SnapshotDx Quiz: August 2021
2021; Elsevier BV; Volume: 141; Issue: 8 Linguagem: Inglês
10.1016/j.jid.2021.06.004
ISSN1523-1747
Autores Tópico(s)IL-33, ST2, and ILC Pathways
ResumoEditorial note: Welcome to the Journal of Investigative Dermatology (JID) Snapshot Dx Quiz. In this monthly online-only quiz, the first question (“What is your diagnosis?”) relates to the clinical image shown, while additional questions concern the findings reported in the JID article by Zeng et al., 2021Zeng F. Chen H. Chen L. Mao J. Cai S. Xiao Y. et al.An autocrine circuit of IL-33 in keratinocytes is involved in progression of psoriasis.J Invest Dermatol. 2021; 141: 596-606.e7Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar (https://doi.org/10.1016/j.jid.2020.07.027). Detailed answers and a list of relevant references are available following the Quiz Questions below. 1.What is your diagnosis based on the two clinical images?a.Allergic contact dermatitisb.Plaque psoriasisc.Pityriasis rubra pilarisd.Pityriasis roseae.Lichen planus2.Which of the following answers is TRUE?a.Patients with psoriasis have a decreased incidence of type 2 diabetes mellitus when controlling for body mass index, smoking, cardiovascular disease, hypertension, and hyperlipidemia.b.Immune cells infiltrating the psoriatic skin secrete high amounts of proinflammatory cytokines IL-17, TNF-α, IL-21, and IL-36.c.The primary effects of IL-17 on keratinocytes (KCs) include direct induction of epidermal hyperplasia.d.Inhibition of one cytokine is sufficient to achieve disease resolution in essentially all patients with psoriasis.e.The efficacy of TNF antagonists in patients with psoriasis is unrelated to their effects on IL-23/T helper type 17 cell signaling.3.Which of the following answers is FALSE according to the article by Zeng et al., 2021Zeng F. Chen H. Chen L. Mao J. Cai S. Xiao Y. et al.An autocrine circuit of IL-33 in keratinocytes is involved in progression of psoriasis.J Invest Dermatol. 2021; 141: 596-606.e7Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar?a.IL-33 is increased in the lesional skin of patients with psoriasis.b.IL33 mRNA expression decreased in the lesional psoriatic skin after treatment with anti–IL-17 receptor antibody.c.Intradermal injection of IL-33 alone failed to induce psoriatic-like dermatitis.d.KCs are the major cells producing IL-33 in the skin.e.In addition to NF-κB, IL-33 induces Jak2/signal transducer and activator of transcription 3 axis activation in the KCs. See following pages for detailed answers 1.What is your diagnosis based on the two clinical images?CORRECT ANSWER: b. Plaque psoriasis.The images highlight a classic clinical picture of plaque psoriasis. There are several manifestations of psoriasis, with the plaque type being the most prevalent. About 90% of psoriasis cases are chronic plaque‒type psoriasis (Nestle et al., 2009Nestle F.O. Kaplan D.H. Barker J. Psoriasis.N Engl J Med. 2009; 361: 496-509Crossref PubMed Scopus (2015) Google Scholar). The classic clinical presentations are sharply demarcated, pink, symmetric, sometimes pruritic plaques with overlying silvery scale as highlighted by our photos. Common locations include the trunk, scalp, and extensor surfaces, but plaques can occur anywhere on the body. Patients may also demonstrate nail involvement. Diagnosis is usually made clinically. Less common variants of psoriasis include guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, and annular psoriasis. The location of the plaques in our photos highlights the Koebner phenomenon because the ankles and knees are areas subjected to repeated friction and trauma. The Koebner phenomenon consists of the appearance of psoriatic plaques at sites of previous trauma, with lesions usually developing after 7 days (Weiss et al., 2002Weiss G. Shemer A. Trau H. The Koebner phenomenon: review of the literature.J Eur Acad Dematol Vernerol. 