title: Acute generalized exanthematous pustulosis: role of cytotoxic T cells in pustule formation.
abstract: Extensive formation of nonfollicular sterile pustules on erythematous background combined with fever and peripheral blood leukocytosis are the characteristics of acute generalized exanthematous pustulosis. This uncommon eruption most often is an allergic reaction because of drugs such as aminopenicillins and sulfonamides inter alia. We recently demonstrated the important role of drug-specific T cells in the pathogenesis of this disease, showing that they produce high amounts of the neutrophil-attracting chemokine interleukin-8 and therefore stand out as a special subgroup of T cells, differing from the usual Th1 and Th2 subsets. In this study we use immunohistochemistry as well as cytotoxicity assays (4- and 18-hour assays) and fluorescence-activated cell-sorting analysis of drug-specific circulating T cells and of cells eluted from the skin of five patients with acute generalized exanthematous pustulosis, to analyze whether cytotoxic T-cell functions are important in the pathogenesis of this disease, in particular for the formation of vesicles. The data reveal that drug-specific CD4(+) as well as CD8(+) T cells both are activated and cytotoxic; perforin/granzyme B and to a variable degree the Fas/FasL-killing mechanism is involved in tissue destruction. These features allow the formation of vesicles. Additional secretion of interleukin-8 by T cells and keratinocytes attracts neutrophils that fill the vesicles and transform them into pustules.
authors.affiliation: Clinic of Rheumatology and Clinical Immunology/Allergology, Inselspital, CH-3010 Bern, Switzerland.
authors.forename: Simone
authors.initials: S
authors.lastname: Schmid
authors.forename: Petra C
authors.initials: PC
authors.lastname: Kuechler
authors.forename: Markus
authors.initials: M
authors.lastname: Britschgi
authors.forename: Urs C
authors.initials: UC
authors.lastname: Steiner
authors.forename: Nikhil
authors.initials: N
authors.lastname: Yawalkar
authors.forename: Alain
authors.initials: A
authors.lastname: Limat
authors.forename: Kurt
authors.initials: K
authors.lastname: Baltensperger
authors.forename: Lasse
authors.initials: L
authors.lastname: Braathen
authors.forename: Werner J
authors.initials: WJ
authors.lastname: Pichler
mesh_terms: D000818:Animals; D001706:Biopsy; D003601:Cytotoxicity Tests, Immunologic; D003875:Drug Eruptions / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005076:Exanthema / Q000139:chemically induced / Q000276:immunology / Q000473:pathology*; D053222:Fas Ligand Protein; D053804:Granzymes; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D007509:Irritants / Q000494:pharmacology / Q000633:toxicity; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000494:pharmacology; D051379:Mice; D054353:Perforin; D010641:Phenotype; D052899:Pore Forming Cytotoxic Proteins; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D012697:Serine Endopeptidases / Q000494:pharmacology; D012867:Skin / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism*; D019014:fas Receptor / Q000494:pharmacology
chemical_list: C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D006684:HLA-DR Antigens; D007509:Irritants; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D015375:Receptors, Interleukin-2; D019014:fas Receptor; D054353:Perforin; C509213:GZMB protein, human; D053804:Granzymes; C509214:Gzmb protein, mouse; D012697:Serine Endopeptidases