1. ^*Virology/Immunology Laboratories The University of Maryland School of Medicine, Baltimore, Maryland, U.S.A.
2. ^†Departments of Pharmacology and Experimental Therapeutics, The University of Maryland School of Medicine, Baltimore, Maryland, U.S.A.
3. ^‡Department of Dermatology³, The University of Maryland School of Medicine, Baltimore, Maryland, U.S.A.

Correspondence: Dr Laure Aurelian, Virology/Immunology Laboratories, University of Maryland School of Medicine, 10S. Pine Street, Baltimore, MD 21201, U.S.A. Email: laurelia@umaryland.edu

Received 16 February 1999; Revised 27 July 1999; Accepted 5 August 1999.

Abstract

Erythema multiforme follows administration of several drugs or infection with various agents, including herpes simplex virus, a syndrome designated herpes simplex virus associated erythema multiforme. Lesional skin from 21 of 26 (81%) herpes simplex virus associated erythema multiforme patients was positive for herpes simplex virus gene expression as evidenced by reverse transcriptase–polymerase chain reaction with primers for DNA polymerase and/or immunohistochemistry with DNA polymerase antibody. Reverse transcriptase–polymerase chain reaction and immunohistochemistry studies indicated that herpes simplex virus associated erythema multiforme lesional skin from 16 of 21 (76%) DNA polymerase positive herpes simplex virus associated erythema multiforme patients was also positive for interferon-, a product of T cells involved in delayed-type hypersensitivity (p < 0.0001 by Pearson correlation coefficient). Interferon- signals were in infiltrating mononuclear cells and in intercellular spaces within inflammatory sites in the epidermis and at the epidermis/dermis junction. Herpes simplex virus lesional skin was also positive for DNA polymerase [five of five (100%)] and interferon-[four of five (80%)], but lesional skin from drug-induced erythema multiforme patients was negative. Lesional herpes simplex virus associated erythema multiforme keratinocytes also stained with antibody to transforming growth factor-[14 of 23 (61%)] and cyclin-dependent kinase inhibitor waf [12 of 18 (67%)]. Staining was also seen in keratinocytes from herpes simplex virus lesions [five of five (100%)], but not in normal skin. By contrast, staining with antibody to tumor necrosis factor-, another pro-inflammatory cytokine, was seen in seven of 11 (64%) drug-induced erythema multiforme patients, but not in herpes simplex virus or herpes simplex virus associated erythema multiforme patients, and lesional keratinocytes from drug-induced erythema multiforme patients were negative for transforming growth factor- and cyclin-dependent kinase inhibitor waf. We interpret the data to indicate that herpes simplex virus associated erythema multiforme pathology includes a delayed-type hypersensitivity component and is mechanistically distinct from drug-induced erythema multiforme.