodermatitis continua of Hallopeau, severe acute generalized exanthematous pustulosis and 73 impetigo herpetiformis. 74  75 IL-36Ra expression is seen primarily in the skin. IL-36Ra works as an antagonist to the 76 interleukin-1 family members IL-36 ,  and (Fig 1). Thus, deficiency of IL-36Ra due to 77 IL36RN loss-of-function mutations is thought to result in the acceleration of IL-36-driven skin 78 inflammation. 79  80 These facts clearly demonstrate that, among psoriasis and its related disorders, rare subtypes, GPP, 81 impetigo herpetiformis and acrodermatitis continua with IL36RN mutations, and GPP and 82 palmoplantar pustular psoriasis (palmoplantar pustulosis) with CARD14 variants are thought to be 83 catagorizable as AIKD. 84  85 Pityriasis rubra pilaris (PRP) is an inflammatory erythematous keratinization disorder showing 86 perifollicular erythema often with confluent configurations, follicular plugging, pityriasis capitis 87 and palmoplantar hyperkeratosis. Most PRP cases are regarded as sporadic cases, although 88  4 familial occurrence is also seen, particularly in one subtype, type V (atypical juvenile type). 89 Notably, the skin eruptions in type V PRP first appear in infancy or early childhood and tend to run 90 a chronic course with no sustained clearance of the skin. Gain-of-function mutations in CARD14 91 were identified in some autosomal dominant familial cases of PRP. In our recent study of 22 92 patients with PRP, all three patients with PRP type V were found to have CARD14 mutations.9 In 93 addition, detailed clinical features of the reported PRP cases with CARD14 mutations in the 94 literature were reviewed and it was confirmed that all the PRP cases with CARD14 mutations in 95 the literature were affected with type V PRP.9 To date, eight heterozygous mutations in CARD14 96 have been reported in patients with type V PRP. We propose that PRP type V, the atypical juvenile 97 type, is a distinct variant of PRP that is caused by CARD14 mutations9 and should be regarded as 98 an AIKD. 99  100 Keratosis lichenoides chronica (KLC) is a rare inflammatory keratinization disorder of unknown 101 pathomechanism. Characteristic clinical features of KLC are tiny papules on the trunk and 102 extremities, which become confluent, resulting in linear and reticulate patterns, and seborrheic 103 dermatitis-like eruptions on the face. The lesions have a chronic and often progressive course. 104 Recently, a distinct gain-of-function mutation in the inflammasome sensor protein, NLR family, 105 pyrin domain containing protein 1 (NLRP1) was found as the cause in a family with KLC.10 106  107 NLRP1 is considered to be the most prominently expressed inflammasome sensor in human skin, 108 and keratinocytes express all other inflammasome components, including CASP1, ASC, IL-1 109 and IL-18.10 Evidence for spontaneous inflammasome activation by the KLC-causing NLRP1 110 mutation in patients’ keratinocytes has been provided, and inflammasome-dependent IL-1 111 cytokines have been demonstrated to cause familial KLC.10 In this context, we now consider that 112 autoinflammatory mechanisms play an important role in the pathogenesis of KLC, at least in that 113 of familial KLC. 114  115  5 Here we advocate for the new disease category AIKD, which describes inflammatory 116 keratinization disorders with autoinflammatory mechanisms as their predominant etiology, 117 including minor subsets of psoriasis and related diseases, PRP type V and KLC, as mentioned 118 above (Table I). Inflammatory hyperkeratotic skin lesions are not common in conventional 119 autoinflammatory diseases. Thus, although AIKD is thought to have autoinflammatory pathogenic 120 mechanisms, unique pathomechanisms with inflammation that involves epidermal keratinocytes 121 and results in hyperkeratosis are assumed in AIKD. As the causes/predisposing factors for 122 inflammatory keratinization disorders come to be successively elucidated, a larger number of 123 disorders will be categorized into AIKD. 124  125   126  6 REFERENCES 127  128 1. Jordan CT, Cao L, Roberson ED, Pierson KC, Yang CF, Joyce CE, et al. PSORS2 is due to 129 mutations in CARD14. Am J Hum Genet 2012; 90: 784-95. 