All Title Author
Keywords Abstract

Gene Expression Profiling in Dermatitis Herpetiformis Skin Lesions

DOI: 10.1155/2012/198956

Full-Text   Cite this paper   Add to My Lib


Dermatitis herpetiformis (DH) is an autoimmune blistering skin disease associated with gluten-sensitive enteropathy (CD). In order to investigate the pathogenesis of skin lesions at molecular level, we analysed the gene expression profiles in skin biopsies from 6 CD patients with DH and 6 healthy controls using Affymetrix HG-U133A 2.0 arrays. 486 genes were differentially expressed in DH skin compared to normal skin: 225 were upregulated and 261 were downregulated. Consistently with the autoimmune origin of DH, functional classification of the differentially expressed genes (DEGs) indicates a B- and T-cell immune response (LAG3, TRAF5, DPP4, and NT5E). In addition, gene modulation provides evidence for a local inflammatory response (IL8, PTGFR, FSTL1, IFI16, BDKRD2, and NAMPT) with concomitant leukocyte recruitment (CCL5, ENPP2), endothelial cell activation, and neutrophil extravasation (SELL, SELE). DEGs also indicate overproduction of matrix proteases (MMP9, ADAM9, and ADAM19) and proteolytic enzymes (CTSG, ELA2, CPA3, TPSB2, and CMA1) that may contribute to epidermal splitting and blister formation. Finally, we observed modulation of genes involved in cell growth inhibition (CGREF1, PA2G4, and PPP2R1B), increased apoptosis (FAS, TNFSF10, and BASP1), and reduced adhesion at the dermal epidermal junction (PLEC1, ITGB4, and LAMA5). In conclusion, our results identify genes that are involved in the pathogenesis of DH skin lesions. 1. Introduction Dermatitis herpetiformis (DH) is an autoimmune subepidermal blistering skin disease characterized by intense pruritic papulovesicular eruptions mainly localized on extensor surfaces [1]. DH typically develops in patients with celiac disease (CD). The two conditions share the same genetic background (HLA genes DQ2–DQ8), improve following a gluten-free diet (GFD), and are mediated by IgA autoantibodies [2]. IgA antibodies against tissue transglutaminase (tTG) are detectable both in CD and DH, while autoantibodies directed against epidermal transglutaminase (eTG) are a typical serological marker of patients with DH [3]. The key feature of DH is a granular deposition of IgA within the tips of dermal papillae and along the basement membrane of perilesional skin. eTG has been shown to colocalize with such IgA deposits [4]. Typical histopathologic features of DH consist of accumulation of neutrophils and a few eosinophils with formation of papillary microabscesses which then coalescence to form a subepidermal bulla. Moreover, a perivascular cellular infiltrate composed mainly by CD4+ lymphocytes is also present [5]. In


