Mowat-Wilson syndrome (MOWS) is a congenital disease characterized by intellectual disability, delayed motor development, characteristic facial features, epilepsy, and a wide spectrum of neurocristopathies. MOWS is caused by de novo heterozygous loss-of-function mutations or deletions in the zinc finger E-box-binding homeobox2 (ZEB2) gene, which is a multifunctional regulator of neuronal development and cancer progression/metastasis through epithelial-to-mesenchymal transition. We recognized that patients with MOWS have brown to red hair. In the present study, we report that hair from patients with MOWS has reduced eumelanin and elevated pheomelanin contents, resulting in an increased pheomelanin-to-eumelanin ratio. Furthermore, ZEB2-mutated human epidermal melanocytes show a predominance of pheomelanin biosynthesis over eumelanin and decreased expression of SLC45A2, the gene responsible for oculocutaneous albinism 4. Our results suggest that ZEB2 plays a role in mixed melanogenesis by regulating the melanosomal ion transporter gene, SLC45A2.

V-domain Immunoglobulin Suppressor of T cell activation (VISTA) is an inhibitory B7 family immune-checkpoint molecule expressed on myeloid cells. VISTA-KO mice exhibit Psoriasis-like inflammation. Myeloid cells in psoriasis have multiple abnormalities, including aberrancies in monocytic myeloid-derived suppressor cells and adhesiveness. Whether VISTA signaling is related to Psoriasis myeloid dysfunction is unknown. Indeed, psoriasis monocytes contain a subset with dysregulated VISTA expression (MCF of 347±32 in psoriasis, n=10, vs MCF of 462±77 in controls , n=6), p< 0.05). To examine VISTA function in monocytes, we generated lentivirus-induced VISTA overexpressing human monocytes (THP-1), and stable VISTA overexpressing THP-1 cells (THP-1VISTA) were established. Flow cytometric analysis showed that stable THP-1VISTA transfectants induced VISTA expression when activated by LPS alone or in combination with Interferon-γ. Morphologically, activated THP-1VISTA transfectants, but not GFP transfectants, showed decreased aggregation. Next, we interrogated the inflammatory cytokine profile observed in activated THP-1VISTA cells using mRNA expression arrays. Relative to GFP-transfectants, VISTA-overexpressing monocytes showed upregulated disintegrin-like and metalloprotease domain with thrombospondin type 1 motif (ADAMTS1), yet downregulated TGF-β, tissue inhibitor of metalloproteinase (TIMP3), catenins (CTNNA1, CTNND1), matrix metalloproteinase (MMP14), and an extracellular cell adhesion protein (ANOS1). Add-back experiments using recombinant TGF-b to activated THP-1VISTA cells restored aggregation, likely via its restoration of integrin A6 (ITGA6) expression to the same level as control THP-1GFP. These findings uncover a previously unappreciated connectivity between VISTA, TGF-b, and monocyte adhesion, perhaps offering a new intervention point relevant to psoriasis and its monocyte-mediated associated comorbidities.

