Nao Saito

An annexin A1–FPR1 interaction contributes to necroptosis of keratinocytes in severe cutaneous adverse drug reactions

Annexin A1 secreted from drug-stimulated monocytes contributes to keratinocyte necroptosis in serious drug-related adverse events in skin. Subduing a Severe Skin Side Effect Certain pain relievers and antiepileptic drugs can cause a very rare, but sometimes fatal, side effect in which skin painfully blisters and peels, caused by the patients’ immune response to the drug. Saito et al. now find that, in susceptible patients, the drug causes secretion of the protein annexin A1 from immune cells, with deadly effect on skin cells. Annexin acts on these cells to cause necroptosis, a programmed form of cell death. The authors confirmed their results in mice, showing that an inhibitor of necroptosis blocked skin blistering. With these findings, Saito et al. lay the groundwork for a countermeasure to this dangerous side effect of otherwise extremely beneficial drugs. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening, cutaneous adverse drug reactions that are accompanied by keratinocyte cell death. Dead keratinocytes from SJS/TEN lesions exhibited necrosis, by morphological criteria. Supernatant from peripheral blood mononuclear cells (PBMCs) that had been exposed to the causative drug from patients with SJS/TEN induced the death of SJS/TEN keratinocytes, whereas supernatant from PBMCs of patients with ordinary drug skin reactions (ODSRs) exposed to the same drug did not. Keratinocytes from ODSR patients or from healthy controls were unaffected by supernatant from SJS/TEN or ODSR PBMCs. Mass spectrometric analysis identified annexin A1 as a key mediator of keratinocyte death; depletion of annexin A1 by a specific antibody diminished supernatant cytotoxicity. The necroptosis-mediating complex of RIP1 and RIP3 was indispensable for SJS/TEN supernatant–induced keratinocyte death, and SJS/TEN keratinocytes expressed abundant formyl peptide receptor 1 (FPR1), the receptor for annexin A1, whereas control keratinocytes did not. Inhibition of necroptosis completely prevented SJS/TEN-like responses in a mouse model of SJS/TEN. Our results demonstrate that a necroptosis pathway, likely mediated by annexin 1 acting through the FPR1 receptor, contributes to SJS/TEN.

Prolonged elevation of serum granulysin in drug‐induced hypersensitivity syndrome

and soluble CD40 ligand in serum and plasma. J Thromb Haemost 2004; 11:2067–9. 6 Kasperska-Zajac A, Sztylc J, Machura E, Jop G. Plasma IL-6 concentration correlates with clinical disease activity and serum C-reactive protein concentration in chronic urticaria patients. Clin Exp Allergy 2011; 41:1386–91. 7 Toubi E, Adir-Shani A, Kessel A et al. Immune aberrations in B and T lymphocytes derived from chronic urticaria patients. J Clin Immunol 2000; 20:371–8. 8 Hermes B, Worm M, Nowak F et al. Upregulation of CD40 and CD40 ligand expression in IgE-associated cutaneous diseases. Acta Derm Venereol 1997; 77:441–5. 9 Kasperska-Zajac A, Rogala B. Platelet activation during allergic inflammation. Inflammation 2007; 30:161–6. 10 Kasperska-Zając A, Rogala B, Nowakowski M. Assessment of platelet activity as expressed by plasma levels of platelet factor 4 and b-thromboglobulin in patients with chronic idiopathic urticaria. Exp Dermatol 2005; 14:515–18. 11 Kasperska-Zajac A, Brzoza Z, Rogala B. Platelet function in cutaneous diseases. Platelets 2008; 19:317–21. 12 Kasperska-Zajac A. Acute phase response in chronic urticaria. J Eur Acad Dermatol Venereol 2011; (in press). 13 Kasperska-Zając A, Grzanka A, Czecior E, Misiolek M, Rogala B, Machura E. Acute phase inflammatory markers in patients with non-steroidal anti-inflammatory drugs (NSAIDs)-induced acute urticaria ⁄angioedema and after aspirin challenge. J Eur Acad Dermatol Venereol 2012; 21 February. doi: 10.1111/j.1468-3083.2012. 04486.x.

Generalized exacerbation of systemic allergic dermatitis due to zinc patch test and dental treatments.

