Review articleAutoinflammatory keratinization diseases: An emerging concept encompassing various inflammatory keratinization disorders of the skin
Introduction
Among the myriad diseases affecting the skin are a subset of disorders whose main pathobiology is inflammation, predominantly in the epidermis and the superficial dermis, that leads to hyperkeratosis, manifesting clinically as thickened scaly skin. These are designated as “inflammatory keratinization disorders”. The category includes many conditions that are poorly defined, although some, including psoriasis and lichen planus, are better categorized.
Nevertheless, the pathogenic mechanisms of most inflammatory keratinization disorders remain unresolved. However, new pathogenic mechanisms relating to autoinflammation have been demonstrated in some inflammatory keratinization disorders, providing unexpected mechanistic insights and new ideas for targeted therapies. In 2017, we proposed a new umbrella term, “autoinflammatory keratinization diseases” (AIKD), to encompass inflammatory keratinization disorders with autoinflammatory pathogenic mechanisms [1]. We herein summarize the concept of AIKD, review the diseases included in this disease subgrouping, and discuss the clinical value of grouping conditions as AIKD.
Section snippets
What are AIKD?
Our initial concept paper on AIKD defined the disease entities as having four inclusion criteria [1]: (1) the primary and main inflammation sites are the epidermis and the upper dermis; (2) the inflammation leads to hyperkeratosis, which is the main and characteristic phenotype of AIKD; (3) AIKD have primary genetic causative factors associated with the hyperactivation of innate immunity (autoinflammation), mainly in the epidermis and the upper dermis; (4) the spectrum of AIKD encompasses
IL-36RA-related pustulosis
In 2011, Marrakchi et al. [3] reported that IL36RN mutations leading to IL-36Ra deficiency were present in nine Tunisian families with recessively inherited familial generalized pustular psoriasis (GPP). IL36RN mutations were also reported as a genetic cause in three sporadic European GPP patients [4] and a Japanese GPP patient [5] (Fig. 1A, B). Subsequently, it was established that most sporadic GPP patients without preceding or concomitant psoriasis vulgaris (PV) skin lesions have IL36RN
CARD14-mediated pustular psoriasis
Psoriasis, one of the most common inflammatory keratinization disorders, is a chronic multifactorial inflammatory disease involving the skin, nails and joints [17]. The most common plaque-type psoriasis is psoriasis vulgaris (PV). Various inflammatory keratinization disorders such as psoriatic arthritis, GPP and palmoplantar pustular psoriasis (palmoplantar pustulosis) are known to be psoriasis-related diseases [18]. Recently, Arakawa et al. [19] demonstrated that melanocyte antigens can
Pityriasis rubra pilaris (PRP)
In addition, the concept of AIKD can also be applied to CARD14 mutation-driven inflammatory keratinization diseases, such as PRP type V. PRP is an inflammatory keratinization disease that shows general follicular plugging and perifollicular erythema with confluent configurations [31]. Pityriasis capitis and palmoplantar keratoderma are also seen in PRP [31]. In 1980, PRP was classified into five subgroups, types I–V, based on clinical criteria (age of onset, distribution of lesions, disease
Familial keratosis lichenoides chronica (KLC)
KLC is an infrequently seen inflammatory keratinization disorder. Kaposi first described KLC in 1895, but the term KLC was formally proposed by Margolis in 1972 [38]. Patients with KLC show multiple small papules with confluent, linear and reticulate configurations on the trunk and extremities. KLC patients may also have seborrheic dermatitis-like eruptions on the face, palmoplantar keratoderma and hypertrophic nail deformities. These skin lesions are usually asymptomatic, but typically show
Therapies based on the pathomechanisms of AIKD
Recently, various therapies based on the pathomechanisms of AIKD have achieved sufficient efficacy in several kinds of AIKD.
Neutrophils are thought to be frequently involved in the inflammatory reaction induced in AIKD (Fig. 2). Thus, granulocyte and monocyte adsorption apheresis is expected to be effective for AIKD cases. Indeed, the treatment efficacy of granulocyte and monocyte adsorption apheresis was reported in a GPP case that resulted from an IL36RN mutation [45].
Concerning molecularly
Conclusions and future perspectives
In 2017, the disease terminology AIKD was proposed for inflammatory keratinization disorders with autoinflammatory mechanisms as their main etiology (Fig. 2) [1]. The clinical entity of AIKD contains certain PRP type V, KLC, and subgroups of psoriasis-related diseases as described above (Table 2).
The data summarized indicate that certain subsets of psoriasis and diseases related to it have genetic causes and predisposing factors associated with autoinflammatory mechanisms, such as CARD14
Conflict of interest
The authors declare no conflict of interest.
Acknowledgements
This work was supported by funding from Advanced Research and Development Programs for Medical Innovation (AMED-CREST: JP17gm0910002) to M.A. from Japan Agency for Medical Research and Development (AMED), and by a Grant-in-Aid for Scientific Research (B)15H04887 to M.A. from the Japan Society for the Promotion of Science (JSPS).