V-domain Immunoglobulin Suppressor of T cell activation (VISTA) is an inhibitory B7 family immune-checkpoint molecule. VISTA is highly expressed on myeloid, hematopoietic and cancer cells and participates in T cell-mediated autoimmunity and antitumor immunity, playing a broad role in regulation of myeloid- and T cell-mediated immunity. VISTA is upregulated on myeloid-derived suppressor cells (MDSCs) from AML patients. We previously reported MDSCs are increased but functionally impaired in psoriasis (Pso); VISTA knock-out (KO) mice exhibit Pso-like inflammation. VISTA-KO mice exhibit Pso-like inflammation. Whether VISTA signaling is related to Pso MDSC dysfunction is unknown. We analyzed VISTA expression on CD14+ Pso and healthy control (HC) monocytes (Mo) using flow cytometry. Mo-MDSC (CD14+HLA-DRneg) were elevated in Pso patients, and, as hypothesized, VISTA surface expression was elevated (1.6±0.9 % vs 13.2±4.0 % of Mo in HC vs Pso, n=4, 3, p<0.01). Innate signaling for human Mo activation via LPS attenuated VISTA gene expression in HC and Pso patients, suggesting VISTA expression is sensitive to inflammatory status. A novel VISTA ligand is V-Set and Immunoglobulin domain containing 3 (VSIG-3); consistent with a functional role for VISTA in human Mo, we found that VSIG-3 stimulation of CD14+ Mo attenuates IL-6 expression. In Pso patients, VSIG-3 was less effective in reducing IL-6 in Pso-Mo compared to HC (average IL-6 after VSIG-3 relative to LPS alone of 66±7.1% in HC versus a minimal effect on IL-6 of 89±7.0% in Pso, n=2, 3, p<0.05). Thus, in addition to T cell signals, VISTA expression/signaling is implicated in human Mo and dysregulated in Pso. VISTA pathway targeting may represent a novel immune rebalancing approach in Pso and related inflammatory diseases whose engagement inhibits T-cell proliferation as well as cytokine and chemokine production, demonstrated previously by VSIG-3 inhibition of anti-CD3-induced IL-17 secretion on PBMCs

Leucine-rich alpha-2 glycoprotein (LRG), one of the acute phase proteins mainly produced by the liver, similar to C-reactive protein, has been recognized as an inflammatory biomarker for rheumatoid arthritis and inflammatory bowel diseases. We recently demonstrated that LRG was also increased in the sera of psoriasis patients and correlated well with disease activity with a sensitivity and specificity much higher than C-reactive protein; however, whether LRG mechanistically contributed to the pathogenesis of psoriasis remained unclear. In this study, we explored the role of LRG in psoriasiform inflammation using LRG-knockout (KO) mice in an imiquimod (IMQ)-mediated model. Following topical treatment with IMQ, serum levels of LRG and its expression in the liver were abruptly elevated. Similarly, an acute surge of proinflammatory cytokines was observed in the liver, including IL-1 beta, TNF-alpha, and IL-6, although LRG-KO mice showed delayed responses. LRG-KO mice showed less skin inflammation in the IMQ model than wild-type mice. K5.Stat3C mice developed psoriasis-like lesions following tape stripping, which also abruptly induced LRG expression in the liver. A deficiency of Lrg mitigated tape stripping-induced lesions, similar to the IMQ model. These results indicate that LRG modulates both feed-forward and feedback loops of cytokines in the skin-liver axis involved with psoriasiform inflammation.

Cantu syndrome is an autosomal dominant disorder, first described by Cantu in 1982, that is characterized by congenital hypertrichosis, characteristic facial anomalies and cardiomegaly. Recent investigations have revealed that this syndrome is caused by mutations of ABCC9, which encodes a regulatory subunit of SUR2, an adenosine triphosphate-mediated potassium channel opener, expressed not only in smooth muscle but also in hair follicles. However, the abnormalities of skin and hair in patients with Cantu syndrome have not been well explored. We herein report three Japanese patients with Cantu syndrome and describe their specific skin manifestations and alterations in the histopathology of their hair follicles and sebaceous glands. Similar alterations were shared among those three patients and may be related to the function of SUR2, namely the regulation of hair follicle growth, because SUR2 is a known pharmacological target of minoxidil.

The frequency of fish allergy (FA) has been increasing since seafood cuisine such as raw fish has become popular. FA is caused by many allergens, among which parvalbumin was most frequently documented; however, little is known about other allergens in a real-world setting. In this study we explored IgE-reactivity with fish allergens using FA patients’ serum. Western blot analysis revealed that a newly found protein of approximately 250kD was recognized by serum IgE in five out of six FA patients but not in control individuals. The protein of interest separated on the two-dimensional gel electrophoresis was identified as myosin heavy chain (MYHC) by LS-MS/MS. The IgE immunoreactivity was reproduced when used newly synthesized recombinant MYHC. The patients’ serum IgE, which had been pre-absorbed with fish extracts, lost the reactivity to MYHC recombinant protein, strongly suggesting the antigen specificity for MYHC. Finally, the basophil activation test revealed rsMYHC- dependent IgE reactivity as well as pathogenetic relevance. Results from the present study implicated that FA patients were heterogenous in their allergen specificities since some showed positive for parvalbumin but not for MYHC, and the others showed vice versa. All the FA patients with MYHC-specific IgE had atopic dermatitis at present or in the past. Therefore, impaired permeability barrier might have contributed to the sensitization of this high molecular allergen, MYHC, after touching fish by bear hands. Because raw fish cuisine is popular not only in Japan but also outside of Japan, the risk of FA may be increasing.

