The Herpes Simplex Virus Gene Pol Expressed in Herpes-Associated Erythema Multiforme Lesions Upregulates/Activates SP1 and Inflammatory Cytokines

Abstract

Background/Aims: Herpes-simplex-virus-associated erythema multiforme (HAEM) is characterized by lesional skin expression of the viral protein Pol and localized inflammation. The objective of this study is to examine the mechanism whereby Pol induces localized inflammation. Methods: A431 cells transfected with Pol or an empty vector and lesional skin from HAEM or drug-induced erythema multiforme patients were examined for expression of the transcription factor SP1 and SP1-regulated genes by immunoblotting, immunohistochemistry and immunofluorescence. Results: SP1, TGF-β, p21^waf1 and Hsp27 were upregulated in A431 cells transfected with Pol but not the empty vector. Expression was further increased by exposure to IFN-γ. Pol+ HAEM lesional skin expressed SP1, Hsp27, TGF-β and p21^waf1. Normal skin and drug-induced erythema multiforme lesional skin were negative. Conclusion: The data indicate that Pol activates SP1, causing upregulation of SP1 target genes (notably TGF-β) involved in localized inflammation. Upregulation is potentiated by IFN-γ.

Acute Skin Eruptions That Are Positive for Herpes Simplex Virus DNA Polymerase in Patients With Stem Cell Transplantation

“…The Pol-induced upregulation of the transcription factor SP1 and SP1-regulated genes in HAEM lesional skin are associated with the inflammatory and autoreactive components of HAEM. 7,17 …”

Acute Skin Graft-versus-Host Disease with Molecular Features Mimicking Herpes Simplex Virus-Associated Erythema Multiforme: Report of Three Cases

“…The lesions are free of infectious virus, but they contain viral DNA fragments and express a limited number of viral proteins that are associated with lesion development, notably Pol [6,7,8,9,10,11,12]. The viral DNA fragments are transported to the skin by CD1a+ Langerhans cells that develop through E-cadherin-facilitated differentiation of CD34+ cells infected with HSV while in circulation [6,7,8].…”

“…Also, constraints imposed by the limited availability of tissues and PBMC have restricted our studies to the use of immunofluorescent staining. However, the specificity of the Pol antibody is established [6,7,8,9,10,11,12]. The PBMC from normal subjects are known to be Pol negative [11], and the absence of Pol staining in the pre-HSCT samples suggests that the Pol+CD34+ and Pol+CD1a+ cells in the skin tissues are of donor origin, having been infected while in circulation.…”

“…This is supported by the known histological similarity of GVHD to drug and viral exanthems [5] and the rather diverse clinical presentation of erythematous lesions that fall under the EM umbrella. We still do not know whether the skin GVHD-diagnosed lesions express the markers [IFN-γ, SP1, TGF-β, p21 (waf1) and Hsp27], which differentiate HAEM from other GVHD-like skin diseases such as Stevens-Johnson syndrome [10,12] and we do not exclude the possibility that reactivated HSV increases the risk of GVHD through its ability to stimulate T cell proliferation and induce DC maturation and IL-12 secretion [1,6,11]. Also still unclear is the potential contribution of other herpesviruses that are reactivated from latency by the immunosuppressive drugs used during allogeneic transplantation [2].…”

Manifestations orales de l’érythème polymorphe : présentation de cas cliniques

“…Plus tard, des cellules progénitrices hématopoïétiques CD34+ ont été mises en évidence dans le transport de fragments d'ADN viral (notamment d'ADN polymérase) vers les sites cutanés lésionnels [11] expliquant que des traces d'ADN viral soient parfois retrouvées au sein des lésions d'EP. D'autres travaux ont été réalisés pour mieux comprendre les mécanismes intervenant dans cette pathologie, notamment sur les liens existant entre la présence de fragments d'ADN, la production de TGF-β et le rôle tenu par la molécule p21 waf1 et le facteur de transcription SP1 qui semblent tous augmentés au sein des lésions présentant des fragments d'ADN viraux mais dont les rôles ne sont pas encore bien définis [12]. Des études récentes laissent supposer qu'il pourrait exister un rôle des lymphocytes Th17, sous-population effectrice de lymphocytes T CD4+, dans la pathogenèse de l'EP [13] et certains auteurs ont mis en évidence une augmentation des lymphocytes B périphériques chez des patients atteints d'EP [14].…”