It has been recognized that most autoimmune diseases have a multifaceted etiology. Both a dysregulated immune process, as well as, the local environment within the involved organ-system appear to contribute to pathogenesis. Using a murine model targeted against the epidermal cell alloantigens, Skn, we can induce an autoimmune response by the adoptive transfer of CD4+ Skn-immune lymphocytes to previously immunosuppressed recipients expressing the appropriate Skn alleles who subsequently develop lesions in areas of mild epidermal trauma. The overall hypothesis to be evaluated is that epidermal trauma concomitant with immunosuppression elicits dysfunctional resident skin cells which alter the local microenvironment of the skin, subsequently contributing to the immune-mediated autoaggressive processes. First, we will characterize the sequence of molecular and cellular events that occur in the local skin environment after superficial trauma by analyzing skin-derived cytokine mRNA using PCR and by correlating those cytokines found with several site-modified alterations associated with immunopathology: the induction of adhesion molecules for leukocyte migration into the skin, changes in epidermal cell cycling, and appearance of apoptotic keratinocytes. Another study will address autoregulatory properties of resident skin gamma/delta T-cells and/or circulating lymphocytes, which appear to be inactivated by immunosuppression thereby rendering the recipient susceptible to autoaggressive attack. This will be determined by cotransfer of normal skin cells and/or lymphocytes along with Skn- immune cells to recipients who will be evaluated for reduced incidence of skin lesions and for altered skin cytokine profiles. In addition we will identify the cells expressing cytokines within lesional skin by detection of cytokine mRNA and protein using in situ hybridization and immunohistochemistry. In that Skn antigen appears to have a human counterpart, this animal model can provide information essential for understanding both the immune and the environmental pathogenic processes thought to contribute to human autoimmune dermatoses.
| Staton, Pamela J; Carpenter, A Betts; Jackman, Susan H (2006) IL-7 is a critical factor in modulating lesion development in Skn-directed autoimmunity. J Immunol 176:3978-86 |
| Jackman, Susan H; Keerthy, Shivaleela; Perry, Giselle (2002) Murine epidermal cell antigen (Skn)-directed autoimmunity induced by transfer of CD4+ T cells. Ann Clin Lab Sci 32:171-80 |
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