title: Patients with delayed-onset sulfonamide hypersensitivity reactions have antibodies recognizing endoplasmic reticulum luminal proteins.
abstract: Sulfonamide antimicrobials cause a delayed-onset, hypersensitivity-type syndrome characterized by fever, skin rash and multiorgan toxicity occurring 7 to 14 days after initiation of therapy. The pathogenesis is believed to be immune-mediated. We investigated whether patients with delayed-onset sulfonamide hypersensitivity reactions had antibodies recognizing hapten-microsomal protein conjugates and/or native microsomal proteins. By immunoblotting using rat liver as a source of microsomal protein, 17 of 21 patients had antibodies recognizing one or more of three native endoplasmic reticulum proteins of 55 kDa (14 of 21 patients), 80 kDa (4 of 21 patients) or 96 kDa (3 of 21 patients) in size on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. No control subjects (n = 11) and only 1 of 18 patients with adverse events not consistent with sulfonamide hypersensitivity reactions had antibodies against these microsomal proteins under the conditions used. Only 1 patient had antibodies that recognized the sulfonamide hapten, sulfamethoxazole. The 55-kDa protein was identified as protein disulfide isomerase. The 80-kDa protein was identified as grp78. The 96-kDa protein was not identified. Delayed-onset sulfonamide hypersensitivity reactions are therefore primarily associated with antibodies recognizing specific protein epitopes and not anti-drug antibodies.
authors.affiliation: Merck Research Laboratories, West Point, Pennsylvania, USA. acribb@upei.ca
authors.forename: A E
authors.initials: AE
authors.lastname: Cribb
authors.forename: L R
authors.initials: LR
authors.lastname: Pohl
authors.forename: S P
authors.initials: SP
authors.lastname: Spielberg
authors.forename: J S
authors.initials: JS
authors.lastname: Leeder
mesh_terms: D000818:Animals; D000906:Antibodies / Q000032:analysis* / Q000276:immunology; D002352:Carrier Proteins / Q000276:immunology; D003429:Cross Reactions; D004342:Drug Hypersensitivity / Q000276:immunology*; D004721:Endoplasmic Reticulum / Q000276:immunology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000276:immunology*; D007535:Isomerases / Q000276:immunology; D008297:Male; D018832:Molecular Chaperones / Q000276:immunology; D011233:Precipitin Tests; D019704:Protein Disulfide-Isomerases; D011506:Proteins / Q000276:immunology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000009:adverse effects* / Q000276:immunology
chemical_list: D000906:Antibodies; D002352:Carrier Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D011506:Proteins; D013449:Sulfonamides; D007535:Isomerases; D019704:Protein Disulfide-Isomerases