IL-36 cytokines are composed of three agonists, namely IL-36α, IL-36β, and IL-36γ, and a natural antagonist, IL-36Ra (Sims and Smith, 2010Sims J.E. Smith D.E. The IL-1 family: regulators of immunity.Nat Rev Immunol. 2010; 10: 89-102Crossref PubMed Scopus (995) Google Scholar). IL-36 cytokines are abundantly expressed by the skin and other epithelial tissues, whereas the IL-36 receptor (IL-36R) is expressed by skin and immune cells, including dendritic cells (DCs) (Gabay and Towne, 2015Gabay C. Towne J.E. Regulation and function of interleukin-36 cytokines in homeostasis and pathological conditions.J Leukoc Biol. 2015; 97: 645-652Crossref PubMed Scopus (171) Google Scholar, Vigne et al., 2011Vigne S. Palmer G. Lamacchia C. Martin P. Talabot-Ayer D. Rodriguez E. et al.IL-36R ligands are potent regulators of dendritic and T cells.Blood. 2011; 118: 5813-5823Crossref PubMed Scopus (245) Google Scholar). Earlier studies have demonstrated that IL-36 cytokines play important roles in the development of psoriasiform inflammation by enhancing the function of T helper type 17 cytokines (Carrier et al., 2011Carrier Y. Ma H.L. Ramon H.E. Napierata L. Small C. O'Toole M. 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; 131: 2428-2437Abstract Full Text Full Text PDF PubMed Scopus (314) Google Scholar, Tortola et al., 2012Tortola L. Rosenwald E. Abel B. Blumberg H. Schafer M. Coyle A.J. et al.Psoriasiform dermatitis is driven by IL-36-mediated DC-keratinocyte crosstalk.J Clin Invest. 2012; 122: 3965-3976Crossref PubMed Scopus (300) Google Scholar). Indeed, IL-36 signaling–regulated genes in keratinocytes (KCs) are largely shared with those observed in psoriatic lesions, and they form interconnected feedback loops that potentiate IL-17 signaling and leukocyte chemotaxis (Carrier et al., 2011Carrier Y. Ma H.L. Ramon H.E. Napierata L. Small C. O'Toole M. 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; 131: 2428-2437Abstract Full Text Full Text PDF PubMed Scopus (314) Google Scholar, Mahil et al., 2017Mahil S.K. Catapano M. Di Meglio P. Dand N. Ahlfors H. Carr I.M. et al.An analysis of IL-36 signature genes and individuals with IL1RL2 knockout mutations validates IL-36 as a psoriasis therapeutic target.Sci Transl Med. 2017; 9Crossref PubMed Scopus (93) Google Scholar), although the details remain largely unknown. Psoriatic lesions demonstrated increased IL-36α, IL36-γ, IL-36Ra, but not IL-36β, as reported previously (see Supplementary Figure S1a online). Similarly, all of the IL-36 family members were upregulated in 12-O-tetradecanoylphorbol-13-acetate (TPA)–induced psoriatic lesions in K5.Stat3C model (see Supplementary Figure S1b), which required the IL-23/Th17 pathway (Nakajima et al., 2011Nakajima K. Kanda T. Takaishi M. Shiga T. Miyoshi K. Nakajima H. et al.Distinct roles of IL-23 and IL-17 in the development of psoriasis-like lesions in a mouse model.J Immunol. 2011; 186: 4481-4489Crossref PubMed Scopus (136) Google Scholar). To explore the role of IL-36 signaling in KCs, we examined psoriasis-related gene expression in response to exogenous IL-36 in between control and IL-36R–/– (knockout [KO]) KCs derived from IL-36R KO mice. Following IL-36α stimulation, wild-type KCs expressed increased Il36a, S100a8, Defb3, and Il17c mRNAs, and also IL-17C protein (Figure 1a ). In contrast, the upregulation of those was not observed in IL-36R KO KCs. Similar results were obtained when we used other IL-36 cytokines, namely, IL-36β and IL-36γ (Supplementary Figure S2 online). These results strongly implicated the participation of the IL-36/IL-36R autocrine loop within KCs in psoriasis development. Our recent study revealed that in vitro IL-36 stimulation of KCs elicited Stat3 phosphorylation at the early time point (Takaishi et al., 2018Takaishi M. Satoh T. Akira S. Sano S. Regnase-1, an immunomodulator, limits the IL-36/IL-36R autostimulatory loop in keratinocytes to suppress skin inflammation.J Invest Dermatol. 2018; 138: 1439-1442Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar), suggesting that the IL-36/IL-36R autocrine loop may facilitate the Stat3-mediated innate immunity within KCs. There are immunologic similarities between anti-Candida defense and psoriasis, including the IL-23/IL-17 axis (Saunte et al., 2017Saunte D.M. Mrowietz U. Puig L. Zachariae C. Candida infections in patients with psoriasis and psoriatic arthritis treated with interleukin-17 inhibitors and their practical management.Br J Dermatol. 2017; 177: 47-62Crossref PubMed Scopus (180) Google Scholar). Psoriasis signature molecules were upregulated in keratinocytes when treated in vitro with heat-killed Candida albicans, including IL-8 (Kobayashi et al., 2009Kobayashi M. Yoshiki R. Sakabe J. Kabashima K. Nakamura M. Tokura Y. Expression of toll-like receptor 2, NOD2 and dectin-1 and stimulatory effects of their ligands and histamine in normal human keratinocytes.Br J Dermatol. 2009; 160: 297-304Crossref PubMed Scopus (59) Google Scholar, Pivarcsi et al., 2003Pivarcsi A. Bodai L. Rethi B. Kenderessy-Szabo A. Koreck A. Szell M. et al.Expression and function of Toll-like receptors 2 and 4 in human keratinocytes.Int Immunol. 2003; 15: 721-730Crossref PubMed Scopus (286) Google Scholar). Interestingly, stimulation with heat-killed C. albicans resulted in the upregulation of Il36a, Il17c, and Ccl20 in wild-type KCs, but not in IL-36R KO KCs (Figure 1b). In addition, heat-killed C. albicans stimulation exerted an additive effect on IL-36 signaling in IL36a and Ccl20 expression in KCs (Figure 1c and Supplementary Figure S3 online). This result suggested that KCs could respond to C. albicans through pattern recognition receptors, leading to the transcriptional activation of Il36a, Il17c, and Ccl20 in a manner depending on the IL-36/IL-36R autocrine loop, which is shared with psoriasis and may involve the IL-23/T helper type 17 axis (Saunte et al., 2017Saunte D.M. Mrowietz U. Puig L. Zachariae C. Candida infections in patients with psoriasis and psoriatic arthritis treated with interleukin-17 inhibitors and their practical management.Br J Dermatol. 