130  131 2. Jordan CT, Cao L, Roberson ED, Duan S, Helms CA, Nair RP, et al. Rare and common variants 132 in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis. Am J Hum Genet 2012; 133 90: 796-808. 134  135 3. Sugiura K, Muto M, Akiyama M. CARD14 c.526G>C (p.Asp176His) is a significant risk factor 136 for generalized pustular psoriasis with psoriasis vulgaris in the Japanese cohort. J Invest Dermatol 137 2014; 134: 1755-7. 138  139 4. Mössner R, Frambach Y, Wilsmann-Theis D, Löhr S, Jacobi A, Weyergraf A, et al. 140 Palmoplantar pustular psoriasis is associated with missense variants in CARD14, but not with 141 loss-of-function mutations in IL36RN in European patients. J Invest Dermatol 2015; 135: 142 2538-41. 143  144 5. Marrakchi S, Guigue P, Renshaw BR, Puel A, Pei XY, Fraitag S, et al. Interleukin-36-receptor 145 antagonist deficiency and generalized pustular psoriasis. N Engl J Med 2011; 365: 620-8. 146  147 6. Onoufriadis A, Simpson MA, Pink AE, Di Meglio P, Smith CH, Pullabhatla V, et al. Mutations 148 in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as 149 generalized pustular psoriasis. Am J Hum Genet 2011; 89: 432-7. 150  151 7. Sugiura K, Takemoto A, Yamaguchi M, Takahashi H, Shoda Y, Mitsuma T, et al. The majority 152 of generalized pustular psoriasis without psoriasis vulgaris is caused by deficiency of 153 interleukin-36 receptor antagonist. J Invest Dermatol 2013; 133: 2514-21. 154  155 8. Hussain S, Berki DM, Choon SE, Burden AD, Allen MH, Arostegui JI, et al. IL36RN mutations 156 define a severe autoinflammatory phenotype of generalized pustular psoriasis. J Allergy Clin 157 Immunol 2015; 135: 1067-70.e9. 158  159  7 9. Takeichi T, Sugiura K, Nomura T, Sakamoto T, Ogawa Y, Oiso N, et al. Pityriasis rubra pilaris 160 type V as an autoinflammatory disease by CARD14 mutations. JAMA Dermatol 2017; 153: 161 66-70. 162  163 10. Zhong FL, Mamaï O, Sborgi L, Boussofara L, Hopkins R, Robinson K, et al. Germline NLRP1 164 mutations cause skin inflammatory and cancer susceptibility syndromes via inflammasome 165 activation. Cell 2016; 167: 187-202.e17. 166  167 168  8 Figure legend 169  170 FIG 1. Pathways and processes of inflammatory responses induced by CARD14 gain-of-function 171 mutations and IL-36Ra deficiency. 172 Mutant CARD14 hyperactivates NFB (red arrows with *), leading to the secretion of 173 chemokines/cytokines, IL-36, IL-8, CXCL1, CXCL2 and CCL20, from the keratinocyte and 174 resulting in the activation of neutrophils and dendritic cells in the dermis. In addition, Th1 and 175 Th17 cells are induced and Th1 cytokines and IL-17 are secreted. IL-36Ra deficiency (red x-mark 176 with *) causes up-regulation of IL-36 signaling, also leading to the secretion of 177 chemokines/cytokines from the keratinocytes. Up-regulated IL-36 signaling finally activates 178 neutrophils and dendritic cells and promotes Th1 and Th17 cell polarization. Black arrows: 179 secretion or activation; brown arrows: cell differentiation or chemotaxis; ⊥: inhibition. 180  181   182  9 TABLE I. Inflammatory keratinization disorders included in AIKD and their pathogeneses 183 Disease Genetic causative factor (frequency) Pathogenic inflammatory mechanisms and pathways in keratinocytes IL36Ra-related pustulosis   generalized pustular psoriasis (GPP) without PV IL36RN mutations (prevalent) IL-36→MyD88→NFkB/MAPK →TNF, IL-1, IL-8, IL-17, IL-36, CXCL1, CXCL2, CCL20 impetigo herpetiformis IL36RN mutations (prevalent) acrodermatitis continua IL36RN mutations (not rare) CARD14-mediated pustular psoriasis     CARD14→NFkB→IL-36, IL-8, CXCL1, CXCL2, CCL20 GPP with PV CARD14 variants (not rare) palmoplantar pustular psoriasis (palmoplantar pustulosis)  CARD14 variants (not rare) Pityriasis rubra pylaris (PRP)  PRP type V CARD14 mutations (prevalent) PRP other types CARD14 variants (rare) Keratosis lichenoides chronica (familial) NLRP1 mutation (unknown) NLRP1→inflammasome →caspase-1→IL-1 →TNF, GM-CSF, IL-36  184  185 

