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.