2017; 177: 47-62Crossref PubMed Scopus (180) Google Scholar). The role of IL-36 signaling in splenic DCs was clearly shown by the increase of IL-12/IL-23p40 and tumor necrosis factor–α following stimulation with IL-36α. This DC activation was mediated by IL-36R because DCs from IL-36RKO mice are impaired in the production of these cytokines (Figure 1d). Our previous study demonstrated that a cathepsin K inhibitor, which damped toll-like receptor 7–mediated DCs activation leading to IL-23 production, attenuated TPA–induced psoriasiform development in K5.Stat3C mice, suggesting the role of innate immunity with DCs (Hirai et al., 2013Hirai T. Kanda T. Sato K. Takaishi M. Nakajima K. Yamamoto M. et al.Cathepsin K is involved in development of psoriasis-like skin lesions through TLR-dependent Th17 activation.J Immunol. 2013; 190: 4805-4811Crossref PubMed Scopus (38) Google Scholar). Notably, stimulation of toll-like receptor 7 with imiquimod resulted in an increase of tumor necrosis factor–α and IL-12/IL-23p40 production by control DCs, but not by IL-36R KO DCs (Figure 1e). This result highlights the role of IL-36 signaling to enhance the innate immune response through toll-like receptor 7 in DCs. We next sought to address the in vivo effect of IL-36R deficiency on psoriasiform inflammation in K5.Stat3C mice. Deficiency of IL-36R protected from TPA–induced skin lesions in K5.Stat3C mice (Figure 1f, g), while those with IL-36R+/– background (heterozygous [Ht]) developed lesions similar to IL-36R+/+ (see Supplementary Figure S4 online). Further, the upregulation of psoriasis signature genes, including Il36a, Tnfa, Il23a, Il17c, Ccl20, and Cxcl2, were all attenuated by IL-36R deficiency (Figure 1h). To dissect the roles of KCs and DCs in IL-36 signaling, IL-36R KO or control bone marrow cells were transferred to lethally irradiated recipient K5.Stat3C mice in a criss-cross manner. Skin lesions were dramatically attenuated in Ht:K5.Stat3C mice reconstituted with IL-36R KO bone marrow (KO>Ht) cells compared with mice with the opposite combination (Ht>KO), whose lesions were only marginally affected, comparable to the positive controls (Ht>Ht) at the later time point (Figure 1i, j, and Supplementary Figure S5 online); however, at the early time point (6 hours), both chimeric mice with Ht>KO and KO>Ht showed impaired ear swelling like KO>KO chimeras. Analysis of gene expression of skin lesions revealed that Il17c mRNA levels were significantly down-modulated in mice with Ht>KO, but not with KO>Ht chimeras (Figure 1k), supporting that IL-17C was produced by the radio-resistant epidermis via IL-36 signaling (Figure 1a). However, Il36 mRNA levels were decreased in lesions of mice with both Ht>KO and KO>Ht chimeras (Figure 1k). Collectively, these results suggested that bona fide psoriasiform lesions depended on IL-36 signaling both in the epidermis and in bone marrow–derived cells, including DCs. In contrast, the previous study showed that IL-36R expression on radio-resistant skin-resident cells, but not on bone marrow–derived cells, was essential for pathology upon imiquimod treatment (Tortola et al., 2012Tortola L. Rosenwald E. Abel B. Blumberg H. Schafer M. Coyle A.J. et al.Psoriasiform dermatitis is driven by IL-36-mediated DC-keratinocyte crosstalk.J Clin Invest. 2012; 122: 3965-3976Crossref PubMed Scopus (300) Google Scholar). The discrepancy of the results in the present and previous studies might be due to the difference in mouse models, although the underlying mechanism remains unknown. Given that psoriasis develops via IL-36 signaling, the inhibition of that pathway should attenuate psoriatic inflammation. To explore this possibility, we treated K5.Stat3C mice and ex vivo tissue cultures of human plaque psoriasis with recombinant IL-36Ra. Subcutaneous injection of IL-36Ra attenuated the development of TPA–induced skin lesions in K5.Stat3C mice (Figure 2a, b , and Supplementary Figure S6 online). In addition, the epidermal thickness of psoriasis lesions in ex vivo cultures was attenuated by the addition of IL-36Ra (Figure 2c, d), which also downregulated IL8, CCL20, and IL17A mRNAs (Figure 2e). In conclusion, these results strongly suggest that the inhibition of IL-36 signaling would be relevant for new treatments of psoriasis. Supplementary Figure S7 online illustrates the role of IL-36 signaling (red jagged mark) both in KCs and in DCs in the augmentation of innate immune responses, which leads to the development of psoriasis through activation of the IL-23/IL-17 axis. All experimental procedures performed on mice were approved by the Institutional Animal Care and Use Committee of the Kochi Medical School. The written informed consent and approval of the ethics committee were obtained from all patients. Kentar Ohko: http://orcid.org/0000-0002-7614-126X The authors state no conflict of interest. We thank Reiko Kamijima for her help with the histopathology, and JE Sims, JE Towne, and Amgen Inc for providing us with IL-36RKO mice. This work was supported in part by a Grant-in-Aid for Scientific Research (26461695) from the Ministry of Education, Culture, Sports, Science and Technology of Japan. Download .pdf (8.42 MB) Help with pdf files Supplementary Data