2002; 16: 241-248Crossref PubMed Scopus (244) Google Scholar).Discussion of incorrect answers:a.Allergic contact dermatitis: Allergic contact dermatitis is a frequent inflammatory skin disease that can easily be confused with psoriasis in the more chronic phase as well as with irritant dermatitis and atopic dermatitis. Acute allergic contact dermatitis presents with redness, erythema, and vesiculation. Chronic allergic contact dermatitis presents with lichenification, fissures, and ulcerations. Many cases of acute and chronic allergic contact dermatitis are well-demarcated and are localized to the site of contact with the allergen, but it can present as patchy and diffuse depending on the allergen. Patch testing is the gold standard for diagnosis (Scharnagl et al., 2009Scharnagl H. März W. Böhm M. Luger T.A. Fracassi F. Diana A. et al.Allergic contact dermatitis.in: Lang F. Encyclopedia of Molecular Mechanisms of Disease. Springer, Berlin, Germany2009: 61Crossref Google Scholar).c.Pityriasis rubra pilaris: Pityriasis rubra pilaris is a chronic inflammatory papulosquamous disorder. It is characterized by orangish-colored, scaly plaques (as opposed to salmon-colored plaques in psoriasis), palmoplantar keratoderma with an orangish hue, and keratotic follicular papules on the elbows, wrist, and proximal phalanges (Wang et al., 2018Wang D. Chong V.C. Chong W.S. Oon H.H. A review on Pityriasis rubra pilaris.Am J Clin Dermatol. 2018; 19: 377-390Crossref PubMed Scopus (30) Google Scholar). Similar to psoriasis, the disease may progress to erythroderma; however, there are distinct islands of sparing, and it typically spreads in a craniocaudal direction. The nail changes seen in pityriasis rubra pilaris differ from those in psoriasis. The nail changes include subungual hyperkeratosis, longitudinal ridging, splinter hemorrhages, and distal yellow–brown discoloration. Differentiating early pityriasis rubra pilaris can sometimes be challenging, but prominent follicular involvement with less scale on clinical examination, in correlation to the histological result, can help.d.Pityriasis rosea: Pityriasis rosea is a common, benign, self-limiting papulosquamous eruption. It is seen primarily in adolescents and young adults, and it favors the trunk and proximal extremities. The condition usually starts with a pink patch or plaque with slightly raised margins called the herald patch. The center of the patch shows the fine scale associated with pityriasis rosea that differs from the scale seen in plaque psoriasis. Within the next few days, the patient develops papules and plaques that look like the herald patch and follow the Langer’s line of cleavage in a Christmas tree pattern. Pityriasis rosea usually persists for 6‒8 weeks and then spontaneously resolves, unlike psoriasis (Drago et al., 2016Drago F. Ciccarese G. Rebora A. Broccolo F. Parodi A. Pityriasis rosea: a comprehensive classification.Dermatology. 2016; 232: 431-437Crossref PubMed Scopus (55) Google Scholar).e.Lichen planus: Lichen planus is an idiopathic inflammatory condition that affects the skin and mucous membranes. It is characterized by purple, extremely pruritic, flat-topped papules that favor the extremities. It is characterized by fine white lines, called Wickhman striae, which are often found on the papules (Tziotzios et al., 2018Tziotzios C. Lee J.Y.W. Brier T. Saito R. Hsu C.K. Bhargava K. et al.Lichen planus and lichenoid dermatoses: clinical overview and molecular basis.J Am Acad Dermatol. 2018; 79: 789-804Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar). This differs from the salmon pink color with a thick silver scale seen in psoriatic plaques. Hypertrophic lichen planus, a variant of lichen planus, is commonly seen on the lower extremities, especially around the ankles, and presents as an extremely pruritic, well-demarcated verrucous plaque. Similar to psoriasis, the Koebner phenomenon is commonly seen in lichen planus. Lichen planus can affect the nails and presents with lateral thinning, longitudinal ridging, and fissuring and can eventually lead to scarring and dorsal pterygium formation.2.Which of the following answers is TRUE?CORRECT ANSWER: b. Immune cells infiltrating the psoriatic skin secrete high amounts of proinflammatory cytokines IL-17, TNF-α, IL-21, and IL-36.Expression of IL-17 is elevated in psoriatic lesions compared with that in nonlesional tissue (Johansen et al., 2009Johansen C. Usher P.A. Kjellerup R.B. Lundsgaard D. Iversen L. Kragballe K. Characterization of the interleukin-17 isoforms and receptors in lesional psoriatic skin.Br J Dermatol. 