Thursday, May 1, 2025
5/1/2025
Skin-lymph node axis in SLE - Project Summary Patients with systemic lupus erythematosus (SLE) are photosensitive, demonstrating an increased skin sensitivity to ultraviolet radiation (UVR) whereby even ambient exposure to sunlight can result in the development of inflammatory skin lesions. Beyond the skin, however, UVR exposure can also trigger systemic disease flares, with increased circulating autoantibodies and further injury of end organs. The mechanisms by which UVR exposure at the skin can lead to flares of systemic autoimmunity are not well understood. Our long-term goal is to delineate the mechanisms that connect photosensitivity with systemic disease flares. In this proposal, we focus on the communication between skin and the immune system. Interstitial fluid from skin is transported as lymph via lymphatic vessels to draining lymph nodes where immune responses occur and can be regulated. Within the lymph node, lymph fluid is channeled from the lymphatic vessels into a conduit system that is lined by fibroblastic reticular cells (FRCs). Because of their location in the conduits, FRCs are among the first cellular sensors of signals flowing from the skin. FRCs, in turn, are in direct contact with dendritic cells and lymphocytes sitting outside the conduits and play critical roles in regulating immune cell function. We have recently shown that FRC-derived CCL2 limits plasmablast responses in healthy (ie non- lupus) mice, indicating that factors that modulate lymph node stromal CCL2 can potentially impact antibody or autoantibody generation. We now present preliminary data that, in SLE model mice, CCL2-expressing FRCs have an activated phenotype and UVR exposure of the skin triggers both a loss of these FRCs and increased plasmablasts in skin-draining lymph nodes. We also show that non-lesional skin from lupus patients and murine models express interferon (IFN) signatures and that pre-treatment with type I IFN blockade reduces photosensitivity in two murine lupus models These results together suggest that IFNs and other signals activate and sensitize draining lymph node CCL2-expressing FRCs, making them more likely to die upon UVR exposure, with consequent increases in plasmablast accumulation. While our preliminary results are focused on CCL2-expressing FRCs, our results more broadly suggest a model of FRC priming whereby signals from even non-lesional skin in SLE constitutively modulate FRCs in draining nodes, which shapes FRC (and thus lymph node) responses to additional stressors such as UVR-induced skin inflammation. Here, we propose the hypothesis that there are signals specific to non-lesional SLE but not healthy control skin that impact FRC phenotype. We will test the hypothesis by 1) assessing the roles of IFNs and lymph-borne signals in modulating FRC and lymph node function in vivo, and 2) delineating the scope of signals that are transmitted from non-lesional skin to impact FRCs in human SLE. These studies are anticipated to provide insight into the importance and nature of skin-lymph node communication, the connection between photosensitivity and systemic disease flares, and new potential therapeutic approaches.
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