Immunohistochemical Comparison of IL-36 and the IL-23/Th17 Axis of Generalized Pustular Psoriasis and Acute Generalized Exanthematous Pustulosis

Song, Hyo Sang; Kim, Sang Jin; Park, Tae In; Jang, Yong Hyun; Lee, Eun‐So

doi:10.5021/ad.2016.28.4.451

Cited by 37 publications

(26 citation statements)

References 29 publications

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“…Also, IL-36g staining was particularly intense in nonpustular epidermis surrounding the pustules in AGEP. As previously reported (Song et al, 2016), IL-36a was also expressed in pustules from patients suffering from pustular psoriasis and, as in AGEP biopsy samples, IL-36g was the predominant form in the epidermis (Figure 1c). Neither IL-36a nor IL-36g could be detected in skin specimens from healthy donors (see Supplementary Figure S1 online).…”

Section: Enhanced Il-36 Expression In Lesional Skin Of Agep Patientssupporting

confidence: 85%

Culprit Drugs Induce Specific IL-36 Overexpression in Acute Generalized Exanthematous Pustulosis

Meier‐Schiesser

Feldmeyer

Janković

et al. 2019

Journal of Investigative Dermatology

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Acute generalized exanthematous pustulosis (AGEP) is a severe adverse cutaneous drug reaction. Although an involvement of drug-specific T cells has been reported, the physiopathology of AGEP and mechanism of neutrophilic skin inflammation remain incompletely understood. Recently, mutations in IL-36RN, the gene encoding the IL-36 receptor antagonist, have been reported to be more frequent in AGEP patients and pustular psoriasis. Here, we show that IL-36 cytokines, in particular IL-36g, are highly expressed in lesional skin of AGEP patients, keratinocytes and macrophages being a major source of IL-36g. Such an IL-36g overexpression was not observed in patients with drug-induced maculopapular rash. In vitro, the causative drug specifically induced IL-36g release either directly by the patient's peripheral blood monocytes or indirectly by keratinocytes in the presence of autologous peripheral blood mononuclear cells. Such culprit drug induction of IL-36g secretion in vitro was specific for AGEP and involved toll-like receptor 4 sensing the drug/albumin complex as a danger signal. Our results suggest that IL-36g secretion by monocytes/macrophages and keratinocytes in response to culprit drug exposure likely plays a key role in the pathogenesis of AGEP.

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Section: Enhanced Il-36 Expression In Lesional Skin Of Agep Patientssupporting

confidence: 85%

Culprit Drugs Induce Specific IL-36 Overexpression in Acute Generalized Exanthematous Pustulosis

Meier‐Schiesser

Feldmeyer

Janković

et al. 2019

Journal of Investigative Dermatology

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“…NTM, an infection due to Talaromyces marneffei and histoplasmosis that was not in the non-OI group. Furthermore, immune dysregulation of IL-23/Th17 axis, similar to that of pustular psoriasis and acute generalized exanthematous pustulosis (AGEP) may also be responsible for increased neutrophils recruitment, activation and/or survival in the skin in these patients (29). Further studies are needed to verify this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

Skin Manifestations in Patients with Adult-onset Immunodeficiency due to Anti-interferon-gamma Autoantibody: A Relationship with Systemic Infections

Jutivorakool¹,

Sittiwattanawong²,

Kantikosum³

et al. 2018

Acta Derm Venerol

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Adult-onset immunodeficiency due to anti-interferon-γ autoantibody is an emerging acquired immunodeficiency with frequent skin manifestations. A retrospective chart review was conducted and identified 41 patients with the syndrome. Skin involvement was detected in 33 (80%) patients, 15 (45%) with infective skin diseases and 27 (82%) with reactive skin disorders. Reactive lesions were mostly neutrophilic dermatoses, e.g. Sweet syndrome. Of note, the presence of neutrophilic dermatoses was highly associated with infections of other sites. An adjusted odds ratio for the existence of infections in patients with neutrophilic dermatoses was 14.79 (95% CI: 5.13, 42.70; p < 0.001). Moreover, neutrophilic dermatoses were significantly correlated with opportunistic infections observed in those with defects in cell-mediated immunity including non-tuberculous mycobacterium and disseminated fungal infection. The odds ratio for opportunistic infections in the presence of neutrophilic dermatoses was 12.35 (95% CI: 5.00, 30.55; p <0.001). Thus, the presence of neutrophilic dermatoses in patients with the syndrome can signal opportunistic infections that warrant physician attention.

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“…Psoriatic skin lesions are disordered throughout the full skin thickness and exhibit marked infiltration of mononuclear leukocytes into the dermis. The IL-23 cytokine axis plays a critical role in the pathogenesis of psoriasis (Deyrieux and Wilson, 2007;Song et al, 2016). A possible link between LMO4 and psoriasiform inflammation was suggested by data on overexpression of LMO4 and IL-23 in psoriatic skin.…”

Section: Discussionmentioning

confidence: 99%

LMO4 Is a Disease-Provocative Transcription Coregulator Activated by IL-23 in Psoriatic Keratinocytes

Zhang

Zhou

et al. 2018

Journal of Investigative Dermatology

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Psoriasis is an autoimmune disease characterized by abnormal differentiation and hyperproliferation of epidermal keratinocytes. LIM-domain only protein 4 (LMO4) is a transcription factor coregulator that promotes the assembly of multiprotein complexes to regulate mammary epithelium and keratinocyte differentiation and proliferation during embryogenesis. In this study, LMO4 has been found to be abundantly expressed in psoriatic epidermis. LMO4 expression is increased in human keratinocytes induced to differentiate by calcium ex vivo, and LMO4 overexpression induces spontaneous differentiation and growth acceleration of human keratinocytes in the absence of calcium. IL-23, a cytokine highly expressed in psoriatic skin lesions, induces differentiation and promotes proliferation of human keratinocytes. The IL-23-mediated effects are accompanied by an increase in LMO4 expression mediated by signal transducer and activator of transcription 3 through an IL-23/acutely transforming retrovirus AKT8 in rodent T-cell lymphoma/signal transducer and activator of transcription 3 pathway in keratinocytes. Knockdown of LMO4 effectively inhibits differentiation and growth of keratinocytes both ex vivo and in IL-23-injected ears of mice. LMO4 appears to mediate IL-23-related responses in psoriatic keratinocytes and is a potential therapeutic target in psoriasis.

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Immunohistochemical Comparison of IL-36 and the IL-23/Th17 Axis of Generalized Pustular Psoriasis and Acute Generalized Exanthematous Pustulosis

Cited by 37 publications

References 29 publications

Culprit Drugs Induce Specific IL-36 Overexpression in Acute Generalized Exanthematous Pustulosis

Culprit Drugs Induce Specific IL-36 Overexpression in Acute Generalized Exanthematous Pustulosis

Skin Manifestations in Patients with Adult-onset Immunodeficiency due to Anti-interferon-gamma Autoantibody: A Relationship with Systemic Infections

LMO4 Is a Disease-Provocative Transcription Coregulator Activated by IL-23 in Psoriatic Keratinocytes

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