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Dermatol Online J. 2003 Feb;9(1):1.

Herpes simplex virus (HSV)-associated erythema multiforme (HAEM): a viral disease with an autoimmune component.

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Virology-Immunology Laboratories, Department of Pharmacology and Experimental Therapeutics, University of Maryland, School of Medicine, Baltimore, Maryland 21201, USA.


Erythema multiforme (EM) is a clinical conundrum the name of which reflects the broad morphological spectrum of the lesions. Molecular and immunologic evidence that herpes simplex virus (HSV) causes a subset of EM lesions [herpes-associated EM (HAEM)] is reviewed, and new data are presented which suggest that autoreactive T-cells triggered by virus infection play an important role in HAEM pathogenesis. Disease development begins with viral DNA fragmentation and the transport of the DNA fragments to distant skin sites by peripheral blood mononuclear cells (PBMCs). HSV genes within DNA fragments deposited on the skin [notably DNA polymerase (Pol)] are expressed, leading to recruitment of HSV-specific CD4+ Th1 cells that respond to viral antigens with production of interferon-gamma (IFN-gamma). This step initiates an inflammatory cascade that includes expression of IFN-gamma induced genes, increased sequestration of circulating leukocytes, monocytes and natural killer (NK) cells, and the recruitment of autoreactive T-cells generated by molecular mimicry or the release of cellular antigens from lysed cells. The PBMCs that pick up the HSV DNA [viz. macrophages or CD34+ Langerhans cells (LC) precursors], their ability to process it, the viral proteins expressed in the skin and the presence of epitopes shared with cellular proteins may determine whether a specific HSV episode is followed by HAEM development. Drug-associated EM (DIEM) is a mechanistically distinct EM subset that involves expression of tumor necrosis factor alpha (TNF-alpha) in lesional skin. It is our thesis that the polymerase chain reaction (PCR) assay for HSV DNA detection in lesional skin and staining with antibodies to IFN-gamma and TNF-alpha, are important criteria for the diagnosis of skin eruptions and improved patient management.

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