Masashi Akiyama (M.D., Ph.D.) is a Professor and Chairman of the Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan from 2010. He received the M.D. in 1986 and Ph.D. in 1991 from Keio University, Tokyo, Japan. He was assigned as a Senior Research Fellow at University of Washington, Seattle (1992–1994) and an Associate Professor at Teikyo University Ichihara Hospital, Chiba, Japan (1999–2001). He served as an Assistant Professor (2001–2007) and an Associate
References (50)
- et al.
Autoinflammatory keratinization diseases
J. Allergy Clin. Immunol.
(2017) - 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) - et al.
The majority of generalized pustular psoriasis without psoriasis vulgaris is caused by deficiency of interleukin-36 receptor antagonist
J. Invest. Dermatol.
(2013) - et al.
A newly revealed IL36RN mutation in sibling cases complements our IL36RN mutation statistics for generalized pustular psoriasis
J. Dermatol. Sci.
(2017) - et al.
Rare pathogenic variants in IL36RN underlie a spectrum of psoriasis-associated pustular phenotypes
J. Invest. Dermatol.
(2013) - et al.
Rare variations in IL36RN in severe adverse drug reactions manifesting as acute generalized exanthematous pustulosis
J. Invest. Dermatol.
(2013) - et al.
IL36RN mutations underlie impetigo herpetiformis
J. Invest. Dermatol.
(2014) - et al.
Inter-regulation of Th17 cytokines and the IL-36 cytokines in vitro and in vivo: implications in psoriasis pathogenesis
J. Invest. Dermatol
(2011) - et al.
Neutrophil-derived proteases escalate inflammation through activation of IL-36 family cytokines
Cell Rep.
(2016) - et al.
Interleukin (IL)-1F6, IL-1F8, and IL-1F9 signal through IL-1Rrp2 and IL-1RAcP to activate the pathway leading to NF-kappaB and MAPKs
J. Biol. Chem.
(2004)
The genetic background of generalized pustular psoriasis: IL36RN mutations and CARD14 gain-of-function variants
J. Dermatol. Sci.
Toll-like receptor 4 antagonist TAK-242 inhibits autoinflammatory symptoms in DITRA
J. Autoimmun.
The translational revolution and use of biologics in patients with inflammatory skin diseases
J. Allergy Clin. Immunol.
Psoriasis and autoimmunity
Autoimmun. Rev.
PSORS2 is due to mutations in CARD14
Am. J. Hum. Genet.
Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis
Am. J. Hum. Genet.
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.
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.
Familial pityriasis rubra pilaris is caused by mutations in CARD14
Am. J. Hum. Genet.
CARD14-mediated activation of paracaspase MALT1 in keratinocytes: implications for psoriasis
J. Invest. Dermatol.
Pityriasis rubra pilaris in a patient with human immunodeficiency virus infection
J. Am. Acad. Dermatol.
Autoinflammatory disease reloaded: a clinical perspective
Cell
Autosomal dominant familial generalized pustular psoriasis caused by a CARD14 mutation
Br. J. Dermatol.
Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis
N. Engl. J. Med.
A novel IL36RN/IL1F5 homozygous nonsense mutation, p. Arg10X, in a Japanese patient with adult-onset generalized pustular psoriasis
Br. J. Dermatol.
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2022, CytokineCitation Excerpt :GPP symptoms are preceded by psoriasis vulgaris in approximately two-thirds of patients, and GPP is traditionally classified as a subtype of psoriasis [80,82,87]. More recently, the distinct features of GPP pathology and inflammatory signatures skewed towards hyperactivation of innate immune responses have promoted the classification of GPP as an autoinflammatory keratinization disorder [88–90]. Various missense mutations in IL36RN are present in approximately one-third of GPP patients and occur in both familial and sporadic settings [80].
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2022, Journal of Dermatological ScienceCitation Excerpt :Inflammation induced by the hyperactivation of innate immunity triggered by genetic factors sometimes leads to inflammatory keratinization diseases of the skin. Those inflammatory keratinization diseases with genetic autoinflammatory pathomechanisms are termed “autoinflammatory keratinization diseases” (AiKDs) [7,8]. AiKDs also include disorders that have mixed autoinflammatory and autoimmune pathomechanisms.
Masashi Akiyama (M.D., Ph.D.) is a Professor and Chairman of the Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan from 2010. He received the M.D. in 1986 and Ph.D. in 1991 from Keio University, Tokyo, Japan. He was assigned as a Senior Research Fellow at University of Washington, Seattle (1992–1994) and an Associate Professor at Teikyo University Ichihara Hospital, Chiba, Japan (1999–2001). He served as an Assistant Professor (2001–2007) and an Associate Professor (2007–2010) at Hokkaido University, Sapporo, Japan. His research is in the field of genodermatosis, genetic and autoinflammatory keratinization diseases, skin barrier function and its related allergic diseases.