Masashi Akiyama

Takuya Takeichi

John A. McGrath

Kazumitsu Sugiura

Crossref

                       King’s Research Portal  DOI:10.1016/j.jaci.2017.05.019Document VersionPeer reviewed versionLink to publication record in King's Research PortalCitation for published version (APA):Akiyama, M., Takeichi, T., McGrath, J. A., & Sugiura, K. (2017). Autoinflammatory keratinization diseases.Journal of Allergy and Clinical Immunology. https://doi.org/10.1016/j.jaci.2017.05.019Citing this paperPlease note that where the full-text provided on King's Research Portal is the Author Accepted Manuscript or Post-Print version this maydiffer from the final Published version. If citing, it is advised that you check and use the publisher's definitive version for pagination,volume/issue, and date of publication details. And where the final published version is provided on the Research Portal, if citing you areagain advised to check the publisher's website for any subsequent corrections.General rightsCopyright and moral rights for the publications made accessible in the Research Portal are retained by the authors and/or other copyrightowners and it is a condition of accessing publications that users recognize and abide by the legal requirements associated with these rights.•Users may download and print one copy of any publication from the Research Portal for the purpose of private study or research.•You may not further distribute the material or use it for any profit-making activity or commercial gain•You may freely distribute the URL identifying the publication in the Research PortalTake down policyIf you believe that this document breaches copyright please contact librarypure@kcl.ac.uk providing details, and we will remove access tothe work immediately and investigate your claim.Download date: 06. Oct. 2023 1 The Journal of Allergy and Clinical Immunology 1 Manuscript ID: JACI-D-16-01828 2nd Revised Version 2  3 Paradigms and perspectives 4  5 Autoinflammatory keratinization diseases 6  7 Masashi Akiyama, MD, PhD,a Takuya Takeichi, MD, PhD,a John A. McGrath, MD, 8 FRCPb and Kazumitsu Sugiura, MD, PhDc 9  10 aDepartment of Dermatology, Nagoya University Graduate School of Medicine, 11 Nagoya, Japan, bSt John’s Institute of Dermatology, King’s College London, Guy’s 12 Hospital, London, UK and cDepartment of Dermatology, Fujita Health University 13 School of Medicine, Toyoake, Japan 14  15 Key words: autoinflammation, CARD14, IL-36 receptor antagonist, keratinization, 16 keratosis lichenoides chronica, NLRP1, pityriasis rubra pylaris, psoriasis, psoriatic 17 arthritis, pustular psoriasis 18  19 Corresponding Author: 20 Masashi Akiyama M.D., Ph.D. 21 Department of Dermatology 22 Nagoya University Graduate School of Medicine 23 65 Tsurumai-cho, Showa-ku, Nagoya 24 Aichi 466-8550, Japan 25 Tel: +81-52-744-2318, Fax: +81-52-744-2318 26 E-mail: makiyama@med.nagoya-u.ac.jp 27  28 Funding sources: No external funding 29  30 Conflicts of interest: None declared 31  32 Word, reference, table and figure counts: 996 words, 10 references, 1 table, 1 figure 33   34  2 Among the genetic causes/predisposing factors for inflammatory keratinization disorders, several 35 factors are associated with autoinflammatory mechanisms. Here we review