2009; 160: 319-324Crossref PubMed Scopus (232) Google Scholar). IL-17, one of the most relevant cytokines, is produced mainly by skin-infiltrating IL-17‒producing T cells, referred to as T helper (Th)17 cells, but also by other immune cells such as mast cells, neutrophils, and cytotoxic T cells (Kryczek et al., 2008Kryczek I. Bruce A.T. Gudjonsson J.E. Johnston A. Aphale A. Vatan L. et al.Induction of IL-17+ T cell trafficking and development by IFN-gamma: mechanism and pathological relevance in psoriasis.J Immunol. 2008; 181: 4733-4741Crossref PubMed Scopus (359) Google Scholar), which all contribute to the abundant expression of IL-17 in lesional skin (Yamanaka et al., 2017Yamanaka K. Yamagiwa A. Akeda T. Kondo M. Kakeda M. Habe K. et al.Neutrophils are not the dominant interleukin-17 producer in psoriasis.J Dermatol. 2017; 44: e170-e171Crossref PubMed Scopus (8) Google Scholar). Lowes et al., 2008Lowes M.A. Kikuchi T. Fuentes-Duculan J. Cardinale I. Zaba L.C. Haider A.S. et al.Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells.J Invest Dermatol. 2008; 128: 1207-1211Abstract Full Text Full Text PDF PubMed Scopus (798) Google Scholar showed that Th17 cells are present in higher numbers in psoriatic lesions than in healthy skin and are decreased after treatment. Th17 cells are activated by IL-23, IL-1, and IL-21 to produce IL-17 and other inflammatory factors such as IL-22. IL-17 influences a variety of cell types, ultimately leading to the proliferation of keratinocytes (KCs) and dermal inflammation. IL-17 acts directly on KCs and stimulates the production of numerous molecules that contribute to the psoriatic lesions, such as β-defensins, antimicrobial peptides (AMPs), numerous cytokines, chemokines, proinflammatory AMPs, and angiogenic factors (Martin et al., 2013Martin D.A. Towne J.E. Kricorian G. Klekotka P. Gudjonsson J.E. Krueger J.G. et al.The emerging role of IL-17 in the pathogenesis of psoriasis: preclinical and clinical findings.J Invest Dermatol. 2013; 133: 17-26Abstract Full Text Full Text PDF PubMed Scopus (300) Google Scholar).TNF-α is an important inflammatory cytokine highly expressed in psoriatic skin. It serves a crucial role in psoriasis pathogenesis, which is demonstrated by the effectiveness of TNF-α‒targeted therapies. TNF-α is a strong inducer of inflammation in KCs, many of its actions overlap with those of IL-17 (Zaba et al., 2007Zaba L.C. Cardinale I. Gilleaudeau P. Sullivan-Whalen M. Suárez-Fariñas M. Fuentes-Duculan J. et al.Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses [published correction appears in J Exp Med 2008;205:1941].J Exp Med. 2007; 204: 3183-3194Crossref PubMed Scopus (517) Google Scholar). TNF-α is functionally linked to the IL-23/Th17 pathway by its ability to activate myeloid dendritic cells (DCs) that synthesize IL-23, which leads to the activation of Th17 cells (Gottlieb et al., 2005Gottlieb A.B. Chamian F. Masud S. Cardinale I. Abello M.V. Lowes M.A. et al.TNF inhibition rapidly down-regulates multiple proinflammatory pathways in psoriasis plaques.J Immunol. 2005; 175: 2721-2729Crossref PubMed Scopus (308) Google Scholar; Zaba et al., 2007Zaba L.C. Cardinale I. Gilleaudeau P. Sullivan-Whalen M. Suárez-Fariñas M. Fuentes-Duculan J. et al.Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses [published correction appears in J Exp Med 2008;205:1941].J Exp Med. 2007; 204: 3183-3194Crossref PubMed Scopus (517) Google Scholar). Thus, TNF-α serves as an indirect activator of Th17 through its effect on IL-23. TNF-α also facilitates the entry of inflammatory cells into lesional skin by the induction of adhesion molecules on endothelial cells and stimulates the production of proinflammatory mediators by KCs.In lesional skin, IL-36 cytokines are highly produced by epidermal KCs, fibroblasts, macrophages, Langerhans cells, and DCs infiltrating the dermis of psoriatic skin (Bachmann et al., 2012Bachmann M. Scheiermann P. Härdle L. Pfeilschifter J. Mühl H. IL-36γ/IL-1F9, an innate T-bet target in myeloid cells.J Biol Chem. 2012; 287: 41684-41696Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar). IL-36 upregulation occurs in both the early and late phases of the disease. IL-36 upregulation can strongly be induced by TNF-α, IL-36 itself through an autocrine loop, IL-17, and IL-22, all of which accumulate in the skin in early lesions (Albanesi et al., 2018Albanesi C. Madonna S. Gisondi P. Girolomoni G. The interplay between keratinocytes and immune cells in the pathogenesis of psoriasis.Front Immunol. 2018; 9: 1549Crossref PubMed Scopus (140) Google Scholar). IL-36 has an effect on both KCs and endothelial cells. In endothelial cells, IL-36 causes the expression of T-cell‒attracting and ‒adhesion molecules, ultimately leading to an increase in T-cell migration (Bridgewood et al., 2017Bridgewood C. Stacey M. Alase A. Lagos D. Graham A. Wittmann M. IL-36γ has proinflammatory effects on human endothelial cells.Exp Dermatol. 2017; 26: 402-408Crossref PubMed Scopus (37) Google Scholar). In KCs, IL-36 promotes the release of proinflammatory cytokines and chemokines and interferes with the cornification process. IL-36 can act alone or with IL-17 to interfere with KC differentiation/cornification. IL-36 downregulates the expression of various epidermal differentiation markers, including FLG, keratin (K) 1, and K10 (Pfaff et al., 2017Pfaff C.M. Marquardt Y. Fietkau K. Baron J.M. Lüscher B. The psoriasis-associated IL-17A induces and cooperates with IL-36 cytokines to control keratinocyte differentiation and function.Sci Rep. 2017; 7: 15631Crossref PubMed Scopus (60) Google Scholar).IL-21 has been found to be significantly higher in the serum of patients with psoriasis than in the serum of the healthy cohort, and it correlates with the severity of the psoriasis (Wang et al., 2016Wang Y. Wang L.L. Yang H.Y. Wang F.F. Zhang X.X. Bai Y.P. Interleukin-21 is associated with the severity of psoriasis vulgaris through promoting CD4+ T cells to differentiate into Th17 cells.Am J Transl Res. 2016; 8: 3188-3196PubMed Google Scholar). Furthermore, the levels of IL-21 significantly decrease after psoriasis treatment (Wang et al., 2016Wang Y. Wang L.L. Yang H.Y. Wang F.F. Zhang X.X. Bai Y.P. Interleukin-21 is associated with the severity of psoriasis vulgaris through promoting CD4+ T cells to differentiate into Th17 cells.Am J Transl Res. 2016; 8: 3188-3196PubMed Google Scholar). IL-21 stimulates the increased expression of Th17 cells (Wang et al., 2016Wang Y. Wang L.L. Yang H.Y. Wang F.F. Zhang X.X. Bai Y.P. Interleukin-21 is associated with the severity of psoriasis vulgaris through promoting CD4+ T cells to differentiate into Th17 cells.Am J Transl Res. 2016; 8: 3188-3196PubMed Google Scholar). IL-21 is produced by CD4+ cells, especially Th17 cells (Spolski and Leonard, 2008Spolski R. Leonard W.J. Interleukin-21: basic biology and implications for cancer and autoimmunity.Annu Rev Immunol. 2008; 26: 57-79Crossref PubMed Scopus (536) Google Scholar). Its main effect is on B cells by inducing proliferation or class switching. IL-21 also plays an important role in CD4+ T-cell differentiation and fate (Wang et al., 2016Wang Y. Wang L.L. Yang H.Y. Wang F.F. Zhang X.X. Bai Y.P. Interleukin-21 is associated with the severity of psoriasis vulgaris through promoting CD4+ T cells to differentiate into Th17 cells.Am J Transl Res. 2016; 8: 3188-3196PubMed Google Scholar). The relationship between IL-21 and Th17 cells is unclear.Discussion of incorrect answers:a.Patients with psoriasis have a decreased incidence of type 2 diabetes mellitus when controlling for body mass index, smoking, cardiovascular disease, hypertension, and hyperlipidemia. This statement is false. Patients with psoriasis have an increased incidence of type 2 diabetes mellitus (DM2) even when controlling for body mass index, smoking, hypertension, cardiovascular disease, and hyperlipidemia (Azfar et al., 2012Azfar R.S. Seminara N.M. Shin D.B. Troxel A.B. Margolis D.J. Gelfand J.M. Increased risk of diabetes mellitus and likelihood of receiving diabetes mellitus treatment in patients with psoriasis.Arch Dermatol. 