Symptomatic and disfiguring cutaneous disease accounts for a considerable degree of the physical and psychological disability which results from lupus erythematosus (LE). More knowledge concerning the clinical and pathogenetic aspects of LE-specific skin disease could yield important new insight into the pathogenesis of LE overall, and thereby provide improved management strategies for the systemic as well as cutaneous manifestations of this important human disorder. The focus of the present application will be upon the questions pertaining to skin lesion pathogenesis which are raised by the striking relationship which exists between a humoral autoimmune response to the Ro/SS-A (Ro) cellular ribonucleoprotein (RNP) and LE-specific cutaneous disorders such as subacute cutaneous LE (SCLE) and neonatal LE (NLE).
The specific aims of this application are: 1) TO MORE FULLY ELUCIDATE THE MOLECULAR AND GENETIC ASPECTS OF THE Ro AUTOANTIGEN SYSTEM. The genomic configuration of a human Ro gene expressed by Wil-2 lymphoblastoid cells will be determined and its gene product characterized by epitope mapping, RNA binding site analysis and in vitro translation. In addition, this gene product will be compared to other Ro RNP isoforms which might be expressed by human epidermal keratinocytes. 2) TO FURTHER EXAMINE THE HYPOTHESIS THAT AN AUTOIMMUNE RESPONSE TO THE Ro AUTOANTIGEN SYSTEM IS PRIMARILY RESPONSIBLE FOR THE PATHOGENESIS OF SCLE/NEONATAL SKIN INJURY. The link between photosensitivity in SCLE/NLE patients and the humoral autoimmune response to the Ro RNP will be examined by determining the impact of ultraviolet light (UVL) exposure upon Ro gene transcription/translation in epidermal keratinocytes and characterizing the impact of UVL upon Ro RNP structure and antigenicity. The pathogenetic role played by a cell-mediated autoimmune response to Ro antigens will be examined by attempting to isolate Ro antigen-specific T cell clones from SCLE skin lesions and develop an animal model of SCLE with Ro-specific T cell clones. 3) TO EXAMINE THE FEASIBILITY OF DEVELOPING A TRANSGENIC MOUSE MODEL OF SCLE/NEONATAL LE. As the initial step toward developing a versatile transgenic animal model of SCLE/NLE, an attempt will be made to develop an inducible Ro fusion gene that can be expressed in murine fibroblasts in vitro. 4) TO CARRY OUT A 10 YEAR FOLLOW-UP STUDY OF 115 PATIENTS. In addition, to providing insight into the immunopathogenesis of LE-specified skin disease, the above studies could yield important new insight into the functional significance of the Ro RNP family in cell biology.
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