Issues

Chronic continuous activation of tissue-resident dendritic cells, such as the epidermal Langerhans cells, leads to the development of autoimmune dermatitis and systemic autoimmunity. Langerhans cells can be visualized by I-A immunofluorescence staining of murine epidermal sheets and, true to their sentinel function, exhibit a network-like distribution pattern in wild-type mice (top left panel). In contrast, there is a significant reduction of Langerhans cells especially in the vicinity of I-A-positive keratinocytes in transgenic mice overexpressing CD40 ligand in the epidermis (top right panel). This chronic activation of Langerhans cells by CD40/CD40 ligand cross-linking most likely leads to the emigration of (auto)antigen-laden cells to the regional lymph nodes, where they stimulate T and B cells, which ultimately results in severe autoimmune skin inflammation (hematoxylin and eosin staining of: bottom left panel, wild-type skin; bottom right panel, CD40 ligand transgenic skin). These findings suggest that chronic activation of epidermal Langerhans cells is able to break immunological self-tolerance. See related article in this issue by Mehling et al., pp. 615-628.