[1]  S. K. árpáti, “Dermatitis herpetiformis,” Clinics in Dermatology, vol. 30, no. 1, pp. 56–59, 2012.
[2]  D. Bolotin and V. Petronic-Rosic, “Dermatitis herpetiformis: part I. Epidemiology, pathogenesis, and clinical presentation,” Journal of the American Academy of Dermatology, vol. 64, no. 6, pp. 1017–1024, 2011.
[3]  D. Bolotin and V. Petronic-Rosic, “Dermatitis herpetiformis: part II. Diagnosis, management, and prognosis,” Journal of the American Academy of Dermatology, vol. 64, no. 6, pp. 1027–1033, 2011.
[4]  M. Sárdy, S. Kárpáti, B. Merkl, M. Paulsson, and N. Smyth, “Epidermal transglutaminase (TGase 3) is the autoantigen of dermatitis herpetiformis,” Journal of Experimental Medicine, vol. 195, no. 6, pp. 747–757, 2002.
[5]  L. Fry, “Dermatitis herpetiformis: problems, progress and prospects,” European Journal of Dermatology, vol. 12, no. 6, pp. 523–531, 2002.
[6]  G. Oberhuber, G. Granditsch, and H. Vogelsang, “The histopathology of coeliac disease: time for a standardized report scheme for pathologists,” European Journal of Gastroenterology and Hepatology, vol. 11, no. 10, pp. 1185–1194, 1999.
[7]  F. Triebel, “LAG-3: a regulator of T-cell and DC responses and its use in therapeutic vaccination,” Trends in Immunology, vol. 24, no. 12, pp. 619–622, 2003.
[8]  T. Miyagaki, M. Sugaya, H. Suga, et al., “Serum soluble CD26 levels: diagnostic efficiency for atopic dermatitis, cutaneous T-cell lymphoma and psoriasis in combination with serum thymus and activation-regulated chemokine levels,” Journal of the European Academy of Dermatology and Venereology, 2011. In press.
[9]  A. ?lgars, M. Karikoski, G. G. Yegutkin et al., “Different role of CD73 in leukocyte trafficking via blood and lymph vessels,” Blood, vol. 117, no. 16, pp. 4387–4393, 2011.
[10]  G. I. Rice, J. Bond, A. Asipu et al., “Mutations involved in Aicardi-Goutières syndrome implicate SAMHD1 as regulator of the innate immune response,” Nature Genetics, vol. 41, no. 7, pp. 829–832, 2009.
[11]  K. Gronert, A. Kantarci, B. D. Levy et al., “A molecular defect in intracellular lipid signaling in human neutrophils in localized aggressive periodontal tissue damage,” Journal of Immunology, vol. 172, no. 3, pp. 1856–1861, 2004.
[12]  B. Bukau, J. Weissman, and A. Horwich, “Molecular chaperones and protein quality control,” Cell, vol. 125, no. 3, pp. 443–451, 2006.
[13]  S. Rosebeck and D. W. Leaman, “Mitochondrial localization and pro-apoptotic effects of the interferon-inducible protein ISG12a,” Apoptosis, vol. 13, no. 4, pp. 562–572, 2008.
[14]  Z. Liu, S. M. Oh, M. Okada et al., “Human BRE1 is an E3 ubiquitin ligase for Ebp1 tumor suppressor,” Molecular Biology of the Cell, vol. 20, no. 3, pp. 757–768, 2009.
[15]  R. H. Tammi, A. G. Passi, K. Rilla et al., “Transcriptional and post-translational regulation of hyaluronan synthesis,” FEBS Journal, vol. 278, no. 9, pp. 1419–1428, 2011.
[16]  K. Hasegawa, M. Yoneda, H. Kuwabara et al., “Versican, a major hyaluronan-binding component in the dermis, loses its hyaluronan-binding ability in solar elastosis,” Journal of Investigative Dermatology, vol. 127, no. 7, pp. 1657–1663, 2007.
[17]  K. Airola, M. Vaalamo, T. Reunala, and U. K. Saarialho-Kere, “Enhanced expression of interstitial collagenase, stromelysin-1, and urokinase plasminogen activator in lesions of dermatitis herpetiformis,” Journal of Investigative Dermatology, vol. 105, no. 2, pp. 184–189, 1995.