A 37-year-old Japanese man was referred with a one-year history of multiple pruritic eruptions covering his entire body. The skin lesions had been refractory to topical corticosteroids and anti-histamines. Examination showed an oedematous erythema with lesions 3–10 mm in diameter that were distributed over his entire body. A detailed history revealed that the patient had had dental fillings 3 months prior to the onset of the rash. We suspected systemic allergic dermatitis because of the dental fillings. We performed patch test with a metal series (Torii Pharmaceutical Co., Ltd., Tokyo, Japan) consisting of aluminium chloride, gold chloride, tin chloride, iron chloride, platinum chloride, palladium chloride, indium chloride, manganese chloride, silver bromide, cobalt chloride, potassium dichromate, nickel sulfate, and zinc chloride. He developed a positive (+) reaction (ICDRG criteria) to zinc chloride on D2 (Table 1) and this persisted to D7. During patch testing, the skin lesions dramatically flared at previous lesion sites (Fig. 1). Serum zinc concentration was within normal limits; there was an eosinophilia. Lymphocyte stimulation test revealed a reaction to zinc chloride with a stimulation index of 518% (normal is <180%). A skin biopsy from erythema lesion on the back showed spongiosis and perivascular lymphocytic infiltration. Based on these clinical and histological findings, we diagnosed his pruritic eruption as systemic allergic dermatitis because of zinc. Dental inspection showed that he had 11 teeth with zinc-containing metal fillings. We have been removing the fillings one by one, but with each

Establishment of a novel experimental model of human angiosarcoma and a VEGF-targeting therapeutic experiment

BACKGROUND Angiosarcoma is one of the most life-threatening neoplasms with strong resistance to conventional chemotherapy/radiotherapy; consequently, alternative therapeutic agents are urgently required. One factor in delaying the therapy development is the limitation of experimental models. OBJECTIVE We established a novel experimental angiosarcoma model. METHODS From surgically resected tissue, human AS cell line was established. Using xenograft of AS cell line, we performed therapeutic experiments with the anti-human VEGF Ab or the receptor tyrosine kinase inhibitor. RESULTS First we generated an angiosarcoma cell line, HAMON (human angiosarcoma, monoclonal), which expresses CD31 and produces tumors in immunodeficient mice. HAMON expresses VEGFR2 and that exogenous VEGF leads to HAMON proliferation in vitro. Anti-human VEGF Ab bevacizumab treatment failed to suppress HAMON proliferation in vitro and in vivo. Furthermore, the receptor tyrosine kinase inhibitor sunitinib did not suppress HAMON proliferation in vitro. Similarly, in in vivo therapeutic experiments, even high doses of sunitinib failed to inhibit tumor growth. Finally, we checked whether compensatory activation of VEGF signaling occurred after sunitinib addition. VEGF protein secretion, VEGF mRNA synthesis and VEGFR2 phosphorylation all were unaffected in HAMON after sunitinib treatment. CONCLUSION A novel in vitro and in vivo experimental model of human angiosarcoma has been successfully established. With this model, we were able to perform therapeutic experiments. In addition, our angiosarcoma cell line, HAMON, is quite useful for identifying key molecules in angiosarcoma.

Pyoderma Gangrenosum of the Eyelid: Report of Two Cases and Review of the Literature

Pyoderma gangrenosum (PG) of the eyelid is extremely rare, and its proper management is essential for the preservation of visual function. Here, we report 2 cases of PG of the eyelid with intraorbital involvement. In both cases, the skin and intraorbital lesions improved after systemic immunosuppressive therapies; however, corneal perforation occurred in 1 case. In order to assess the clinical features of PG of the eyelid and to obtain clues for optimal treatment, we reviewed 15 well-documented cases in the literature, including the present cases. Corneal perforation occurred in 4 cases and defective ocular motility in 1 case. Three patients eventually underwent enucleation of the affected eye. Our cases and the literature review clearly indicate that MRI is a powerful tool for evaluating the extent of extracutaneous PG lesions around the eye and that early diagnosis and immediate immunosuppressive therapy are crucial for the preservation of visual acuity.

MUC5AC expression correlates with invasiveness and progression of extramammary Paget's disease

Patients with in situ extramammary Pagets disease (EMPD) tend to have a good prognosis, although dermal invasion and metastasis are associated with significantly increased morbidity and mortality. Previous studies have addressed mechanisms underlying the EMPD pathogenesis; however, no molecular markers that reflect invasiveness or progression have been established.

Bowen's disease of the nail matrix presenting as melanonychia: detection of human papillomavirus type 56.

