[en] BACKGROUND: Drug-induced toxic epidermal necrolysis (TEN) probably results from a complex and specific immune cell reaction involving lymphocytes and macrophages. OBJECTIVE: To assess the functional role of macrophages in TEN. METHODS: Immunohistochemistry was performed on biopsies from early blisters developed in 9 TEN patients. The amount of extracellular myeloperoxidase (MPO) was measured by ELISA in TEN blister fluid and serum. Controls were blister fluids taken from 9 second-degree burns. In addition, 3-chlorotyrosine (a specific marker of MPO activity) was searched for using liquid mass chromatography both in TEN and burn blister fluids. RESULTS: Immunohistochemistry revealed numerous CD68+ macrophages in 8/9 TEN patients; 5-20% of these cells and rare CD15+ neutrophils exhibited MPO immunoreactivity, while keratinocytes were negative. The amount of MPO was significantly higher in TEN blister fluid than in TEN serum, suggesting macrophage production of MPO in the skin. In addition, MPO was significantly more abundant in TEN blister fluid than in burn blister fluid. 3-Chlorotyrosine was detected in 7/9 TEN blister fluids, but in only 2/9 burn blister fluids. DISCUSSION: MPO produced by macrophages was functionally active in most TEN patients, leading to the production of hypochlorous acid, a potent oxidative compound that alters keratinocytes.
Disciplines :
Dermatology
Author, co-author :
Paquet, Philippe ; Centre Hospitalier Universitaire de Liège - CHU > Dermatopathologie
De Groote, Donat; Centre Hospitalier Universitaire de Liège - CHU > Giga Research, Liège Belgium
Pierard, Gérald ; Centre Hospitalier Universitaire de Liège - CHU > Dermatopathologie
Language :
English
Title :
Functionally active macrophage-derived myeloperoxidase in the skin of drug-induced toxic epidermal necrolysis.
Wolf R, Wolf D, Davidovici B: In the pursuit of classifying severe cutaneous adverse reactions. Clin Dermatol 2007; 25: 438-439. (Pubitemid 46863478)
Paquet P, Piérard GE: Toxic epidermal necrolysis: revisiting the tentative link between early apoptosis and late necrosis. Int J Mol Med 2007; 19: 3-10.
Nassif A, Bensussan A, Boumsell L, Deniaud A, Moslehi H, Wolkenstein P: Toxic epidermal necrolysis: effector cells are drug-specific cytotoxic T cells. J Allergy Clin Immunol 2004; 114: 1209-1215. (Pubitemid 39469167)
Chung WH, Hung SI, Yang JY, Su SC, Huang SP, Wei CH, Chin SW, Chiou CC, Chu SC, Ho HC, Yang CH, Lu CF, Wu JY, Liao YD, Chen YS: Granulysin is a key mediator for disseminated keratinocyte death in Stevens- Johnson syndrome and toxic epidermal necrolysis. Nat Med 2008; 14: 1343-1350.
Abe R: Toxic epidermal necrolysis and Stevens- Johnson syndrome: soluble Fas ligand involvement in the pathomechanisms of these diseases. J Dermatol Sci 2008; 52: 151-159.
Le Cleach L, Delaire S, Boumsell L, Bagot M, Bourgault-Villada I, Bensussan A, Roujeau JC: Blister fluid T lymphocytes during toxic epidermal necrolysis are functional cytotoxic cells which express human natural killer (NK) inhibitory receptors. Clin Exp Immunol 2000; 119: 225-230. (Pubitemid 30064614)
Pitt AR, Spickett CM: Mass spectrometric analysis of HOCl- and free-radical-induced damage to lipids and proteins. Biochem Soc Trans 2008; 36: 1077-1082.
Winterbourn CC: Biological reactivity and biomarkers of the neutrophil oxidant, hypochlorous acid. Toxicology 2002; 181-182: 223-277.
Buss IH, Senthilmohan R, Darlow BA, Mogridge N, Kettle AJ, Winterbourn C: 3-chlorotyrosine as a marker of protein damage by myeloperoxidase in tracheal aspirates from preterm infants: association with adverse respiratory outcome. Pediatr Res 2003; 53: 455-462. (Pubitemid 36237401)
Mohiuddin I, Chai H, Lin PH, Lumsden AB, Yao Q, Chen C: Nitrotyrosine and chlorotyrosine: clinical significance and biological functions in the vascular system. J Surg Res 2006; 133: 143-149. (Pubitemid 43765765)
Paquet P, Nikkels A, Arrese J, Vanderkelen A, Piérard GE: Macrophages and tumor necrosis factorαin toxic epidermal necrolysis. Arch Dermatol 1994; 130: 605-608. (Pubitemid 24150940)
Caproni M, Torchia D, Schincaglia E, Volpi W, Frezzolini A, Schena D, Marzano A, Quaglino P, De Simone C, Parodi A, Barletta E, Fabbri P: The CD40/CD40 ligand system is expressed in the cutaneous lesions of erythema multiforme and Stevens-Johnson syndrome/ toxic epidermal necrolysis spectrum. Br J Dermatol 2006; 154: 319-324. (Pubitemid 43382704)
Moore N, Biour M, Paux G, Loupi E, Begaud B, Boismare F, Royer RJ: Adverse drug reaction monitoring: doing it in the French way. Lancet 1985;ii:1056-1058. (Pubitemid 16206749)
Paquet P, Paquet F, Al Saleh W, Reper P, Vanderkelen A, Piérard GE: Immunoregulatory effectors in drug-induced toxic epidermal necrolysis. Am J Dermatopathol 2000; 22: 413-417.
