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1204 Improving lymphatic function to reduce B cell responses in lupus
  1. William G Ambler1,2,†††,
  2. Mir Howlader1,3,
  3. Madhavi Latha S Chalasani1,4,,
  4. Ethan S Seltzer1,
  5. JiHyun Sim1,4,
  6. Jinyeon Shin4,
  7. Noa Schwartz1,6,,
  8. Dragos Dasoveanu1,7,,
  9. Camila B Carballo8,
  10. Ecem Sevim5,§,
  11. Salma Siddique2,6,††,
  12. Scott Rodeo8,9,
  13. Doruk Erkan6,
  14. Raghu P Kataru5,
  15. Babak Mehrara5 and
  16. Theresa T Lu1,2,4,6,10
  1. 1Autoimmunity and Inflammation Program, Hospital for Special Surgery Research Institute; New York, NY, USA
  2. 2Pediatric Rheumatology, Department of Medicine, Hospital for Special Surgery; New York, NY, USA
  3. 3Biochemistry, Structural Biology, Cell Biology, Developmental Biology and Molecular Biology Graduate Program, Weill Cornell Medicine; New York, NY, USA
  4. 4Department of Microbiology and Immunology, Weill Cornell Medicine; New York, NY, USA
  5. 5Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan Kettering Cancer Center; New York, NY, USA
  6. 6Rheumatology, Department of Medicine, Hospital for Special Surgery; New York, USA
  7. 7Physiology, Biophysics, and Systems Biology Graduate Program, Weill Cornell Medicine, New York, NY USA
  8. 8Orthopedic Soft Tissue Research Program, Hospital for Special Surgery Research Institute; New York, NY, USA
  9. 9Department of Orthopedics, Hospital for Special Surgery; New York, NY, USA
  10. 10Department of Pediatrics, Weill Cornell Medicine; New York, NY, USA
  11. †††Current address: NIAMS, Bethesda, MD, USA
  12. †Current address: Mnemo Therapeutics; Princeton, NJ, USA
  13. ‡Current address Department of Medicine (Rheumatology), Albert Einstein College of Medicine/Montefiore Medical Center; Bronx, NY, USA6
  14. §Current address Department of Medicine, Montefiore Medical Center; Bronx, NY, USA
  15. ¶Current address Department of Cancer Immunology, Genentech; South San Francisco, CA, USA
  16. ††Current address Nemours Hospital for Children, Wilmington, DE, USA


Background In SLE, that ultraviolet radiation exposure can induce both photosensitive skin responses and increased autoantibody titers suggests a critical and targetable role for the communication from skin to draining lymph nodes in regulating lymph node B cell responses. Lymphatic vessels bring cells and signals from skin to draining lymph nodes to regulate immunity and dysfunction of lymphatic flow has the potential to alter immunity. Here we examine lymphatic flow function in SLE humans and models, showing that lymphatic flow from skin to lymph nodes is compromised. that improving lymphatic flow by manual lymphatic drainage (MLD) or in a transgenic model reduces lymph node B cell responses, and delineate the mechanistic underpinnings of how lymphatic flow modulates draining lymph node function.

Methods We examined lymphatic vessel luminal area considered to be reflective of lymphatic flow function in healthy controls, SLE, and control disease (anti-phospholipid antibody+ non-SLE patients) by immunohistochemistry and image analysis. We examined lymphatic function and performed manual lymphatic drainage in both MRL/lpr and imiquimod-induced lupus models. Lymphatic function was assessed by Evans blue tissue clearance assays and lymph node function was assessed by mainly by flow cytometry. Lymphatic flow was improved by either manual lymphatic drainage, adapted to mice based on techniques used in humans, or in a transgenic PTENf/f Flt4-CreER model with increased lymphatic numbers and function.

Results SLE patient skin showed increased lymphatic vessel lumen size in skin and multiple SLE mouse models showed reduced clearance of intradermally-injected Evans blue, both suggesting reduced lymphatic flow in SLE. Improving lymphatic flow by manual lymphatic drainage (MLD) or in imiquimod-treated PTENf/f Flt4-CreER mice reduced both cutaneous photosensitivity and lymph node germinal center and plasma cells.

Mechanistically, improved flow restrains B cell responses by upregulating lymph node fibroblastic reticular cell CCL2, which modulates monocyte phenotype to limit germinal center and plasma cell numbers.

Conclusions Our results suggest a scenario whereby dysfunctional communication between the skin and the immune system alters lymph node function to modulate disease, point to a lymphatic flow-lymph node stromal axis as a therapeutic target, and suggest the possibility of manual lymphatic drainage, an existing treatment modality used in breast adjunctive treatment in SLE.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: .

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