Autoinflammatory Keratinization Diseases (AiKDs): Expansion of Disorders to Be Included

Akiyama, Masashi

doi:10.3389/fimmu.2020.00280

Cited by 20 publications

(14 citation statements)

References 43 publications

(56 reference statements)

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“…The observed lack of correlations between IL-1b and IL-18 and the severity of psoriasis as well as with the increased caspase-1 reactivity in patients with mild PASI suggests an ongoing, low-grade inflammatory process in the blood that is acting independently of the skin manifestations. Moreover, our data support that psoriasis may be a part of the autoinflammatory keratinization diseases (Akiyama, 2020;Akiyama et al, 2017). The CD4þ T cells, despite the primed NLRP3, did not display enhanced caspase-1 reactivity in response to short-term exposure to LPS, which may reflect a requirement for additional T-cell activation, as shown by Arbore et al (2016).…”

Section: Discussionsupporting

confidence: 73%

Enhanced Inflammasome Activity in Patients with Psoriasis Promotes Systemic Inflammation

Verma

Fekri

Sigurdardottir

et al. 2021

Journal of Investigative Dermatology

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Psoriasis is linked to systemic inflammation and cardiovascular comorbidities, but studies of the underlying cellular mechanisms are lacking. The NLRP3 inflammasome is genetically associated with psoriasis, and its activation is increasingly linked with cardiovascular disease. In this study, we show that patients with psoriasis exhibited higher plasma levels of inflammasome-generated IL-1b and IL-18, without any correlation to skin lesion severity. Increased constitutive expression of the inflammasome sensors NLRP3, NLRP1, and AIM2 was found in peripheral blood cells of the patients and also of those with mild disease, and this was accompanied by an increased caspase-1 reactivity in the myeloid blood subsets. TNF-a was found to activate selectively the NLRP3 inflammasome without the requirement for a priming signal. TNF-a was found to signal through the TNFR-caspase-8-caspase-1 alternative inflammasome pathway, which proceeds independently of pyroptosis. Patients who received anti-TNF therapy had normalized plasma IL-1b and IL-18 levels as well as normalized caspase-1 reactivity. This was in contrast to the patients treated with methotrexate who exhibited persistent, increased caspase-1 reactivity. Thus, we show that the TNF-aemediated activation of NLRP3 inflammasomes in patients with psoriasis may contribute to systemic inflammation. Anti-TNF therapy normalized inflammasome function, suggesting a mechanism for the cardiovascular risk-reducing effect.

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Section: Discussionsupporting

confidence: 73%

Enhanced Inflammasome Activity in Patients with Psoriasis Promotes Systemic Inflammation

Verma

Fekri

Sigurdardottir

et al. 2021

Journal of Investigative Dermatology

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“…8,9 Furthermore, long-tract LoH is frequently seen in skin lesions of porokeratosis (MIM: 175900, 614714), 51 a common autoinflammatory keratinization disease. 52 Interestingly, previous studies have shown that it is replication stress, and not I-SceI-induced DSB, which activates the NF-kB signaling pathway, which, in turn, induces HR. 53 The current study indicated that mut-CARD14 does not promote HR when DSBs are exogenously introduced via I-SceI but rather drives BIR under conditions of replication stress.…”

Section: Discussionmentioning

confidence: 99%

Altered replication stress response due to CARD14 mutations promotes recombination-induced revertant mosaicism

Miyauchi

Suzuki

Takeda

et al. 2021

The American Journal of Human Genetics

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“…Several types of IL36RN mutations, including substitution, frameshift, and splicing defects, have been reported as the causative genetic background in numerous GPP cases, in various geographical regions [8,24,46,47,53,[59][60][61][62][63]. In addition, Hussain et al demonstrated that IL36RN mutation carriers exhibit a more severe clinical phenotype (e.g., earlier age of disease onset, increased risk of systemic manifestations) and the absence of co-existing plaque psoriasis, when compared to individuals without IL36RN mutation [64].…”

Section: Mutations Of Il-36 Receptor Antagonistmentioning

confidence: 99%

“…Importantly, since AiKDs include conditions with mixed pathological mechanisms of autoinflammation and autoimmunity, they are unique, and in many ways different, from classic autoinflammatory diseases. Initially, AiKDs comprised pustular psoriasis and related entities, including GPP, impetigo herpetiformis, and acrodermatitis continua Hallopeau due to mutations in IL36RN, GPP and palmoplantar pustular psoriasis due to CARD14 variants [72], and pityriasis rubra pilaris caused by CARD14 mutations/variants [73]; the AiKDs spectrum has since been extended and now includes several entities [61,62].…”

Section: Gpp As An Autoinflammatory Keratinization Disordermentioning

confidence: 99%

Generalized Pustular Psoriasis: Divergence of Innate and Adaptive Immunity

Samotij

Szczęch

Reich

2021

IJMS

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Generalized pustular psoriasis (GPP) is a severe, relapsing, immune-mediated disease characterized by the presence of multiple sterile pustules all over the body. The exact pathomechanisms behind GPP remain elusive, although increased interest in the genetic basis and immunological disturbances have provided some revealing insights into the underlying signaling pathways and their mutual interaction. The genetic background of GPP has been thoroughly investigated over the past few years. The conducted studies have identified genetic variants that predispose to pustular forms of psoriasis. The loss-of-function mutation of the interleukin 36 receptor antagonist gene, along with rare gain-of-function mutations in the gene that encodes the keratinocyte signaling molecule (CARD14), are examples of the uncovered abnormalities. Interleukin 36 (IL-36), along with neutrophils, is now considered a central cytokine in GPP pathogenesis, with IL-36 signaling providing a link between innate and adaptive immune responses. More recently, a new concept of inflammation, caused by a predominantly genetically determined abnormal activation of innate immune response and leading to inflammatory keratinization, has arisen. GPP is currently considered a representative of this novel group of skin conditions, called autoinflammatory keratinization diseases. As no therapeutic agents have been approved for GPP to date in the United States and Europe, the novel anti-IL-36R antibodies are particularly promising and may revolutionize management of the disease.

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Autoinflammatory Keratinization Diseases (AiKDs): Expansion of Disorders to Be Included

Cited by 20 publications

References 43 publications

Enhanced Inflammasome Activity in Patients with Psoriasis Promotes Systemic Inflammation

Enhanced Inflammasome Activity in Patients with Psoriasis Promotes Systemic Inflammation

Altered replication stress response due to CARD14 mutations promotes recombination-induced revertant mosaicism

Generalized Pustular Psoriasis: Divergence of Innate and Adaptive Immunity

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