2012; 148: 995-1000Crossref PubMed Scopus (98) Google Scholar; Brauchli et al., 2008Brauchli Y.B. Jick S.S. Meier C.R. Psoriasis and the risk of incident diabetes mellitus: a population-based study.Br J Dermatol. 2008; 159: 1331-1337Crossref PubMed Scopus (97) Google Scholar; Khalid et al., 2013Khalid U. Hansen P.R. Gislason G.H. Lindhardsen J. Kristensen S.L. Winther S.A. et al.Psoriasis and new-onset diabetes: a Danish nationwide cohort study.Diabetes Care. 2013; 36: 2402-2407Crossref PubMed Scopus (59) Google Scholar). Studies have shown that the risk of DM2 is correlated in a dose-dependent fashion with the surface area of the involved skin (Noe et al., 2018Noe M.H. Shin D.B. Wan M.T. Gelfand J.M. Objective measures of psoriasis severity predict mortality: a prospective population-based cohort study [published correction appears in J Invest Dermatol 2018;138:998].J Invest Dermatol. 2018; 138: 228-230Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar). The presence of psoriatic arthritis also increases the risk of DM2 (Wan et al., 2018Wan M.T. Shin D.B. Hubbard R.A. Noe M.H. Mehta N.N. Gelfand J.M. Psoriasis and the risk of diabetes: a prospective population-based cohort study.J Am Acad Dermatol. 2018; 78: 315-322.e1Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar). Patrick et al., 2021Patrick M.T. Stuart P.E. Zhang H. Zhao Q. Yin X. He K. et al.Causal relationship and shared genetic loci between psoriasis and type 2 diabetes through trans-disease meta-analysis.J Invest Dermatol. 2021; 141: 1493-1502Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar showed a shared genetic locus between psoriasis and DM2 through overlapping NF-κB signaling mechanisms. Both DM2 and psoriasis are characterized by chronic inflammatory states with proinflammatory cytokines such as TNF-α. TNF-α inhibits insulin receptors’ activity, which ultimately leads to insulin resistance and increases the risk of developing DM2 (Gupta et al., 2007Gupta D. Varma S. Khandelwal R.L. Long-term effects of tumor necrosis factor-alpha treatment on insulin signaling pathway in HepG2 cells and HepG2 cells overexpressing constitutively active Akt/PKB.J Cell Biochem. 2007; 100: 593-607Crossref PubMed Scopus (41) Google Scholar). Patients with psoriasis should be counseled on the correlation with DM2 and screened appropriately.c.The primary effects of IL-17 on keratinocytes (KCs) include direct induction of epidermal hyperplasia. The IL-23/Th17 axis has an important role in the induction of epidermal hyperplasia. However, the induction of epidermal hyperplasia is not a direct effect of IL-17. IL-23 causes epidermal hyperplasia by IL-22, not directly through IL-17. IL-22 is produced by Th17 cells and mediates the acanthosis induced by IL-23 (Zheng et al., 2007Zheng Y. Danilenko D.M. Valdez P. Kasman I. Eastham-Anderson J. Wu J. et al.Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis.Nature. 2007; 445: 648-651Crossref PubMed Scopus (1499) Google Scholar). IL-23 stimulates Th17 cells, which produce both IL-17 and IL-22. However, the production of IL-22 by Th17 cells is regulated differently from the production of IL-17 by Th17 cells (Zheng et al., 2007Zheng Y. Danilenko D.M. Valdez P. Kasman I. Eastham-Anderson J. Wu J. et al.Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis.Nature. 2007; 445: 648-651Crossref PubMed Scopus (1499) Google Scholar). For example, TNF-β, which promotes the production of IL-17 by Th17 cells, inhibits IL-22 production (Zheng et al., 2007Zheng Y. Danilenko D.M. Valdez P. Kasman I. Eastham-Anderson J. Wu J. et al.Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis.Nature. 