IL-36, a newly named member of the IL-1 cytokine family, includes 3 isoforms, IL-36α, IL-36β, and IL-36γ, all of which bind to a heterodimer containing the IL-36 receptor (IL-36R). Little is known about the role of the IL-36 axis in acute kidney injury (AKI) pathogenesis. Therefore, we evaluated IL-36 function in the bilateral renal ischemia-reperfusion injury model of AKI using IL-36R knockout and wild-type mice. IL-36R was found to be expressed in the kidney, mainly in proximal tubules. In IL-36R knockout mice, plasma creatinine, blood urea nitrogen, and IL-6 levels after ischemia-reperfusion injury were significantly lower than those in wild-type mice. Immunohistological analysis revealed mild tubular injury. IL-36α/β/γ levels were increased after ischemia-reperfusion injury, and IL-36α was expressed in lymphocytes and proximal tubular cells, but post-ischemia-reperfusion injury mRNA levels of IL-6 and TNF-α were low in IL-36R knockout mice. In primary cultures of renal tubular epithelial cells, IL-36α treatment upregulated NF-κB activity and Erk phosphorylation. Notably, in patients with AKI, urine IL-36α levels were increased, and IL-36α staining in renal biopsy samples was enhanced. Thus, IL-36α/IL-36R blockage could serve as a potential therapeutic target in AKI.

