william ambler1, Madhavi Somaraju1, JiHyun Sim1, Ethan Seltzer1, Noa Schwartz2, Ecem Sevim3, Doruk Erkan1, Jinyeon Shin4, Rahgu Kataru4, Babak Mehrara5 and theresa Lu1, 1Hospital for Special Surgery, New York, NY, 2Albert Einstein College of Medicine, New York, NY, 3Montefiore Medical Center - Wakefield Campus, New York, NY, 4Memorial Sloan Kettering, New York, NY, 5Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering, New York, NY
Background/Purpose: Systemic lupus erythematosus is a prototypic autoimmune disease in which patients frequently have photosensitivity. Exposure to ultraviolet radiation (UVR) causes the eruption of cutaneous lesions and can induce systemic disease flare. The lymphatic system removes fluid, soluble molecules, and cells from the skin and communicates with the immune system via draining lymph node. Dysfunctional lymphatics have been shown to exacerbate acute inflammation and to alter draining lymph node responses. Lymphatic flow is decreased after viral infection and is dependent on IFN-I signaling and IFN-I signaling is important in lupus pathophysiology. We thus hypothesized that lymphatics are dysfunctional in lupus and contribute to photosensitivity. The purpose of this study is to investigate lymphatic function in patients with lupus and murine lupus models as well as to assess the immunologic consequences of manipulating lymphatics.
Methods: We assessed lymphatics in patients with lupus by performing immunohistochemistry of skin biopsies. Murine lupus models were used to assess and manipulate lymphatics in vivo. MRL/lpr and an inducible model using chronic epicutaneous application of imiquimod (IMQ) on B6 mice were used. Lymphatic flow was increased using manual lymphatic drainage (MLD) or by using tamoxifen-treated B6 PTENfl/fl Flt4ERT2 mice (LECPTEN) with enhanced lymphatics. Lymphatic flow was examined in murine lupus models by assessing Evan's blue retention in the skin at 24 hours after injection. Skin and draining lymph node responses were investigated by flow cytometric analysis after tissue digestion.
Results: Patients with lupus have dilated cutaneous lymphatics, consistent with poor lymphatic flow. Both MRL/lpr and IMQ lupus model mice had reduced lymphatic drainage compared to healthy controls after exposure to UVR. Improving lymphatic flow with MLD of MRL/lpr and IMQ lupus model mice or in IMQ-treated LECPTEN mice reduced cutaneous photosensitivity, as evidenced by decreased ear swelling and reduced immune cell infiltration. Furthermore, improving lymphatic flow reduced lymph node B cell responses with decreased germinal center B cells and plasmablasts. Mechanistically, improving lymphatic flow reduced B cell responses by acting on a lymph node fibroblastic reticular cell (FRC) CCL2-monocyte axis that we have previously shown to limit B cell responses.
Conclusion: Together, our results demonstrate that lupus skin is characterized in part by lymphatic dysfunction, and that this dysfunction contributes to both cutaneous photosensitivity and draining lymph node B cell responses. In lymph nodes, improved lymphatic flow limits B cell responses by acting on a FRC CCL2-monocyte axis that we have previously established. Our data suggest that dysfunctional lymphatic flow is a contributing factor to lupus pathophysiology and points to lymphatic function as a therapeutic target.
Disclosures: w. ambler, None; M. Somaraju, None; J. Sim, None; E. Seltzer, None; N. Schwartz, None; E. Sevim, None; D. Erkan, None; J. Shin, None; R. Kataru, None; B. Mehrara, PureTech corp, Regeneron corp, Pfizer; t. Lu, None.