Paquet P, Jacob E, Damas P, Pirson J, Piérard GE: Analytical quantification of the inflammatory cell infiltrate and CD95R expression during treatment of drug-induced toxic epidermal necrolysis. Arch Dermatol Res 2005; 297: 266-273. (Pubitemid 41712814)
Lau D, Baldus S: Myeloperoxidase and its contributory role in inflammatory vascular disease. Pharmacol Ther 2006; 111: 16-26. (Pubitemid 43765542)
Wu CT, Eiserich J, Ansari AA, Coppel RL, Balasubramanian S, Bowlus CL, Gershwin ME, Van de Water J, et al: Myeloperoxidasepositive inflammatory cells participate in bile duct damage in primary biliary cirrhosis through nitric oxide-mediated reactions. Hepatology 2003; 38: 1018-1025. (Pubitemid 37221685)
Fernandez-Flores A, Bouso M, Alonso A, Manjon JA: The histiocytic component of cutaneous manifestations of Kikuchi disease expresses myeloperoxidase. Appl Immunohistochem Mol Morphol 2008; 16: 202-203.
Daugherty A, Dunn JL, Rateri DL, Heinecke J: Myeloperoxidase, a catalyst for lipoprotein oxidation, is expressed in human atherosclerotic lesions. J Clin Invest 1994; 94: 437-444. (Pubitemid 24218123)
Vyas P, Roychowdhury S, Koukouritaki S, Hines RN, Krueger SK, Williams DE, Nauseef WM, Svensson CK: Enzyme-mediated protein haptenation of dapsone and sulfamethoxazole in human keratinocytes: II. Expression and role of flavin-containing monooxygenases and peroxidases. J Pharmacol Exp Ther 2006; 319: 497-505. (Pubitemid 44455157)
Kumar AP, Piedrafita FJ, Reynolds WF: Peroxisome proliferator-activated receptorγ ligands regulate myeloperoxidase expression in macrophages by an estrogen-dependent mechanism involving the -463 GA promoter polymorphism. J Biol Chem 2004; 279: 8300-8315.
Sugiyama S, Okada Y, Sakhov G, Virmani R, Heinecke JW, Libby P: Macrophage myeloperoxidase regulation by granulocyte macrophage colony-stimulating factor in human atherosclerosis and implications in acute coronary syndromes. Am J Pathol 2001; 158: 879-891. (Pubitemid 32221781)
Reynolds WF, Rhees J, Maciejewski D, Paladino T, Sieburg H, Maki RA: Myeloperoxidase polymorphism is associated with gender specific risk for Alzheimer's disease. Exp Neurol 1999; 155: 31-41. (Pubitemid 29072602)
Vissers MCM, Pullar J, Hampton MB: Hypochlorous acid causes caspase activation and apoptosis or growth arrest in human endothelial cells. Biochem J 1999; 344: 443-449. (Pubitemid 30011601)
Yap YW, Whiteman M, Bay BH, Li Y, Sheu FS, Qi RZ, Tan CH, Cheung NS: Hypochlorous acid induces apoptosis of cultured cortical neurons through activation of calpains and rupture of lysosomes. J Neurochem 2006; 98: 1597-1609. (Pubitemid 44200449)
Whiteman M, Chu SH, Siau JL, Rose P, Sabapathy K, Schantz JT, Cheug NS, Spencer JP, Armstrong JS: The pro-inflammatory oxidant hypochlorous acid induces Bax-dependent mitochondrial permeabilisation and cell death through AIF-/Endo G-dependent pathways. Cell Signal 2007; 19: 705-714. (Pubitemid 46275363)
Schraufstätter I, Browne K, Harris A, Hyslop PA, Jackson JH, Quehenberger O, Cochrane CG: Mechanisms of hypochloride injury of target cells. J Clin Invest 1990; 85: 554-562. (Pubitemid 20070065)
Malle E, Furtmüller PG, Sattler W, Obinger C: Myeloperoxidase: a target for new drug development? Br J Pharmacol 2007; 152: 838-854. (Pubitemid 350100486)
Guilpain P, Servettaz A, Goulvestre C, Barrieu S, Borderie D, Chéreau C, Kavian N, Pagnoux C, Guillevin L, Weill B, Mouthon L, Batteux F: Pathogenic effects of antimyeloperoxidase antibodies in patients with microscopic polyangiitis. Arthritis Rheum 2007; 56: 2455-2463. (Pubitemid 47173595)
Redondo P, De Felipe I, De la Pena A, Azamendia JM, Vanaclocha U: Drug-induced hypersensitivity syndrome and toxic epidermal necrolysis: treatment with N-acetylcysteine. Br J Dermatol 1997; 136: 633-634. (Pubitemid 27160362)
Velez A, Moreno JC: Toxic epidermal necrolysis treated with N-acetylcysteine. J Am Acad Dermatol 2002; 46: 469-470. (Pubitemid 34225424)
Paquet P, Piérard GE: New insights in toxic epidermal necrolysis (Lyell's Syndrome): clinical considerations, pathobiology and targeted treatments revisited. Drug Saf 2010; 33: 189-212.