[18]  K. Airola, T. Reunala, S. Salo, and U. K. Saarialho-Kere, “Urokinase plasminogen activator is expressed by basal keratinocytes before interstitial collagenase, stromelysin-1, and laminin-5 in experimentally induced dermatitis herpetiformis lesions,” Journal of Investigative Dermatology, vol. 108, no. 1, pp. 7–11, 1997.
[19]  J. Koster, D. Geerts, B. Favre, L. Borradori, and A. Sonnenberg, “Analysis of the interactions between BP180, BP230, plectin and the integrin α6β4 important for hemidesmosome assembly,” Journal of Cell Science, vol. 116, no. 2, pp. 387–399, 2003.
[20]  M. Bettini, A. L. Szymczak-Workman, K. Forbes, et al., “Cutting edge: accelerated autoimmune diabetes in the absence of LAG-3,” Journal of Immunology, vol. 187, no. 7, pp. 3493–3498, 2011.
[21]  T. Okazaki, I. M. Okazaki, J. Wang et al., “PD-1 and LAG-3 inhibitory co-receptors act synergistically to prevent autoimmunity in mice,” Journal of Experimental Medicine, vol. 208, no. 2, pp. 395–407, 2011.
[22]  S. Sponza, M. De Andrea, M. Mondini, F. Gugliesi, M. Gariglio, and S. Landolfo, “Role of the interferon-inducible IFI16 gene in the induction of ICAM-1 by TNF-α,” Cellular Immunology, vol. 257, no. 1-2, pp. 55–60, 2009.
[23]  T. Miyamae, A. D. Marinov, D. Sowders et al., “Follistatin-like protein-1 is a novel proinflammatory molecule,” Journal of Immunology, vol. 177, no. 7, pp. 4758–4762, 2006.
[24]  S. D. Clutter, D. C. Wilson, A. D. Marinov, and R. Hirsch, “Follistatin-like protein 1 promotes arthritis by up-regulating IFN-γ,” Journal of Immunology, vol. 182, no. 1, pp. 234–239, 2009.
[25]  L. Forstrom, T. Reunala, H. Vapaatalo, and I. B. Linden, “Increased suction blister concentrations of prostaglandin E and F(2α) in dermatitis herpetiformis,” Acta Dermato-Venereologica, vol. 59, no. 5, pp. 458–460, 1979.
[26]  O. M. Shaw and J. L. Harper, “Bradykinin receptor 2 extends inflammatory cell recruitment in a model of acute gouty arthritis,” Biochemical Biophysical Research Communications, vol. 416, no. 3-4, pp. 266–269, 2011.
[27]  R. P. Hall III, K. M. Benbenisty, C. Mickle, F. Takeuchi, and R. D. Streilein, “Serum IL-8 in patients with dermatitis herpetiformis is produced in response to dietary gluten,” Journal of Investigative Dermatology, vol. 127, no. 9, pp. 2158–2165, 2007.
[28]  R. P. Hall III, F. Takeuchi, K. M. Benbenisty, and R. D. Streilein, “Cutaneous endothelial cell activation in normal skin of patients with dermatitis herpetiformis associated with increased serum levels of IL-8, sE-selectin, and TNF-α,” Journal of Investigative Dermatology, vol. 126, no. 6, pp. 1331–1337, 2006.
[29]  A. Li, M. L. Varney, J. Valasek, M. Godfrey, B. J. Dave, and R. K. Singh, “Autocrine role of interleukin-8 in induction of endothelial cell proliferation, survival, migration and MMP-2 production and angiogenesis,” Angiogenesis, vol. 8, no. 1, pp. 63–71, 2005.
[30]  C. A. Gabel, “P2 purinergic receptor modulation of cytokine production,” Purinergic Signalling, vol. 3, no. 1-2, pp. 27–38, 2007.
[31]  R. S. Cotran, M. A. Gimbrone, and M. P. Bevilacqua, “Induction and detection of a human endothelial activation antigen in vivo,” Journal of Experimental Medicine, vol. 164, no. 2, pp. 661–666, 1986.
[32]  M. B. Lawrence and T. A. Springer, “Neutrophils roll on E-selectin,” Journal of Immunology, vol. 151, no. 11, pp. 6338–6346, 1993.
[33]  S. Kannan, “Neutrophil chemotaxis: autotaxin induced attenuation of purine/pyrimidine signaling precede the overexpression of integrin(s),” Medical Hypotheses, vol. 65, no. 1, pp. 197–198, 2005.
