“Autoinflammatory psoriasis”—genetics and biology of pustular psoriasis

Uppala, Rattapon; Tsoi, Lam C.; Harms, Paul W.; Wang, Bo; Billi, Allison C.; Maverakis, Emanual; Kahlenberg, J. Michelle; Ward, Nicole L.; Guðjónsson, Jóhann E.

doi:10.1038/s41423-020-0519-3

Cited by 69 publications

(111 citation statements)

References 136 publications

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“…The innate immune response has a predominant role in the immunopathogenesis of pustular psoriasis, with activation of the IL-1/IL-36 inflammatory axis leading to neutrophil chemotaxis and neutrophil-driven inflammatory responses [ 16 ]. Mutations in genes coding for IL-36 axis components—mainly the IL-36RN gene but also the SERPINA3 gene—and NFκB signaling pathways (CARD14, AP1S3, TNIP1) have been associated with both GPP and palmoplantar/acral pustular psoriasis [ 14 , 44 ].…”

Section: The Role Of Il-36 Family Cytokines In Psoriasis Pathogenesismentioning

confidence: 99%

“…More recently, the identification of specific mutations in the IL36RN gene encoding the IL-36 receptor antagonist (IL-36Ra) have been linked to an autoinflammatory condition characterized by a severe form of GPP called “deficiency of interleukin-36-receptor antagonist” (DITRA); this highlights the importance of IL-36 family cytokines as critical mediators of psoriatic disease [ 14 , 15 ]. Other genes with mutations associated with pustular psoriasis include caspase-activating recruitment domain member 14 (CARD14), adaptor protein complex 1 subunit sigma 3 (AP1S3), TNFAIP3-interacting protein 1 (TNIP1), and serpin family A member 3 (SERPINA 3) [ 16 ]. All of them are involved in IL-1/IL-36 signaling pathways, further underscoring the relevance of these cytokines in pustular psoriasis.…”

Section: Introductionmentioning

confidence: 99%

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Exploring the Role of IL-36 Cytokines as a New Target in Psoriatic Disease

Iznardo

Puig

2021

IJMS

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Unmet needs in the treatment of psoriasis call for novel therapeutic strategies. Pustular psoriasis and psoriatic arthritis often represent a therapeutic challenge. Focus on IL-36 cytokines offers an interesting approach, as the IL-36 axis has been appointed a critical driver of the autoinflammatory responses involved in pustular psoriasis. Two IL-36R blocking antibodies, imsidolimab and spesolimab, are currently undergoing phase II and III clinical trials, with promising results.

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Section: The Role Of Il-36 Family Cytokines In Psoriasis Pathogenesismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Exploring the Role of IL-36 Cytokines as a New Target in Psoriatic Disease

Iznardo

Puig

2021

IJMS

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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%

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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“…Functionally, SERPINA3 is a protease inhibitor that inhibits neutrophil cathepsin G. Previously loss-of-function mutations in SERPINA3 have been demonstrated in some cases of GPP. 3 In AOID, we hypothesize that reduced SERPINA3 expression leads to overactivation of proinflammatory cytokines, including IFNγ, IL-17, IL-22, and TGFβ, which then results in overactivation of KRT17 via IL-1β and JAK/STAT1/3 signaling pathways, leading to amplification of inflammatory reactions with neutrophil recruitment 3,4 (Figure S1).…”

Section: A Truncating Variant In Serpina3 Skin Pustules and Adult-onset Immunodeficiencymentioning

confidence: 99%

“…Providing the link between AOID and GPP, IL-36γ expression is regulated by cathepsin G and cathepsin G is regulated by SERPINA3. 3,4 Regarding anti-IFNγ antibody production, it is hypothesized that the SERPINA3 mutation leads to dysregulation of the T-cell/regulatory T-cell compartment, altered B-cell receptor signaling, impaired B cell tolerance and subsequent anti-IFN-gamma antibody production (Figure S1). 5 Thus, our genetic data offer a possible new mechanistic association between AOID and GPP.…”

Section: A Truncating Variant In Serpina3 Skin Pustules and Adult-onset Immunodeficiencymentioning

confidence: 99%