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: http://creativecommons.org/licenses/by-nc/4.0/ .
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.