Erythema multiforme (EM) is a polymorphous cutaneous eruption composed of symmetrically distributed macules, papules, bullae and targetoid lesions which have a propensity for the distant extremities and oral mucosae. It is estimated that 15-63% of EM cases are secondary to infection with herpes simplex virus (HSV). Like HSV, EM is a self-limited, often recurrent disorder. In scattered reports, EM skin lesions were found to be positive for infectious virus, virus particles, or viral antigens. However, HSV cultures of EM lesions are usually negative, and the exact role of HSV in EM pathogenesis is unclear. An additional component of EM pathogenesis is cell mediated immune (CMI) reactions, but the antigenic specificity of the involved T cells and identity of the T cell receptor (TCR) are unknown. The studies proposed in this application are a continuation of our previous observation using the polymerase chain reaction (PCR), indicating that DNA sequences homologous to a 92 bp fragment of the HSV DNA polymerase gene are present in EM lesions. They seek to determine the relationship of HSV to BM and establish the potential contribution of HSV and self antigens to the EM-related CMI responses.
The specific aims are: (i) to determine, by PCR, the presence in EM tissues of DNA sequences homologous to fragments of HSV genes that map along the entire HSV genome and represent all three kinetic classes, and identify their location in the dermis or epidermis, (ii) to determine whether the HSV genes that apparently persist in EM lesions, and the latency associated transcript (LAT) that is associated with latency are expressed by using the reverse transcriptase linked PCR (RT/PCR), and establish their cellular localization by in situ hybridization, (iii) to determine, in RT/PCR, whether expression of heat shock proteins (hsp) (that can be induced by HSV infection) is increased in EM lesions as compared to normal tissues, and (iv) to determine the TCR repertoire of T cells in EM lesions as compared to peripheral blood leukocytes and establish whether they proliferate in response to HSV or hsp antigens. These studies will provide a better understanding of the immunopathogenesis of EM and its relationship to HSV (and potentially hsp) thereby allowing the development of novel therapeutic interventions based on TCR Vbeta targeting. They will generate clinically relevant information for the diagnosis and management of the patients with post-herpetic EM as well as their differentiation from those with EM caused by other pathogens or by drug sensitivity.
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