Contact DermatitisVolume 78, Issue 1 p. 94-95 Contact Point Can patch test sensitization with gold sodium thiosulfate be ruled out? – a case report Yuka Shibata, Yuka Shibata Department of Dermatology, Kochi Medical School, Kochi University, Kochi 783-8505, JapanSearch for more papers by this authorKentaro Ohko, Corresponding Author Kentaro Ohko kentaro-ohko@kochi-u.ac.jp orcid.org/0000-0002-7614-126X Department of Dermatology, Kochi Medical School, Kochi University, Kochi 783-8505, JapanCorrespondence: Dr. Kentaro Ohko, Department of Dermatology, Kochi Medical School, Kochi University, Kohasu, Okocho, Nankoku-shi, Kochi 783-8505, Japan. Tel: 81-88-880-2363. E-mail: kentaro-ohko@kochi-u.ac.jpSearch for more papers by this authorShigetoshi Sano, Shigetoshi Sano Department of Dermatology, Kochi Medical School, Kochi University, Kochi 783-8505, JapanSearch for more papers by this author Yuka Shibata, Yuka Shibata Department of Dermatology, Kochi Medical School, Kochi University, Kochi 783-8505, JapanSearch for more papers by this authorKentaro Ohko, Corresponding Author Kentaro Ohko kentaro-ohko@kochi-u.ac.jp orcid.org/0000-0002-7614-126X Department of Dermatology, Kochi Medical School, Kochi University, Kochi 783-8505, JapanCorrespondence: Dr. Kentaro Ohko, Department of Dermatology, Kochi Medical School, Kochi University, Kohasu, Okocho, Nankoku-shi, Kochi 783-8505, Japan. Tel: 81-88-880-2363. E-mail: kentaro-ohko@kochi-u.ac.jpSearch for more papers by this authorShigetoshi Sano, Shigetoshi Sano Department of Dermatology, Kochi Medical School, Kochi University, Kochi 783-8505, JapanSearch for more papers by this author First published: 20 December 2017 https://doi.org/10.1111/cod.12864Citations: 6 Conflict of Interest: The authors declare no conflict of interests. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume78, Issue1January 2018Pages 94-95 RelatedInformation

