This proposal will test our hypothesis that lupus erythematosus (LE)-specific skin injury results from a humoral and/or cell- mediated immune response that is directed toward auto- or neo- antigens present in the epidermis or at the (D-E) dermal- epidermal junction. A key to better understanding the pathogenetic basis of this highly characteristic cutaneous injury pattern lies in identifying those auto-/neo-antigens and better characterizing the immune response which is directed toward them. Such studies could yield both the tools and strategies necessary for developing in vitro and in vivo models of this histopathological reaction.
Our specific aims for achieving these goals are: 1) To further characterize Ro/SS-A and the autoimmune response which occurs to this antigen. 2) To identify and isolate other cutaneous auto-/neo-antigens relevant to the expression of cutaneous LE. 3) To develop human T-cell clones from LE-specific skin lesions which could then be used to probe for cutaneous LE-relevant auto-/neo-antigens and to develop a human in vitro model of the cutaneous LE histopathological reaction. 4) To develop an animal model of cutaneous LE utilizing T-cell clones which exhibit epidermal or D-E junctional auto-neo- antigen specificity. 5) To characterize further the pathogenetic mechanism(s) involved in the photosensitivity exhibited by some cutaneous LE patients. 6) To characterize further the immunoregulatory disorders present in cutaneous LE patients. 7) To identify additional risk factors for severe SLE in subacute cutaneous lupus erythematosus patients. It has long been our feeling that a better understanding of the pathogenesis of cutaneous LE could yield not only significant improvement in the clinical management of this aspect of the disease, but might also furnish new insight into the etiology of the LE tissue injury mechanisms which occur in less accessible target organs such as the kidney and central nervous system and large vessels. These studies might also yield insight into the pathogenesis of other related inflammatory skin diseases such as lichen planus, dermatomyositis and lichenoid drug eruptions.