2007; 445: 648-651Crossref PubMed Scopus (1499) Google Scholar). Mouse models have been used to exemplify the importance of IL-22 in causing hyperplasia. Injection of recombinant murine IL-23 into the skin of wild-type mice induces epidermal hyperplasia (Chan et al., 2006Chan J.R. Blumenschein W. Murphy E. Diveu C. Wiekowski M. Abbondanzo S. et al.IL-23 stimulates epidermal hyperplasia via TNF and IL-20R2-dependent mechanisms with implications for psoriasis pathogenesis.J Exp Med. 2006; 203: 2577-2587Crossref PubMed Scopus (528) Google Scholar). Administration of anti–IL-17 antibodies to mice did not inhibit the IL-23‒stimulated acanthosis (Chan et al., 2006Chan J.R. Blumenschein W. Murphy E. Diveu C. Wiekowski M. Abbondanzo S. et al.IL-23 stimulates epidermal hyperplasia via TNF and IL-20R2-dependent mechanisms with implications for psoriasis pathogenesis.J Exp Med. 2006; 203: 2577-2587Crossref PubMed Scopus (528) Google Scholar), demonstrating that IL-23 stimulates hyperplasia regardless of IL-17. However, injection of IL-23 into mice lacking IL-22 failed to induce epidermal hyperplasia (Zheng et al., 2007Zheng Y. Danilenko D.M. Valdez P. Kasman I. Eastham-Anderson J. Wu J. et al.Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis.Nature. 2007; 445: 648-651Crossref PubMed Scopus (1499) Google Scholar), signifying that IL-22 is a key downstream regulator of IL-23‒induced hyperplasia. In conclusion, IL-22 has a direct proliferative effect on KCs, whereas IL-17 does not (Nograles et al., 2008Nograles K.E. Zaba L.C. Guttman-Yassky E. Fuentes-Duculan J. Suárez-Fariñas M. Cardinale I. et al.Th17 cytokines interleukin (IL)-17 and IL-22 modulate distinct inflammatory and keratinocyte-response pathways.Br J Dermatol. 2008; 159: 1092-1102PubMed Google Scholar).d.Inhibition of one cytokine is sufficient to achieve disease resolution in essentially all patients with psoriasis. As we have seen in practice, patients do not always respond to initial treatment with biologics. Although biologic agents are effective for moderate to severe psoriasis, there are variations in treatment response among patients. The variation may reflect the clinical genetic heterogeneity of the disease as well as the drug metabolism and response (Leman and Burden, 2012Leman J. Burden A.D. Sequential use of biologics in the treatment of moderate-to-severe plaque psoriasis.Br J Dermatol. 2012; 167: 12-20Crossref PubMed Scopus (42) Google Scholar). The lack of a response mechanism is largely unknown. Antidrug antibodies may lead to increased drug clearance through the formation of drug–antidrug complexes (van der Laken et al., 2007van der Laken C.J. Voskuyl A.E. Roos J.C. Stigter van Walsum M. de Groot E.R. Wolbink G. et al.Imaging and serum analysis of immune complex formation of radiolabelled infliximab and anti-infliximab in responders and non-responders to therapy for rheumatoid arthritis.Ann Rheum Dis. 2007; 66: 253-256Crossref PubMed Scopus (156) Google Scholar). The lack of response to one biologic does not preclude the response to another biologic. For example, of 65 patients who had failed anti–TNF-α therapy, 72% achieved significant improvement, defined as PASI 75, after 12 weeks of ustekinumab (Qiang et al., 2016Qiang J.K. Shahbaz A. Kim W. Marinas J. Greaves S. Yeung J. Effectiveness of sequential use of biologics in the treatment of moderate to severe psoriasis in real world Canadian academic clinical practice: a cohort study.J Am Acad Dermatol. 2016; 74: 176-177Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar).e.The efficacy of TNF antagonists in patients with psoriasis is unrelated to their effects on IL-23/T helper type 17 cell signaling. TNF antagonist efficacy is likely related to their indirect effects on IL-23‒IL-17 cell signaling (Hawkes et al., 2017Hawkes J.E. Chan T.C. Krueger J.G. Psoriasis pathogenesis and the development of novel targeted immune therapies.J Allergy Clin Immunol. 2017; 140: 645-653Abstract Full Text Full Text PDF PubMed Scopus (357) Google Scholar). One of the major roles of TNF is the regulation of IL-23. After an inciting event to the skin, such as trauma or infection, TNF is released by DCs and causes an increase in the production of IL-23 from DCs (Martin et al., 2013Lowes M.A. Suarez-Farinas M. Krueger J.G. Immunology of psoriasis.Annu Rev Immunol. 