Immunopathology of human skin: Adapting recent advances in immunobiology to the specialized environment of the skin (with emphasis on NK, NK T-cells, and psoriasis).

摘要

The skin has commonly been used as a tool to investigate the immune system. Despite this, the unique immunobiology and immunopathology of the skin itself remains poorly understood. The skin, while providing its function as a barrier to the environment, must respond to a number of highly diverse challenges, including constant immune challenge by exposure to foreign antigens. One skin disease, psoriasis, has a strong immune component. The search for a disease mechanism has focused on peptide antigens and classic T-cells. Recently, our understanding two types of immune cells, natural killer cells (NK) and a subset of classic T-cells with NK markers, NK T-cells, has increased substantially. NK T-cells have been implicated in autoimmune disease models in mice and proposed to play a fundamental role in shaping the immune response. Little is known about their function in the skin.; We found immunocytes bearing markers of NK-T cells in several skin diseases, including psoriasis. We hypothesize they play a fundamental role in psoriasis, and interact with keratinocytes. If they interact, we expected to see keratinocyte expression of NK-T cell stimulatory molecules such as CD1d, and this interaction would cause NK-T cell activation. We examined this interaction by co-culture experiments and injection of an NK-T cell line into a human skin:SCID mouse chimera model. We found NK-T cells can be stimulated by keratinocytes through CD1d. They produce IFN-γ and IL-13 in-vitro. In addition, the NK-T cell line was found capable of forming a psoriatic plaque. We also hypothesized that cytokines secreted by activated immunocytes in psoriatic plaques alter differentiation of keratinocytes. To study this, keratinocytes were exposed to cytokines secreted by stimulated T-cells and found to increase the markers of senescence p16 and p21. In order to answer questions about more complex environments likely to be present in disease states, the effects IFN-γ and IL-4/IL-13 on cultured keratinocytes were examined using the marker CDw60. We found CDw60 was induced by IL-13, and induction was blocked by IFN-γ. Taken together, these results point to a role for a previously overlooked subset of immunocytes, i.e. NK-T cells, in the pathogenesis of psoriasis.