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ResearchIn-Press PreviewAutoimmunityImmunologyInflammationVascular biology Open Access | 10.1172/JCI168412

Lymphatic dysfunction in lupus contributes to cutaneous photosensitivity and lymph node B cell responses

Mir J. Howlader,1 William G. Ambler,1 Madhavi Latha S. Chalasani,1 Aahna Rathod,1 Ethan S. Seltzer,1 Ji Hyun Sim,1 Jinyeon Shin,2 Noa Schwartz,1 William D. Shipman III,1 Dragos C. Dasoveanu,1 Camila B. Carballo,3 Ecem Sevim,4 Salma Siddique,5 Yurii Chinenov,6 Scott A. Rodeo,3 Doruk Erkan,4 Raghu P. Kataru,2 Babak J. Mehrara,2 and Theresa T. Lu1

1Autoimmunity and Inflammation Program, Hospital for Special Surgery Research Institute, New York, United States of America

2Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Orthopedic Soft Tissue Research Program, Hospital for Special Surgery Research Institute, New York, United States of America

4Rheumatology, Department of Medicine, Hospital for Special Surgery Research Institute, New York, United States of America

5Biochemistry, Structural Biology, Cell Biology, Developmental Biology and M, Weill Cornell Medicine, New York, United States of America

6David Z. Rosenweig Genomics Research Center, Hospital for Special Surgery Research Institute, New York, United States of America

Find articles by Howlader, M. in: PubMed | Google Scholar

1Autoimmunity and Inflammation Program, Hospital for Special Surgery Research Institute, New York, United States of America

2Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Orthopedic Soft Tissue Research Program, Hospital for Special Surgery Research Institute, New York, United States of America

4Rheumatology, Department of Medicine, Hospital for Special Surgery Research Institute, New York, United States of America

5Biochemistry, Structural Biology, Cell Biology, Developmental Biology and M, Weill Cornell Medicine, New York, United States of America

6David Z. Rosenweig Genomics Research Center, Hospital for Special Surgery Research Institute, New York, United States of America

Find articles by Ambler, W. in: PubMed | Google Scholar

1Autoimmunity and Inflammation Program, Hospital for Special Surgery Research Institute, New York, United States of America

2Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Orthopedic Soft Tissue Research Program, Hospital for Special Surgery Research Institute, New York, United States of America

4Rheumatology, Department of Medicine, Hospital for Special Surgery Research Institute, New York, United States of America

5Biochemistry, Structural Biology, Cell Biology, Developmental Biology and M, Weill Cornell Medicine, New York, United States of America

6David Z. Rosenweig Genomics Research Center, Hospital for Special Surgery Research Institute, New York, United States of America

Find articles by Chalasani, M. in: PubMed | Google Scholar

1Autoimmunity and Inflammation Program, Hospital for Special Surgery Research Institute, New York, United States of America

2Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Orthopedic Soft Tissue Research Program, Hospital for Special Surgery Research Institute, New York, United States of America

4Rheumatology, Department of Medicine, Hospital for Special Surgery Research Institute, New York, United States of America

5Biochemistry, Structural Biology, Cell Biology, Developmental Biology and M, Weill Cornell Medicine, New York, United States of America

6David Z. Rosenweig Genomics Research Center, Hospital for Special Surgery Research Institute, New York, United States of America

Find articles by Rathod, A. in: PubMed | Google Scholar

1Autoimmunity and Inflammation Program, Hospital for Special Surgery Research Institute, New York, United States of America

2Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Orthopedic Soft Tissue Research Program, Hospital for Special Surgery Research Institute, New York, United States of America

4Rheumatology, Department of Medicine, Hospital for Special Surgery Research Institute, New York, United States of America

5Biochemistry, Structural Biology, Cell Biology, Developmental Biology and M, Weill Cornell Medicine, New York, United States of America

6David Z. Rosenweig Genomics Research Center, Hospital for Special Surgery Research Institute, New York, United States of America

Find articles by Seltzer, E. in: PubMed | Google Scholar |

1Autoimmunity and Inflammation Program, Hospital for Special Surgery Research Institute, New York, United States of America

2Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Orthopedic Soft Tissue Research Program, Hospital for Special Surgery Research Institute, New York, United States of America

4Rheumatology, Department of Medicine, Hospital for Special Surgery Research Institute, New York, United States of America

5Biochemistry, Structural Biology, Cell Biology, Developmental Biology and M, Weill Cornell Medicine, New York, United States of America

6David Z. Rosenweig Genomics Research Center, Hospital for Special Surgery Research Institute, New York, United States of America

Find articles by Sim, J. in: PubMed | Google Scholar

1Autoimmunity and Inflammation Program, Hospital for Special Surgery Research Institute, New York, United States of America

2Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Orthopedic Soft Tissue Research Program, Hospital for Special Surgery Research Institute, New York, United States of America

4Rheumatology, Department of Medicine, Hospital for Special Surgery Research Institute, New York, United States of America

5Biochemistry, Structural Biology, Cell Biology, Developmental Biology and M, Weill Cornell Medicine, New York, United States of America

6David Z. Rosenweig Genomics Research Center, Hospital for Special Surgery Research Institute, New York, United States of America

Find articles by Shin, J. in: PubMed | Google Scholar

1Autoimmunity and Inflammation Program, Hospital for Special Surgery Research Institute, New York, United States of America

2Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Orthopedic Soft Tissue Research Program, Hospital for Special Surgery Research Institute, New York, United States of America

4Rheumatology, Department of Medicine, Hospital for Special Surgery Research Institute, New York, United States of America

5Biochemistry, Structural Biology, Cell Biology, Developmental Biology and M, Weill Cornell Medicine, New York, United States of America

6David Z. Rosenweig Genomics Research Center, Hospital for Special Surgery Research Institute, New York, United States of America

Find articles by Schwartz, N. in: PubMed | Google Scholar

1Autoimmunity and Inflammation Program, Hospital for Special Surgery Research Institute, New York, United States of America

2Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Orthopedic Soft Tissue Research Program, Hospital for Special Surgery Research Institute, New York, United States of America

4Rheumatology, Department of Medicine, Hospital for Special Surgery Research Institute, New York, United States of America

5Biochemistry, Structural Biology, Cell Biology, Developmental Biology and M, Weill Cornell Medicine, New York, United States of America

6David Z. Rosenweig Genomics Research Center, Hospital for Special Surgery Research Institute, New York, United States of America

Find articles by Shipman III, W. in: PubMed | Google Scholar

1Autoimmunity and Inflammation Program, Hospital for Special Surgery Research Institute, New York, United States of America

2Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Orthopedic Soft Tissue Research Program, Hospital for Special Surgery Research Institute, New York, United States of America

4Rheumatology, Department of Medicine, Hospital for Special Surgery Research Institute, New York, United States of America

5Biochemistry, Structural Biology, Cell Biology, Developmental Biology and M, Weill Cornell Medicine, New York, United States of America

6David Z. Rosenweig Genomics Research Center, Hospital for Special Surgery Research Institute, New York, United States of America

Find articles by Dasoveanu, D. in: PubMed | Google Scholar

1Autoimmunity and Inflammation Program, Hospital for Special Surgery Research Institute, New York, United States of America

2Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Orthopedic Soft Tissue Research Program, Hospital for Special Surgery Research Institute, New York, United States of America

4Rheumatology, Department of Medicine, Hospital for Special Surgery Research Institute, New York, United States of America

5Biochemistry, Structural Biology, Cell Biology, Developmental Biology and M, Weill Cornell Medicine, New York, United States of America

6David Z. Rosenweig Genomics Research Center, Hospital for Special Surgery Research Institute, New York, United States of America

Find articles by Carballo, C. in: PubMed | Google Scholar

1Autoimmunity and Inflammation Program, Hospital for Special Surgery Research Institute, New York, United States of America

2Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Orthopedic Soft Tissue Research Program, Hospital for Special Surgery Research Institute, New York, United States of America

4Rheumatology, Department of Medicine, Hospital for Special Surgery Research Institute, New York, United States of America

5Biochemistry, Structural Biology, Cell Biology, Developmental Biology and M, Weill Cornell Medicine, New York, United States of America

6David Z. Rosenweig Genomics Research Center, Hospital for Special Surgery Research Institute, New York, United States of America

Find articles by Sevim, E. in: PubMed | Google Scholar

1Autoimmunity and Inflammation Program, Hospital for Special Surgery Research Institute, New York, United States of America

2Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Orthopedic Soft Tissue Research Program, Hospital for Special Surgery Research Institute, New York, United States of America

4Rheumatology, Department of Medicine, Hospital for Special Surgery Research Institute, New York, United States of America

5Biochemistry, Structural Biology, Cell Biology, Developmental Biology and M, Weill Cornell Medicine, New York, United States of America

6David Z. Rosenweig Genomics Research Center, Hospital for Special Surgery Research Institute, New York, United States of America

Find articles by Siddique, S. in: PubMed | Google Scholar

1Autoimmunity and Inflammation Program, Hospital for Special Surgery Research Institute, New York, United States of America

2Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Orthopedic Soft Tissue Research Program, Hospital for Special Surgery Research Institute, New York, United States of America

4Rheumatology, Department of Medicine, Hospital for Special Surgery Research Institute, New York, United States of America

5Biochemistry, Structural Biology, Cell Biology, Developmental Biology and M, Weill Cornell Medicine, New York, United States of America

