Rationale, Objective, and Aims: Patients with lupus often have an increased skin sensitivity to sunlight and other forms of ultraviolet radiation (UVR) whereby even ambient sunlight exposure can result in the development of inflammatory skin lesions. Advances have provided insight into the reasons that lupus skin is photosensitive, but beyond the skin, sun and other UVR exposure can also trigger systemic disease flares, resulting in increased autoantibodies levels which can then further injure kidneys and other affected organs. How skin sensitivity to UVR can lead to systemic disease flares, however, is not well understood.

Our objective is to understand this connection between sunlight exposure and systemic disease flares. We will test the hypothesis that sunlight-induced systemic flares occur because even non-lesional skin has high levels of inflammatory molecules and is constantly sending signals to lymph nodes that make these immune tissues less able to suppress autoantibody generation. The skin constantly communicates directly via lymphatic vessels to lymph nodes, telling lymph nodes about the state of the skin (homeostasis, injury, infection, etc.).

Within the lymph nodes, fibroblast cells that provide structural support for the immune cells are among the first to receive skin signals and, in turn under healthy conditions, limit autoantibody-generating immune cells.

Because these lymph node fibroblasts are direct recipients of skin signals, because of their critical role in limiting autoimmune responses, and because we have preliminary data that lymph node fibroblasts in lupus are dysfunctional, we will focus on the communication between skin and the lymph node fibroblasts. Our Aims are: (1) Identify the nature of the signals in lupus that are transmitted from non-lesional skin to lymph nodes, and (2) examine how the lymph node fibroblasts are altered in their immune-regulatory functions by the lupus skin-derived signals.

Focus Area: This study addresses the Fiscal Year 2021 Lupus Research Program Focus Area of “Understanding the biological mechanisms of lupus disease” by understanding the biologic bases of the connection between sunlight exposure and systemic disease flares.

Applicability of the Research: This study will help us better understand the biologic mechanisms that underlie the connection between photosensitivity and systemic disease flares in systemic lupus erythematosus (SLE). The data will help us understand how to better prevent or treat UVR-induced systemic flares in several ways: (1) Identifying the signals from SLE skin that impact lymph node fibroblast function provides the opportunity to develop therapeutics that block these signals, (2) delineating the fibroblast alterations can lead to strategies to reprogram fibroblasts to a more immune-regulatory state, (3) better understanding the pathophysiology can help us better understand how a given medication works, which will help better target medication usage and avoid unexpected side effects, and (4) the level of the relevant skin signals can be used as a biomarker to understand which patients are at higher risk for UVR-induced systemic flares and therapy adjusted accordingly. This study may have both short-term and long-term yields. A biomarker analysis can be undertaken almost immediately. If the relevant skin-derived molecules are already being targeted by medications used for different reasons or different diseases, a clinical trial examining the utility of this medication in lupus can be undertaken and conducted within a span of a few years. A novel target that requires the development of new compounds will be over the longer term, in the range of a decade or more. In addition, unexpected advances in other relevant fields such as the fibroblast research field can also advance the therapeutic strategies that are available for use in lupus. The consequences of photosensitive responses and the lifestyle modifications needed to avoid sun exposure and these consequences contribute to the morbidity and burden of this disease. The expanded understanding of the connection between the skin and the immune system gained from this study will improve lupus patients’ health and quality of life.