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Abstract Number: 2549

VISTA Deficiency Alters the Skin Immune Cell Composition and Confers Skin Sensitivity to UV Light

Zachary Peters1, Lindsay Mendyka2, Angelique Cortez1, J'voughnn Blake1, Alecia Roy1, William Rigby3, Christopher Burns4, Randolph Noelle5 and Sladjana Skopelja-Gardner6, 1Dartmouth College, Lebanon, NH, 2Dartmouth Hitchcock Memorial Hospital, Lyme, NH, 3Dartmouth-Hitchcock, Norwich, VT, 4Dartmouth Hitchcock Medical Center, Lebanon, NH, 5Geisel School of Medicine at Dartmouth, Lebanon, 6Dartmouth Geisel School of Medicine, Lebanon, NH

Meeting: ACR Convergence 2024

Keywords: autoimmune diseases, interferon, lupus-like disease, Mouse Models, Lupus, skin

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Session Information

Date: Monday, November 18, 2024

Title: Abstracts: SLE – Animal Models

Session Type: Abstract Session

Session Time: 1:00PM-2:30PM

Background/Purpose: Persistent production of type I interferons (IFN-Is) is one of the hallmarks of cutaneous lupus erythematosus (CLE) that is exacerbated by ultraviolet (UV) light. Though photosensitivity affects >80% of CLE patients, no therapies address this disease manifestation. Here we demonstrate that decreased VISTA (Vsir) expression, also observed in human lupus non-lesional skin, creates a CLE-like skin environment sensitive to UV light, at least in part due to STING-mediated IFN-I signaling.

Methods: Skin biopsies from B6, B6.Vsir-/- (VISTA-deficient), B6.Vsir-/-Sting-/-, KRT14creVsirfl/fl (Vsir-/- in keratinocytes), and cre-Vsirfl/fl female mice (3 mo) were collected prior to and 48 hr after UVB (500mJ/cm2 one dose). Gene expression was quantified by RNA-seq. Skin infiltrating cells were quantified by flow cytometry and GSVA analysis of RNAseq data. Sc-RNAsq data from GSE186476 was reanalyzed using the Seurat package for Vsir and IFN-I score expression. Cutaneous Lupus disease activity and severity (CLASI) score was calculated as the sum of scores for mouse ears, upper and lower backs for erythema, scaling and scarring. IFN-I score derived as the sum of 6 IFN-stimulated gene (ISGs) normalized expression relative to 18s by qPCR.

Results: At homeostasis, IFN-I signaling and IFNk expression are highly upregulated in B6.Vsir-/-, compared to wild-type (wt, B6) skin, despite the absence of spontaneous skin lesions. Vsir deficiency in keratinocytes only is sufficient to drive the increased IFN-I signaling in the skin. Of relevance to human disease, analysis of skin scRNAseq data revealed lower Vsir expression in non-lesional CLE compared to healthy skin. This was particularly notable in keratinocyte subsets with a high IFN-I signature. Analogous to the immune cell composition in human CLE skin, monocytes, pDCs, CD8 T cells, and B cells are elevated in Vsir-/- skin, while Treg are significantly decreased, compared to wt skin. Enrichment for CD8 T cells, monocytes, and B cells was also seen in the skin of KRT14creVsirfl/fl skin. Acute exposure to UV light results in visible skin sensitivity, marked by significantly higher CLASI score in Vsir-/- vs. wt skin 48hr after UV, accompanied by increased infiltration of inflammatory monocytes and decreased levels of Foxp3+T regulatory cells. Given the role of STING signaling in skin UV responses, we asked if the absence of Sting rescues the photosensitive skin reaction in the Vsir-/- skin. At baseline, Vsir-/-Sting-/- mice have lower skin IFN-I signature compared to Vsir-/- mice. Levels of monocytes, CD8 T cells, and Treg are restored to almost baseline wt levels. Vsir.Sting-/- mice have a reduced CLASI score after UV, accompanied by a decrease in monocyte infiltration and increase in Treg levels, compared to Vsir-/- mice.

Conclusion: These studies demonstrate that VISTA deficient skin, even when limited to keratinocytes, mimics non-lesional CLE skin in terms of inflammatory pathway signatures and immune cell composition. VISTA serves as a guardian against UV-induced damage in the skin, likely by suppressing STING-induced IFN-I production. Decreased Vsir expression in CLE non-lesional skin and IFN-Ihigh keratinocyte suggests clinical relevance.


Disclosures: Z. Peters: None; L. Mendyka: None; A. Cortez: None; J. Blake: None; A. Roy: None; W. Rigby: None; C. Burns: None; R. Noelle: None; S. Skopelja-Gardner: None.

To cite this abstract in AMA style:

Peters Z, Mendyka L, Cortez A, Blake J, Roy A, Rigby W, Burns C, Noelle R, Skopelja-Gardner S. VISTA Deficiency Alters the Skin Immune Cell Composition and Confers Skin Sensitivity to UV Light [abstract]. Arthritis Rheumatol. 2024; 76 (suppl 9). https://acrabstracts.org/abstract/vista-deficiency-alters-the-skin-immune-cell-composition-and-confers-skin-sensitivity-to-uv-light/. Accessed .
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