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Abstract Number: 2853

A Protective Langerhans Cell-Keratinocyte Axis That Is Dysfunctional in Photosensitivity

William D. Shipman1,2,3, Susan Chyou1, Anusha Ramanathan1, Peter M. Izmirly4, Sneh Sharma5, Tania Pannellini6, Dragos Dasoveanu1, Xiaoping Qing7, Cynthia Magro8, Richard Granstein9, Michelle Lowes10, Eric Pamer11, Daniel Kaplan12, Jane E. Salmon13,14, Babak Mehrara15, James Young10,11,16,17, Robert M. Clancy18, Carl Blobel14,19,20 and Theresa T. Lu2,3,21, 1Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, NY, 2Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY, 3Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program, New York, NY, 4Rheumatology, NYU School of Medicine, New York, NY, 5Laboratory of Cellular Immunobiology, Memorial Sloan Kettering Cancer Center, New York, NY, 6Hospital for Special Surgery, New York, NY, 7Program in Inflammation and Autoimmunity, Hospital for Special Surgery, New York, NY, 8Pathology, Weill Cornell Medicine, New York, NY, 9Dermatology, Weill Cornell Medicine, New York, NY, 10Rockefeller University, New York, NY, 11Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 12Immunology, University of Pittsburgh, New, NY, 13Medicine/Rheumatology, Hospital for Special Surgery, New York, NY, 14Weill Cornell Medicine, New York, NY, 15Plastic Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, 16Immunology, Memorial Sloan Kettering Cancer Center, New York, NY, 17Medicine, Weill Cornell Medicine, New York, NY, 18Department of Medicine, Division of Rheumatology, NYU School of Medicine, New York, NY, 19Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY, 20Institute of Advanced Studies, Technical University of Munich, New York, NY, 21Autoimmunity and Inflammation Program and Pediatric Rheumatology, Hospital for Special Surgery, New York, NY

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: Cutaneous manifestations, dendritic cells and skin, SLE

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Session Information

Date: Tuesday, October 23, 2018

Title: 5T105 ACR Abstract: Innate Immunity (2850–2855)

Session Type: ACR Concurrent Abstract Session

Session Time: 4:30PM-6:00PM

Background/Purpose: Photosensitivity, or skin sensitivity to ultraviolet radiation (UVR), is a feature of lupus erythematosus (LE) and other autoimmune conditions. Photosensitive lesions can be disfiguring and photosensitivity can be associated with flares of systemic disease. Increased UVR-induced keratinocyte apoptosis is thought to play a role in the pathogenesis, but factors that regulate keratinocyte apoptosis in photosensitivity are poorly understood. Langerhans cells (LCs), mononuclear phagocytes positioned primarily in the epidermis, can have regulatory roles. As LCs are closely associated with keratinocytes, we hypothesized that LCs can limit UVR-induced keratinocyte apoptosis and skin injury.

Methods: We exposed mice to UVR at a minimal erythema dosage and 24 hours and 5 days later, harvested ear skin for immunohistochemistry to measure activated caspase 3, for flow cytometry to enumerate monocyte infiltration, for histology to measure epidermal thickness, and for toluidine blue dye assays to measure epidermal permeability. Primary mouse and human keratinocyte cultures were exposed to UVR in the presence or absence of LCs and keratinocyte apoptosis was measured. Skin sections from healthy controls and SLE patients were stained for immunofluorescence analysis of LC numbers and epidermal markers.

Results: Here, we identify a Langerhans cell (LC)-keratinocyte axis that limits UVR-induced keratinocyte apoptosis and skin injury via keratinocyte epidermal growth factor receptor (EGFR) stimulation. We show that absence of LCs in Langerin-DTA mice leads to photosensitivity and that, in vitro, mouse and human LCs can directly protect keratinocytes from UVR-induced apoptosis. LCs express EGFR ligands and ADAM17, the metalloprotease that activates EGFR ligands. Deletion of ADAM17 from LCs leads to photosensitivity and UVR induces LC ADAM17 activation and generation of soluble active EGFR ligands, suggesting that LCs protect by providing activated EGFR ligands to keratinocytes. Photosensitive systemic LE (SLE) models and human SLE skin show reduced epidermal EGFR phosphorylation and LC defects, and topical EGFR ligand reduces photosensitivity.

Conclusion: Together, our data establish a direct tissue-protective function for LCs, reveal a mechanistic basis for photosensitivity, and suggest EGFR stimulation as a treatment for photosensitivity in LE and potentially other autoimmune conditions.


Disclosure: W. D. Shipman, None; S. Chyou, None; A. Ramanathan, None; P. M. Izmirly, Exagen, 2; S. Sharma, None; T. Pannellini, None; D. Dasoveanu, None; X. Qing, None; C. Magro, None; R. Granstein, None; M. Lowes, None; E. Pamer, None; D. Kaplan, None; J. E. Salmon, None; B. Mehrara, None; J. Young, None; R. M. Clancy, None; C. Blobel, None; T. T. Lu, None.

To cite this abstract in AMA style:

Shipman WD, Chyou S, Ramanathan A, Izmirly PM, Sharma S, Pannellini T, Dasoveanu D, Qing X, Magro C, Granstein R, Lowes M, Pamer E, Kaplan D, Salmon JE, Mehrara B, Young J, Clancy RM, Blobel C, Lu TT. A Protective Langerhans Cell-Keratinocyte Axis That Is Dysfunctional in Photosensitivity [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/a-protective-langerhans-cell-keratinocyte-axis-that-is-dysfunctional-in-photosensitivity/. Accessed .
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