- Erythema multiforme (EM) is a hypersensitivity reaction caused by many provoking agents including herpes simplex virus (HSV) infection (HAEM). HSV DNA sequences were identified in HAEM lesions, but infectious virus was not isolated. T cell responses were also implicated in HAEM pathogenesis, but their HSV specificity and function are still unclear. The applicants showed that viral DNA clearance is impaired in HAEM relative to HSV lesions, but clinical HAEM symptoms correlate with HSV gene expression. The HSV DNA polymerase gene (Pol) is expressed in HAEM lesions, and they are positive for CD4+ V-beta-2 T cells and IFN-gamma. Healed lesional skin were all negative. The investigator hypothesizes that HAEM is an immunopathological disease resulting from the combination of T cell responses to HSV antigens (likely Pol) and virus-mediated pathological effects.
The specific aims are: (I) To examine the role of virus (Pol)-specific T cell responses in HAEM pathogenesis by establishing T cell lines/clones from HAEM lesional and healed skin and determining their HSV protein specificity and properties (viz. IFN-gamma production). ELISA spot assay will be used to estimate the clonal size of responding T cells in the skin. Both T cell clones and PBMC from HAEM and HSV patients will be examined for the presence of the skin homing receptor CLA.
The second aim (II) is to examine the role of Pol in epidermal damage by determining(a) expression of the Pol accessory protein UL42 and Pol catalytic activity in HAEM lesions, and (b) the induction/activation of TGF-beta and p21waf in keratinocytes transfected with Pol or Pol/UL42 as it relates to growth arrest/apoptosis.
Aim (III) is to define the route of HSV DNA transport to the skin. This will be done by determining the presence of HSV DNA fragments in CLA+ (and CD34+/CLA+) Langerhans cells (LC) precursors from HAEM and HSV patients and examining the ability of these cells to fragment HSV DNA/retain Pol DNA as they mature into LC in vitro. These studies will provide a better understanding of HAEM pathogenesis and its relationship to HSV, thereby allowing the development of novel therapies based on the targeting of disease-related HSV gene(s). They will also generate clinically relevant information for the diagnosis and management of HAEM patients as differentiated from those with EM caused by other pathogens or by drug sensitivity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR042647-07
Application #
6511838
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Moshell, Alan N
Project Start
1994-03-10
Project End
2005-02-28
Budget Start
2002-03-01
Budget End
2003-02-28
Support Year
7
Fiscal Year
2002
Total Cost
$251,657
Indirect Cost
Name
University of Maryland Baltimore
Department
Pharmacology
Type
Schools of Medicine
DUNS #
003255213
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Burnett, Joseph W; Laing, Jennifer M; Aurelian, Laure (2008) Acute skin eruptions that are positive for herpes simplex virus DNA polymerase in patients with stem cell transplantation: a new manifestation within the erythema multiforme reactive dermatoses. Arch Dermatol 144:902-7
Li, B; Smith, C C; Laing, J M et al. (2007) Overload of the heat-shock protein H11/HspB8 triggers melanoma cell apoptosis through activation of transforming growth factor-beta-activated kinase 1. Oncogene 26:3521-31
Gober, Michael D; Laing, Jennifer M; Burnett, Joseph W et al. (2007) The Herpes simplex virus gene Pol expressed in herpes-associated erythema multiforme lesions upregulates/activates SP1 and inflammatory cytokines. Dermatology 215:97-106
Sharma, B K; Smith, Cynthia C; Laing, Jennifer M et al. (2006) Aberrant DNA methylation silences the novel heat shock protein H11 in melanoma but not benign melanocytic lesions. Dermatology 213:192-9
Ono, Fumitake; Sharma, Bhuvnesh K; Smith, Cynthia C et al. (2005) CD34+ cells in the peripheral blood transport herpes simplex virus DNA fragments to the skin of patients with erythema multiforme (HAEM). J Invest Dermatol 124:1215-24
Aurelian, L (2005) HSV-induced apoptosis in herpes encephalitis. Curr Top Microbiol Immunol 289:79-111
Gober, Michael D; Smith, Cynthia C; Ueda, Kaori et al. (2003) Forced expression of the H11 heat shock protein can be regulated by DNA methylation and trigger apoptosis in human cells. J Biol Chem 278:37600-9
Perkins, Dana; Gyure, Kymberly A; Pereira, Edna F R et al. (2003) Herpes simplex virus type 1-induced encephalitis has an apoptotic component associated with activation of c-Jun N-terminal kinase. J Neurovirol 9:101-11
Perkins, D; Pereira, E F R; Aurelian, L (2003) The herpes simplex virus type 2 R1 protein kinase (ICP10 PK) functions as a dominant regulator of apoptosis in hippocampal neurons involving activation of the ERK survival pathway and upregulation of the antiapoptotic protein Bag-1. J Virol 77:1292-305
Aurelian, L; Ono, F; Burnett, J (2003) Herpes simplex virus (HSV)-associated erythema multiforme (HAEM): a viral disease with an autoimmune component. Dermatol Online J 9:1

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