[34]  C. U. Niemann, M. ?brink, G. Pejler et al., “Neutrophil elastase depends on serglycin proteoglycan for localization in granules,” Blood, vol. 109, no. 10, pp. 4478–4486, 2007.
[35]  H. Noma, T. Kato, H. Fujita, M. Kitagawa, T. Yamano, and S. Kitagawa, “Calpain inhibition induces activation of the distinct signalling pathways and cell migration in human monocytes,” Immunology, vol. 128, no. 1, part 2, pp. e487–e496, 2009.
[36]  M. Caproni, D. Torchia, E. Antiga et al., “The role of apoptosis in the pathogenesis of dermatitis herpetiformis,” International Journal of Immunopathology and Pharmacology, vol. 18, no. 4, pp. 691–699, 2005.
[37]  X. Bosch, “Systemic lupus erythematosus and the neutrophil,” The New England Journal of Medicine, vol. 365, no. 8, pp. 758–760, 2011.
[38]  A. Halagovec, F. Héjj, and Z. Baranová, “Fibronectin, interstitial collagens and type IV collagen in dermatitis herpetiformis,” Casopís Lékar? Ceskych, vol. 135, no. 9, pp. 273–276, 1996.
[39]  S. Karpati, M. Meurer, W. Stolz, K. Schrallhammer, T. Krieg, and O. Braun-Falco, “Dermatitis herpetiformis bodies: ultrastructural study on the skin of patients using direct preembedding immunogold labeling,” Archives of Dermatology, vol. 126, no. 11, pp. 1469–1474, 1990.
[40]  T. L. Reunala, “Dermatitis herpetiformis,” Clinics in Dermatology, vol. 19, no. 6, pp. 728–736, 2001.
[41]  M. Zhao, M. E. Trimbeger, N. Li, L. A. Diaz, S. D. Shapiro, and Z. Liu, “Role of FcRs in animal model of autoimmune bullous pemphigoid,” Journal of Immunology, vol. 177, no. 5, pp. 3398–3405, 2006.
[42]  A. I. Oikarinen, T. Reunala, and J. J. Zone, “Proteolytic enzymes in blister fluids from patients with dermatitis herpetiformis,” British Journal of Dermatology, vol. 114, no. 3, pp. 295–302, 1986.
[43]  J. Gornowicz-Porowska, M. Bowszyc-Dmochowska, and M. Dmochowski, “Autoimmunity-driven enzymatic remodeling of the dermal-epidermal junction in bullous pemphigoid and dermatitis herpetiformis,” Autoimmunity, vol. 45, no. 1, pp. 71–80, 2012.
[44]  M. T. Salmela, S. L. F. Pender, T. Reunala, T. Macdonald, and U. Saarialho-Kere, “Parallel expression of macrophage metalloelastase (MMP-12) in duodenal and skin lesions of patients with dermatitis herpetiformis,” Gut, vol. 48, no. 4, pp. 496–502, 2001.
[45]  A. Zebrowska, J. Narbutt, A. Sysa-Jedrzejowska, J. Kobos, and E. Waszczykowska, “The imbalance between metalloproteinases and their tissue inhibitors is involved in the pathogenesis of dermatitis herpetiformis,” Mediators of Inflammation, vol. 2005, no. 6, pp. 373–379, 2005.
[46]  S. Kellouche, S. Mourah, A. Bonnefoy et al., “Platelets, thrombospondin-1 and human dermal fibroblasts cooperate for stimulation of endothelial cell tubulogenesis through VEGF and PAI-1 regulation,” Experimental Cell Research, vol. 313, no. 3, pp. 486–499, 2007.
[47]  M. G. Martínez-Hernández, L. A. Baiza-Gutman, A. Castillo-Trápala, and D. R. Armant, “Regulation of proteinases during mouse peri-implantation development: urokinase-type plasminogen activator expression and cross talk with matrix metalloproteinase 9,” Reproduction, vol. 141, no. 2, pp. 227–239, 2011.
[48]  T. Leivo, J. Lohi, A. L. Kariniemi et al., “Hemidesmosomal molecular changes in dermatitis herpetiformis; decreased expression of BP230 and plectin/HD1 in uninvolved skin,” Histochemical Journal, vol. 31, no. 2, pp. 109–116, 1999.
[49]  S. Hashmi and M. P. Marinkovich, “Molecular organization of the basement membrane zone,” Clinics in Dermatology, vol. 29, no. 4, pp. 398–411, 2011.


comments powered by Disqus

Contact Us


微信:OALib Journal