these inflammatory 36 keratinization disorders with autoinflammatory pathogenic mechanisms and advocate the novel, 37 unique concept of “autoinflammatory keratinization diseases” (AIKD). We propose the following 38 definition of AIKD. (1) The primary and main inflammation sites are the epidermis and the upper 39 dermis. (2) The inflammation in the epidermis and the upper dermis leads to hyperkeratosis, which 40 is the main and characteristic phenotype of AIKD. (3) AIKD have primary genetic causative 41 factors associated with the hyperactivation of innate immunity (autoinflammation), mainly in the 42 epidermis and the upper dermis. (4) The concept of AIKD subsumes diseases with mixed 43 pathomechanisms of autoinflammation and autoimmunity. AIKD have genetic abnormalities as 44 causative factors, and hyperactivation of the innate immune system resulting from those genetic 45 defects plays an important role in the pathogenesis. 46  47 Recently, a number of CARD14 gain-of-function variants/mutations have been reported as 48 predisposing factors for psoriasis vulgaris (plaque-type psoriasis) and psoriatic arthritis.1, 2 Jordan 49 et al.1 found a rare de novo gain-of-function variant in CARD14, p.Glu138Ala, in a sporadic case 50 of severe early-onset generalized pustular psoriasis (GPP). Sugiura et al.3 reported a rare variant in 51 CARD14, p.Asp176His, to be a significant predisposing factor for GPP with preceding or 52 concurrent psoriasis vulgaris lesions, and this variant underlies approximately 20% of GPP cases 53 with psoriasis vulgaris in the Japanese population. CARD14 variants are also disease susceptibility 54 factors of European palmoplantar pustular psoriasis (palmoplantar pustulosis).4  55  56 CARD14 encodes the CARD family member “caspase recruitment domain family, member 14” 57 (CARD14). CARD14 is expressed and localized mainly in the skin, especially in keratinocytes.1 58 Psoriasis-causative CARD14 mutations enhance NF-B activation and upregulate a subset of 59 psoriasis-associated genes in keratinocytes (Fig 1).1, 2 The CARD14 mutations in the keratinocytes 60 are thought to be responsible for pathogeneses and clinical manifestations of inflammatory 61  3 keratinization diseases with CARD14 mutations. However, we cannot rule out the possibility that 62 CARD14 mutations in immune cells other than keratinocytes may be involved in the pathogenesis. 63  64 Deficiency in interleukin 36 receptor antagonist (IL-36Ra) due to mutations in IL36RN has been 65 reported as a genetic cause of familial GPP with recessive inheritance in the Tunisian population.5 66 Onoufriadis et al.6 reported that IL36RN mutations underlie three sporadic European GPP patients. 67 Later, it was elucidated that most sporadic GPP patients without psoriasis vulgaris skin symptoms 68 have IL36RN mutations as a cause of the disease.7 Hussain et al.8 recommended that GPP patients 69 with the clinical triad of early onset, systemic inflammation and absence of concurrent psoriasis 70 vulgaris be screened for IL36RN mutations, based on the results of their GPP cohort study. 71 Mutations in IL36RN have been reported in patients with certain other psoriasis-related diseases, 72 acrodermatitis continua of Hallopeau, severe acute generalized exanthematous pustulosis and 73 impetigo herpetiformis. 74  75 IL-36Ra expression is seen primarily in the skin. IL-36Ra works as an antagonist to the 76 interleukin-1 family members IL-36 ,  and (Fig 1). Thus, deficiency of IL-36Ra due to 77 IL36RN loss-of-function mutations is thought to result in the acceleration of IL-36-driven skin 78 inflammation. 