6David Z. Rosenweig Genomics Research Center, Hospital for Special Surgery Research Institute, New York, United States of America

Find articles by Chinenov, Y. in: PubMed | Google Scholar |

1Autoimmunity and Inflammation Program, Hospital for Special Surgery Research Institute, New York, United States of America

2Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Orthopedic Soft Tissue Research Program, Hospital for Special Surgery Research Institute, New York, United States of America

4Rheumatology, Department of Medicine, Hospital for Special Surgery Research Institute, New York, United States of America

5Biochemistry, Structural Biology, Cell Biology, Developmental Biology and M, Weill Cornell Medicine, New York, United States of America

6David Z. Rosenweig Genomics Research Center, Hospital for Special Surgery Research Institute, New York, United States of America

Find articles by Rodeo, S. in: PubMed | Google Scholar

1Autoimmunity and Inflammation Program, Hospital for Special Surgery Research Institute, New York, United States of America

2Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Orthopedic Soft Tissue Research Program, Hospital for Special Surgery Research Institute, New York, United States of America

4Rheumatology, Department of Medicine, Hospital for Special Surgery Research Institute, New York, United States of America

5Biochemistry, Structural Biology, Cell Biology, Developmental Biology and M, Weill Cornell Medicine, New York, United States of America

6David Z. Rosenweig Genomics Research Center, Hospital for Special Surgery Research Institute, New York, United States of America

Find articles by Erkan, D. in: PubMed | Google Scholar

1Autoimmunity and Inflammation Program, Hospital for Special Surgery Research Institute, New York, United States of America

2Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Orthopedic Soft Tissue Research Program, Hospital for Special Surgery Research Institute, New York, United States of America

4Rheumatology, Department of Medicine, Hospital for Special Surgery Research Institute, New York, United States of America

5Biochemistry, Structural Biology, Cell Biology, Developmental Biology and M, Weill Cornell Medicine, New York, United States of America

6David Z. Rosenweig Genomics Research Center, Hospital for Special Surgery Research Institute, New York, United States of America

Find articles by Kataru, R. in: PubMed | Google Scholar

1Autoimmunity and Inflammation Program, Hospital for Special Surgery Research Institute, New York, United States of America

2Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Orthopedic Soft Tissue Research Program, Hospital for Special Surgery Research Institute, New York, United States of America

4Rheumatology, Department of Medicine, Hospital for Special Surgery Research Institute, New York, United States of America

5Biochemistry, Structural Biology, Cell Biology, Developmental Biology and M, Weill Cornell Medicine, New York, United States of America

6David Z. Rosenweig Genomics Research Center, Hospital for Special Surgery Research Institute, New York, United States of America

Find articles by Mehrara, B. in: PubMed | Google Scholar |

1Autoimmunity and Inflammation Program, Hospital for Special Surgery Research Institute, New York, United States of America

2Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, United States of America

3Orthopedic Soft Tissue Research Program, Hospital for Special Surgery Research Institute, New York, United States of America

4Rheumatology, Department of Medicine, Hospital for Special Surgery Research Institute, New York, United States of America

5Biochemistry, Structural Biology, Cell Biology, Developmental Biology and M, Weill Cornell Medicine, New York, United States of America

6David Z. Rosenweig Genomics Research Center, Hospital for Special Surgery Research Institute, New York, United States of America

Find articles by Lu, T. in: PubMed | Google Scholar

Published April 22, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI168412.
Copyright © 2025, Howlader et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published April 22, 2025 - Version history
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Abstract

Patients with systemic lupus erythematosus (SLE) are photosensitive, developing skin inflammation with even ambient ultraviolet radiation (UVR), and this cutaneous photosensitivity can be associated with UVR-induced flares of systemic disease, which can involve increased autoantibodies and further end organ injury. Mechanistic insight into the link between the skin responses and autoimmunity is limited. Signals from skin are transmitted directly to the immune system via lymphatic vessels, and here we show evidence for potentiation of UVR-induced lymphatic flow dysfunction in SLE patients and murine models. Improving lymphatic flow by manual lymphatic drainage (MLD) or with a transgenic model with increased lymphatic vessels reduces both cutaneous inflammation and lymph node B and T cell responses, and long term MLD reduces splenomegaly and titers of a number of autoantibodies. Mechanistically, improved flow restrains B cell responses in part by stimulating a lymph node fibroblastic reticular cell-monocyte axis. Our results point to lymphatic modulation of lymph node stromal function as a link between photosensitive skin responses and autoimmunity and as a therapeutic target in lupus, provide insight into mechanisms by which the skin state regulates draining lymph node function, and suggest the possibility of MLD as an accessible and cost-effective adjunct to add to ongoing medical therapies for lupus and related diseases.

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