Vol. 282, Issue 2, 1064-1072, 1997

Patients with Delayed-Onset Sulfonamide Hypersensitivity Reactions Have Antibodies Recognizing Endoplasmic Reticulum Luminal Proteins

Alastair E. Cribb, Lance R. Pohl, Stephen P. Spielberg and J. Steven Leeder

Merck Research Laboratories, West Point, Pennsylvania (A.E.C., S.P.S.), Molecular and Cellular Toxicology Section, Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland (L.R.P.), and Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children, Toronto, Ontario (J.S.L.)

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.