79  80 These facts clearly demonstrate that, among psoriasis and its related disorders, rare subtypes, GPP, 81 impetigo herpetiformis and acrodermatitis continua with IL36RN mutations, and GPP and 82 palmoplantar pustular psoriasis (palmoplantar pustulosis) with CARD14 variants are thought to be 83 catagorizable as AIKD. 84  85 Pityriasis rubra pilaris (PRP) is an inflammatory erythematous keratinization disorder showing 86 perifollicular erythema often with confluent configurations, follicular plugging, pityriasis capitis 87 and palmoplantar hyperkeratosis. Most PRP cases are regarded as sporadic cases, although 88  4 familial occurrence is also seen, particularly in one subtype, type V (atypical juvenile type). 89 Notably, the skin eruptions in type V PRP first appear in infancy or early childhood and tend to run 90 a chronic course with no sustained clearance of the skin. Gain-of-function mutations in CARD14 91 were identified in some autosomal dominant familial cases of PRP. In our recent study of 22 92 patients with PRP, all three patients with PRP type V were found to have CARD14 mutations.9 In 93 addition, detailed clinical features of the reported PRP cases with CARD14 mutations in the 94 literature were reviewed and it was confirmed that all the PRP cases with CARD14 mutations in 95 the literature were affected with type V PRP.9 To date, eight heterozygous mutations in CARD14 96 have been reported in patients with type V PRP. We propose that PRP type V, the atypical juvenile 97 type, is a distinct variant of PRP that is caused by CARD14 mutations9 and should be regarded as 98 an AIKD. 99  100 Keratosis lichenoides chronica (KLC) is a rare inflammatory keratinization disorder of unknown 101 pathomechanism. Characteristic clinical features of KLC are tiny papules on the trunk and 102 extremities, which become confluent, resulting in linear and reticulate patterns, and seborrheic 103 dermatitis-like eruptions on the face. The lesions have a chronic and often progressive course. 104 Recently, a distinct gain-of-function mutation in the inflammasome sensor protein, NLR family, 105 pyrin domain containing protein 1 (NLRP1) was found as the cause in a family with KLC.10 106  107 NLRP1 is considered to be the most prominently expressed inflammasome sensor in human skin, 108 and keratinocytes express all other inflammasome components, including CASP1, ASC, IL-1 109 and IL-18.10 Evidence for spontaneous inflammasome activation by the KLC-causing NLRP1 110 mutation in patients’ keratinocytes has been provided, and inflammasome-dependent IL-1 111 cytokines have been demonstrated to cause familial KLC.10 In this context, we now consider that 112 autoinflammatory mechanisms play an important role in the pathogenesis of KLC, at least in that 113 of familial KLC. 114  115  5 Here we advocate for the new disease category AIKD, which describes inflammatory 116 keratinization disorders with autoinflammatory mechanisms as their predominant etiology, 117 including minor subsets of psoriasis and related diseases, PRP type V and KLC, as mentioned 118 above (Table I). Inflammatory hyperkeratotic skin lesions are not common in conventional 119 autoinflammatory diseases. Thus, although AIKD is thought to have autoinflammatory pathogenic 120 mechanisms, unique pathomechanisms with inflammation that involves epidermal keratinocytes 121 and results in hyperkeratosis are assumed in AIKD. As the causes/predisposing factors for 122 inflammatory keratinization disorders come to be successively elucidated, a larger number of 123 disorders will be categorized into AIKD. 124  125   126  6 REFERENCES 127  128 1. Jordan CT, Cao L, Roberson ED, Pierson KC, Yang CF, Joyce CE, et al. PSORS2 is due to 129 mutations in CARD14. Am J Hum Genet 2012; 90: 784-95. 130  131 2. Jordan CT, Cao L, Roberson ED, Duan S, Helms CA, Nair RP, et al. Rare and common variants 132 in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis. Am J Hum Genet 2012; 133 90: 796-808. 