A 21-year old woman with atopic dermatitis (AD) presented with worsening hand eczema, which was refractory to topical corticosteroids. Specifically, since she became a cook she noted repeated episodes of hand swelling and malaise during contacting fish, including sebastes altus, mackerel, codfish, horse mackerel and pacific saury. The skin prick tests (SPT) were positive to a variety of fish, such as cod fish, salmon, sebastes altus, mackerel, horse mackerel, tuna, floundera flatfish and pacific saury. Interestingly, her response of SPT to heat-treated fish showed positive result comparable to raw fish, indicating that the specific antigen for positive SPT was heat-resistant. The radioallergosorbent test using her serum revealed that her IgE specifically reacted to codfish, horse mackerel and sardine. Western blot analysis revealed that IgE in her serum reacted with a 100kDa protein, suggesting the fish collagen, which represents the major allergen in patients with fish allergy in Japan. We are now under investigation of the epitopes in the fish collagen by two-dimensional gel, followed by the proteomic analysis to identify amino acid sequence as the responsible epitope. We assume that this patient was sensitized to the fish collagen via percutaneous since she had AD.

Dear Editor, Ultraviolet (UV) irradiation is a standard treatment for psoriasis; however, it leads to exacerbation of psoriasis in some patients. Here, we report a patient with psoriasis vulgaris, who developed aggravation of psoriatic lesions after a single irradiation of narrowband UV-B (NB-UVB). A-76-year-old Japanese woman presented with plaque-type psoriasis, which was diagnosed at the age of 10 years (Fig. 1a). Her psoriatic

It has been suggested that IL-36 cytokines play important roles in psoriasis development, since psoriatic lesions showed enhanced levels of them and mice harboring IL-36 transgene together with deletion of IL-36Ra gene showed a severe psoriatic phenotype. In addition, we previously demonstrated that IL-36R KO completely abolished the development of psoriatic inflammation in K5.Stat3C model mice. IL-36R is expressed both in epidermal keratinocytes (KCs) and dendritic cells (DCs), but it remains elusive which cells predominantly exert the IL-36R signal to drive psoriatic inflammation. In this study we dissected each cell lineage to verify the contribution of the IL-36R signal during psoriatic development. IL-23p40 is produced by sorted CD11c+ DCs upon in vitro stimulation with IL-36 ligands, however, not by IL-36RKO DCs. In vitro TLR-7 stimulation of wild-type DCs with imiquimod resulted in production of IL-23p40 and TNF, both of which were markedly decreased when IL-36RKO DCs were used. Cultured wild-type KCs produced IL-17C by inclusion of IL-36R ligands, however, no IL-17C was found in IL-36RKO KCs. Interestingly, upregulation of IL-17C, IL-36alpha, and CCL20 transcripts by in vitro stimulation with killed candida albicans in wild-type KCs was markedly attenuated in IL-36R KO KCs. Finally, in vivo psoriasogenic experiments using lethally irradiated IL-36R+/-:K5.Stat3C mice reconstituted with IL-36RKO bone marrow (BM) cells, and vice versa, revealed the predominant contribution of IL-36R signaling in BM-derived cells including DCs over that in KCs, although the bona fide psoriatic phenotype was reproduced in IL-36R+/-:K5.Stat3C mice reconstituted with IL-36R+/- BM cells. In conclusion, we suggest that the IL-36R signaling is involved in the innate immunity in both DCs and KCs to develop the bona fide psoriasis development.