2014; 32: 227-255Crossref PubMed Scopus (844) Google Scholar). The increase in IL-23 is the main signal driving the activation of Th17 cells in psoriatic plaques. IL-23 stimulates Th17 cells to release IL-17 and IL-22, leading to the proliferation of KCs and dermal inflammation (Di Cesare et al., 2009Di Cesare A. Di Meglio P. Nestle F.O. The IL-23/Th17 axis in the immunopathogenesis of psoriasis.J Invest Dermatol. 2009; 129: 1339-1350Abstract Full Text Full Text PDF PubMed Scopus (766) Google Scholar). TNF acts synergistically with IL-17 to increase and sustain the upregulation of many psoriasis-related proinflammatory genes in addition to the induction of IL-23 (Hawkes et al., 2017Hawkes J.E. Chan T.C. Krueger J.G. Psoriasis pathogenesis and the development of novel targeted immune therapies.J Allergy Clin Immunol. 2017; 140: 645-653Abstract Full Text Full Text PDF PubMed Scopus (357) Google Scholar). Therefore, the TNF antagonist effect is likely mainly related to their indirect inhibition of the IL-23/Th17 signaling pathway in the skin.3.Which of the following answers is FALSE according to the article by Zeng et al., 2021Zeng F. Chen H. Chen L. Mao J. Cai S. Xiao Y. et al.An autocrine circuit of IL-33 in keratinocytes is involved in progression of psoriasis.J Invest Dermatol. 2021; 141: 596-606.e7Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar?CORRECT ANSWER: c. Intradermal injection of IL-33 alone failed to induce psoriatic-like dermatitis.This statement is false. IL-33 appears to have a critical role in psoriatic skin inflammation. Zeng et al., 2021Zeng F. Chen H. Chen L. Mao J. Cai S. Xiao Y. et al.An autocrine circuit of IL-33 in keratinocytes is involved in progression of psoriasis.J Invest Dermatol. 2021; 141: 596-606.e7Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar showed the importance of IL-33 through mouse models. Recombinant mouse IL-33 was injected intradermally into wild-type mice and mice deficient in IL-17A. Psoriasis-like phenotype was displayed in both wild-type mice and IL-17A‒deficient mice. The psoriasis-like phenotype and the pathological changes showed no significant difference between the mice (Zeng et al., 2021Zeng F. Chen H. Chen L. Mao J. Cai S. Xiao Y. et al.An autocrine circuit of IL-33 in keratinocytes is involved in progression of psoriasis.J Invest Dermatol. 2021; 141: 596-606.e7Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar). This shows that IL-33 plays an important role in the development of psoriasis-like dermatitis independent of IL-17.Discussion of incorrect answers:a.IL-33 is increased in the lesional skin of patients with psoriasis. This statement is true. Using western blot, Zeng et al., 2021Zeng F. Chen H. Chen L. Mao J. Cai S. Xiao Y. et al.An autocrine circuit of IL-33 in keratinocytes is involved in progression of psoriasis.J Invest Dermatol. 2021; 141: 596-606.e7Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar found that IL33 mRNA was increased in lesional skin compared with that in nonlesional skin. IL33 mRNA in lesional skin was about 1.65 times the amount in the nonlesional skin (Zeng et al., 2021Zeng F. Chen H. Chen L. Mao J. Cai S. Xiao Y. et al.An autocrine circuit of IL-33 in keratinocytes is involved in progression of psoriasis.J Invest Dermatol. 2021; 141: 596-606.e7Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar). IL-33 was also found to be significantly elevated in the lesional skin of mice with imiquimod-induced psoriasis compared with that in normal and nonlesional skin (Zeng et al., 2021Zeng F. Chen H. Chen L. Mao J. Cai S. Xiao Y. et al.An autocrine circuit of IL-33 in keratinocytes is involved in progression of psoriasis.J Invest Dermatol. 2021; 141: 596-606.e7Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar). In addition, IL-33 is increased in the serum of a patient with psoriasis compared with that in the serum of healthy controls (Mitsui et al., 2016Mitsui A. Tada Y. Takahashi T. Shibata S. Kamata M. Miyagaki T. et al.Serum IL-33 levels are increased in patients with psoriasis.Clin Exp Dermatol. 