© 2009 The Authors. doi: 10.2340/00015555-0723 Journal Compilation

Klk8 is required for microabscess formation in a mouse imiquimod model of psoriasis

1 Mohamed M, Voet M, Gardeitchik T et al. Adv Exp Med Biol 2014: 802: 161–184. 2 Berk D R, Bentley D D, Bayliss S J et al. J Am Acad Dermatol 2012: 66: 842 e841–842 e817. 3 Urban Z, Davis E C. Matrix Biol 2014: 33: 16–22. 4 Urban Z, Gao J, Pope F M et al. J Invest Dermatol 2005: 124: 1193–1199. 5 Graul-Neumann L M, Hausser I, Essayie M et al. Am J Med Genet A 2008: 146A: 977–983. 6 Sugitani H, Hirano E, Knutsen R H et al. J Biol Chem 2012: 287: 22055–22067. 7 Zhang M C, He L, Giro M et al. J Biol Chem 1999: 274: 981–986. 8 Uitto J, Li Q, Urban Z. Exp Dermatol 2013: 22: 88–92. 9 Tassabehji M, Metcalfe K, Hurst J et al. Hum Mol Genet 1998: 7: 1021–1028.

Kallikrein-related peptidase 6 promotes psoriasiform skin inflammation through a protease-activated receptor 2-independent mechanism.

Kallikreinrelated peptidases (KLKs) are a family of 15 secreted serine proteases with chymotrypsinand trypsinlike activities.[1] KLKs are expressed in the granular layer of the epidermis and contribute to physiological desquamation by degrading desmosome components such as desmoglein1 and desmocollin1 (S1). Furthermore, KLKs can activate proteaseactivated receptors (PARs) by proteolytic cleavage[2](S2). Several studies have demonstrated that PAR2 on keratinocytes plays an important role in inflammatory skin diseases[3](S3). KLK6 is a trypsinlike protease expressed in diverse tissues including the skin (S4). Increased KLK6 expression is also observed in various cancers.[4] In vitro experiments revealed that KLK6 can degrade components of the extracellular matrix including fibrinogen and various collagens. In addition, KLK6 was shown to be able to activate PAR2 directly. These findings imply that KLK6 participates in a variety of physiological and pathological processes such as inflammation and tumorigenesis. Previous studies also indicated that KLK6 is highly expressed in human psoriatic epidermis.[5] Moreover, serum levels of KLK6 in patients with psoriasis are significantly elevated and correlate with corresponding Psoriasis Area and Severity Index (PASI) scores (S5). Recently, topical treatment with imiquimod (IMQ), a ligand for TLR7/8, was shown to induce psoriasislike skin inflammation in mice.[6,7] Daily application of IMQ cream induces dermatitis with many features of psoriasis including acanthosis, parakeratosis and inflammatory cell infiltration. Moreover, subsequent studies have shown that this psoriasislike reaction depends on IL23, IL17 and IL22, all of which are involved in human psoriasis pathogenesis (S6).

RNA recognition motif of LEMD3 as a key player in the pathogenesis of Buschke–Ollendorff syndrome

[1] W.T. Massengale, K.T. Hodari, E.E. Boh, L.T. Nesbitt, Xanthomas, in: J. Bolognia, J.L. Jorizzo, J.V. Schaffer (Eds.), Dermatology, Elsevier Saunders, Philadelphia, 2012. [2] M. Asahina, T. Mashimo, M. Takeyama, R. Tozawa, T. Hashimoto, A. Takizawa, et al., Hypercholesterolemia and atherosclerosis in low density lipoprotein receptor mutant rats, Biochem. Biophys. Res. Commun. 418 (2012) 553–558. [3] P.R. Hiebert, W.A. Boivin, T. Abraham, S. Pazooki, H. Zhao, D.J. Granville, Granzyme B contributes to extracellular matrix remodeling and skin aging in apolipoprotein E knockout mice, Exp. Gerontol. 46 (2011) 489–499. [4] A. Nakano, M. Kinoshita, R. Okuda, T. Yasuda, M. Abe, M. Shiomi, Pathogenesis of tendinous xanthoma: histopathological study of the extremities of Watanabe heritable hyperlipidemic rabbits, J. Orthop. Sci. 11 (2006) 75–80. [5] R.M. Lavker, G. Dong, P.S. Zheng, G.F. Murphy, Hairless micropig skin. A novel model for studies of cutaneous biology, Am. J. Pathol. 138 (1991) 687–697. [6] M.S. Brown, J.L. Goldstein, Familial hypercholesterolemia: a genetic defect in the low-density lipoprotein receptor, N. Engl. J. Med. 294 (1976) 1386–1390. [7] B.T. Davis, X.J. Wang, J.A. Rohret, J.T. Struzynski, E.P. Merricks, D.A. Bellinger, et al., Targeted disruption of LDLR causes hypercholesterolemia and atherosclerosis in Yucatan miniature pigs, PLoS One 9 (2014) e93457. Zheng Wang, Molly A. Wasserman Courtney E. Morgan Janet M. Vercammen Amy S. Paller Melina R. Kibbe* Division of Vascular Surgery and the Simpson Querrey Institute for BioNanotechnology, and the Department of Dermatology, Northwestern University, Chicago, IL, United States