134  135 3. Sugiura K, Muto M, Akiyama M. CARD14 c.526G>C (p.Asp176His) is a significant risk factor 136 for generalized pustular psoriasis with psoriasis vulgaris in the Japanese cohort. J Invest Dermatol 137 2014; 134: 1755-7. 138  139 4. Mössner R, Frambach Y, Wilsmann-Theis D, Löhr S, Jacobi A, Weyergraf A, et al. 140 Palmoplantar pustular psoriasis is associated with missense variants in CARD14, but not with 141 loss-of-function mutations in IL36RN in European patients. J Invest Dermatol 2015; 135: 142 2538-41. 143  144 5. Marrakchi S, Guigue P, Renshaw BR, Puel A, Pei XY, Fraitag S, et al. Interleukin-36-receptor 145 antagonist deficiency and generalized pustular psoriasis. N Engl J Med 2011; 365: 620-8. 146  147 6. Onoufriadis A, Simpson MA, Pink AE, Di Meglio P, Smith CH, Pullabhatla V, et al. Mutations 148 in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as 149 generalized pustular psoriasis. Am J Hum Genet 2011; 89: 432-7. 150  151 7. Sugiura K, Takemoto A, Yamaguchi M, Takahashi H, Shoda Y, Mitsuma T, et al. The majority 152 of generalized pustular psoriasis without psoriasis vulgaris is caused by deficiency of 153 interleukin-36 receptor antagonist. J Invest Dermatol 2013; 133: 2514-21. 154  155 8. Hussain S, Berki DM, Choon SE, Burden AD, Allen MH, Arostegui JI, et al. IL36RN mutations 156 define a severe autoinflammatory phenotype of generalized pustular psoriasis. J Allergy Clin 157 Immunol 2015; 135: 1067-70.e9. 158  159  7 9. Takeichi T, Sugiura K, Nomura T, Sakamoto T, Ogawa Y, Oiso N, et al. Pityriasis rubra pilaris 160 type V as an autoinflammatory disease by CARD14 mutations. JAMA Dermatol 2017; 153: 161 66-70. 162  163 10. Zhong FL, Mamaï O, Sborgi L, Boussofara L, Hopkins R, Robinson K, et al. Germline NLRP1 164 mutations cause skin inflammatory and cancer susceptibility syndromes via inflammasome 165 activation. Cell 2016; 167: 187-202.e17. 166  167 168  8 Figure legend 169  170 FIG 1. Pathways and processes of inflammatory responses induced by CARD14 gain-of-function 171 mutations and IL-36Ra deficiency. 172 Mutant CARD14 hyperactivates NFB (red arrows with *), leading to the secretion of 173 chemokines/cytokines, IL-36, IL-8, CXCL1, CXCL2 and CCL20, from the keratinocyte and 174 resulting in the activation of neutrophils and dendritic cells in the dermis. In addition, Th1 and 175 Th17 cells are induced and Th1 cytokines and IL-17 are secreted. IL-36Ra deficiency (red x-mark 176 with *) causes up-regulation of IL-36 signaling, also leading to the secretion of 177 chemokines/cytokines from the keratinocytes. Up-regulated IL-36 signaling finally activates 178 neutrophils and dendritic cells and promotes Th1 and Th17 cell polarization. Black arrows: 179 secretion or activation; brown arrows: cell differentiation or chemotaxis; ⊥: inhibition. 180  181   182  9 TABLE I. Inflammatory keratinization disorders included in AIKD and their pathogeneses 183 Disease Genetic causative factor (frequency) Pathogenic inflammatory mechanisms and pathways in keratinocytes IL36Ra-related pustulosis   generalized pustular psoriasis (GPP) without PV IL36RN mutations (prevalent) IL-36→MyD88→NFkB/MAPK →TNF, IL-1, IL-8, IL-17, IL-36, CXCL1, CXCL2, CCL20 impetigo herpetiformis IL36RN mutations (prevalent) acrodermatitis continua IL36RN mutations (not rare) CARD14-mediated pustular psoriasis     CARD14→NFkB→IL-36, IL-8, CXCL1, CXCL2, CCL20 GPP with PV CARD14 variants (not rare) palmoplantar pustular psoriasis (palmoplantar pustulosis)  CARD14 variants (not rare) Pityriasis rubra pylaris (PRP)  PRP type V CARD14 mutations (prevalent) PRP other types CARD14 variants (rare) Keratosis lichenoides chronica (familial) NLRP1 mutation (unknown) NLRP1→inflammasome →caspase-1→IL-1 →TNF, GM-CSF, IL-36  184  185 

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