2016; 41: 183-189Crossref PubMed Scopus (35) Google Scholar).b.IL33 mRNA expression decreased in the lesional psoriatic skin after treatment with anti–IL-17 receptor antibody. This statement is true. IL33 mRNA levels did decrease in lesional skin after treatment with IL-17 receptor antibody for 43 days (Zeng et al., 2021Zeng F. Chen H. Chen L. Mao J. Cai S. Xiao Y. et al.An autocrine circuit of IL-33 in keratinocytes is involved in progression of psoriasis.J Invest Dermatol. 2021; 141: 596-606.e7Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar). Similarly, IL33 mRNA significantly decreased after TNF inhibition for 12 weeks (Zeng et al., 2021Zeng F. Chen H. Chen L. Mao J. Cai S. Xiao Y. et al.An autocrine circuit of IL-33 in keratinocytes is involved in progression of psoriasis.J Invest Dermatol. 2021; 141: 596-606.e7Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar). This shows that IL-33 downregulation is responsive to treatment.d.KCs are the major cells producing IL-33 in the skin. This statement is true. To identify the major source of IL-33, Zeng et al., 2021Zeng F. Chen H. Chen L. Mao J. Cai S. Xiao Y. et al.An autocrine circuit of IL-33 in keratinocytes is involved in progression of psoriasis.J Invest Dermatol. 2021; 141: 596-606.e7Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar collected skin samples from humans and mice. Immunohistochemistry staining showed that IL-33‒positive cells were mainly in the epidermis and almost not present in the dermis (Zeng et al., 2021Zeng F. Chen H. Chen L. Mao J. Cai S. Xiao Y. et al.An autocrine circuit of IL-33 in keratinocytes is involved in progression of psoriasis.J Invest Dermatol. 2021; 141: 596-606.e7Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar). In lesional skin, IL-33‒positive cells were distributed in the epidermis and minimally in the dermis (Zeng et al., 2021Zeng F. Chen H. Chen L. Mao J. Cai S. Xiao Y. et al.An autocrine circuit of IL-33 in keratinocytes is involved in progression of psoriasis.J Invest Dermatol. 2021; 141: 596-606.e7Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar). In both lesional and nonlesional skin, IL-33‒positive cells mainly colocalized with K14-positive signal, indicating that IL-33 was mainly expressed by KCs. KCs are the major cells expressing IL-33 (Zeng et al., 2021Zeng F. Chen H. Chen L. Mao J. Cai S. Xiao Y. et al.An autocrine circuit of IL-33 in keratinocytes is involved in progression of psoriasis.J Invest Dermatol. 2021; 141: 596-606.e7Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar).e.In addition to NF-κB, IL-33 induces Jak2/signal transducer and activator of transcription 3 axis activation in the KCs. This statement is true. Zeng et al., 2021Zeng F. Chen H. Chen L. Mao J. Cai S. Xiao Y. et al.An autocrine circuit of IL-33 in keratinocytes is involved in progression of psoriasis.J Invest Dermatol. 2021; 141: 596-606.e7Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar showed that human KCs treated with recombinant human IL-33 induced the transcription of various cytokines. IL-33 stimulated the phosphorylation of the transcription factor NF-κB and the Jak2/signal transducer and activator of transcription (STAT) 3 axis (Zeng et al., 2021Zeng F. Chen H. Chen L. Mao J. Cai S. Xiao Y. et al.An autocrine circuit of IL-33 in keratinocytes is involved in progression of psoriasis.J Invest Dermatol. 2021; 141: 596-606.e7Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar). Phosphorylation of STAT1 was not detected. The upregulation of STAT3 was reversed by the administration of a Jak2-specific inhibitor (Zeng et al., 2021Zeng F. Chen H. Chen L. Mao J. Cai S. Xiao Y. et al.An autocrine circuit of IL-33 in keratinocytes is involved in progression of psoriasis.J Invest Dermatol. 2021; 141: 596-606.e7Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar). IL-33 released by KCs induces Jak2/STAT3 pathway and NF-κB pathway and thus promotes psoriasis-associated molecule expression. Mariya Miteva: https://orcid.org/0000-0002-0704-7085.
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