IL-36 cytokines are highly expressed in psoriatic lesions and suggested to play a role in the development of psoriasis as shown by studies using transgenic and knockout mice. However, the detail relationship between the IL-36 pathway and the psoriasis signature molecules including the IL-23/Th17 axis still remains elusive. TPA-induced psoriasis-like lesions in K5.Stat3C mice showed up-regulation of IL-36 genes. We found that skin lesions in K5.Stat3C were greatly attenuated when crossed with IL-36 receptor (R) knockout, clearly indicating that the IL-36 signaling is required for psoriasiform phenotype. Furthermore, gene expression of psoriasis-related molecules including the IL-23/Th17 axis and S100As was down-regulated in the lesions of IL-36R−/−:K5.Stat3C mice. IL-36R deficiency resulted in resistance of splenic CD11c+ dendritic cells (DCs) to imiquimod stimulation-induced in vitro production of TNF and IL-12/23p40. Strikingly, IL-36R deficient primary keratinocytes did not respond to beta d-glucan, which otherwise could up-regulate IL-36 members, S100A8, S100A9 and IL-17C in vitro. Taken together, these observations suggest that the IL-36 signaling is independently required for expression of psoriasis signature molecules in both DCs and keratinocytes. We conclude that the IL-36 signaling plays roles as a gatekeeper that links innate immunity to the pathogenesis of psoriasis.

It has been widely recognized that topical treatment of mice with imiquimod (IMQ) cream results in generation of skin inflammation, which resembles human psoriasis. We previously reported that topical treatment with TLR7 agonists including IMQ and resiquimod also induced lupus-like systemic autoimmunity in wild-type mice. Thus, although IMQ treatment induces two distinct diseases, it remains unknown whether the underlying pathomechanism is common between them. In this study, we explored detailed kinetics of development of both diseases.

Toll-like receptor 7 (TLR7) senses microbial-derived RNA but can also potentially respond to self-derived RNA. To prevent autoimmune responses, TLR7 is thought to localize in endolysosomes. Contrary to this view, we show here that TLR7 is present on the cell surface of immune cells and that TLR7 responses can be inhibited by an anti-TLR7 antibody. The anti-TLR7 antibody is internalized with TLR7 and accumulates in endolysosomes as an immune complex. TLR7 responses in dendritic cells, macrophages and B cells are all inhibited by the anti-TLR7 antibody. Furthermore, the anti-TLR7 antibody inhibits in vivo cytokine production induced by a TLR7 ligand. Spontaneous TLR7 activation in Unc93b1(D34A/D34A) mice causes lethal inflammation. Progressive inflammation such as splenomegaly, thrombocytopenia and chronic active hepatitis are ameliorated by anti-TLR7 antibody treatment. These results demonstrate that cell surface TLR7 is a promising target for therapeutic intervention in autoimmune diseases.

Abstract SLE is an autoimmune disease characterized by the production of autoantibodies and inflammatory pathologies such as glomerulonephritis. A number of studies have demonstrated that altered Toll-like receptor 7 (TLR7) signaling contributes to the initiation of SLE in humans and in murine models. Indeed, introduction of Tlr7 null mutation in lupus-prone mice resulted in amelioration of lupus nephritis and reduction of autoantibodies, clearly indicating the contribution of TLR7 to lupus phenotype. We have recently demonstrated that epicutaneous application of TLR7 agonists, imiquimod (IMQ) or R848, leads to systemic autoimmunity in wild-type mice. They developed lupus-like systemic autoimmunity from 4 weeks of topical treatment, but not by peritoneal injection of IMQ, showing elevated autoantibodies to double-stranded DNA and glomerulonephritis, hepatitis, carditis and photosensitivity, indicating that the skin as the primary organ that allows TLR agonists to initiate lupus. Since ultraviolet (UV) irradiation is a worsening factor in SLE, we examined the effect of UVB on the initiation of TLR agonist-induced lupus. Strikingly, UVB irradiation of Balb/c mice facilitated the emergence and increase in the titers of autoantibodies including anti-double stranded DNA induced by topical treatment with R848 from 2 weeks, which was much earlier than R848 alone, strongly suggesting that UV accelerated the TLR7-mediated systemic autoimmunity.