Shared inflammatory and skin-specific gene signatures reveal common drivers of discoid lupus erythematosus in canines, humans and mice

Garelli, Colton J.; Wong, Neil B.; Piedra-Mora, César; Wrijil, Linda M.; Scarglia, Gina; David, Clément N.; Almela, Ramón M.; Robinson, Nicholas A.; Richmond, Julius B.

doi:10.1016/j.crimmu.2021.03.003

Cited by 10 publications

(18 citation statements)

References 64 publications

(69 reference statements)

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“…Comparative analysis of canine CLE cases with human and mouse CLE revealed significant overlapping genes, supporting the conservation of inflammatory signatures across species. We previously published a similar frequency of DEG overlap in discoid lupus, which shares many DEGs with the complex CLE cases presented here (18). Of note, the clinical and histopathological features observed in CLE case 3 led us to consider the mucocutaneous variant of chronic CLE, as the dog experienced recurrent mucoulcerative lesions and a pattern of interface dermatitis mostly involving the hair follicles, similar to what has been previously observed in reported CLE cases (55).…”

Section: Discussionsupporting

confidence: 82%

“…We chose NanoString technology to analyze RNA from these FFPE samples because the technology works well for fragmented RNA and avoids amplification, which could introduce a data acquisition bias ( 29 ). To ascertain whether the cases presented here aligned with cases with confirmed diagnoses, we performed hierarchical clustering using ClustVis with GSE160260 [canine DLE; dataset originally published in Garelli et al ( 18 )] and GSE171079 [canine pemphigus including pemphigus erythematosus; dataset originally published in Raef et al ( 20 )]. Hierarchical clustering of gene expression for the whole panel differentiates between healthy controls and all cases, with a significant overlap between DLE and the cases presented here ( Supplementary Figures 1A,B ).…”

Section: Resultsmentioning

confidence: 99%

“…The 160 custom canine gene dataset presented here (GSE180276), 755 genes murine cancer immune dataset by Mande et al ( 22 ), and GSE95474 dataset ( 23 ) were compared. Common denominator genes were identified in Excel using the formula “=IF(ISERROR(VLOOKUP(A2,$B$2:$B$1001,1,FALSE)),FALSE, TRUE).” Alternate gene names for values that were retrieved as FALSE were queried using GeneCards.org, and naming conventions were matched across all species, which resulted in 160 overlapping genes for canine vs. human (entire canine codeset), and 92 genes overlapping all three species [see also ( 18 )].…”

Section: Methodsmentioning

confidence: 99%

“…RNA was isolated from 30 µm tissue curls using the Qiagen formalin-fixed paraffin-embedded (FFPE) tissue RNeasy kit per the manufacturer's directions and as previously described (18)(19)(20). RNA was quantified using a NanoDrop spectrophotometer.…”

Section: Rna Isolationmentioning

confidence: 99%

“…The “One Health Approach,” which is a collaborative, multisectoral, and transdisciplinary school of thought, recognizes the interconnection between the health of people and animals and their shared environment and emphasizes the need to combine investigative methods and animal models for studying human diseases ( 17 ). We (Garelli et al) recently performed a comparative transcriptomics study of canine and human discoid lupus erythematosus (DLE) and found conserved gene expression patterns ( 18 ). The objective of this study was to determine if we can diagnose unclear CLE cases using gene expression profiling.…”

Section: Introductionmentioning

confidence: 99%

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Using Gene Expression Analysis to Understand Complex Autoimmune Skin Disease Patients: A Series of Four Canine Cutaneous Lupus Erythematosus Cases

et al. 2022

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Cutaneous Lupus Erythematosus (CLE) is an autoimmune skin disease that occurs in almost two-thirds of people with Systemic Lupus Erythematosus (SLE) and can exist as its own entity. Despite its negative impact on the quality of life of patients, lupus pathogenesis is not fully understood. In recent years, the role of gene expression analysis has become important in understanding cellular functions and disease causation within and across species. Interestingly, dogs also develop CLE, providing a spontaneous animal model of disease. Here, we present a targeted transcriptomic analysis of skin biopsies from a case series of four dogs with complex autoimmunity with suspected CLE. We identified 92 differentially expressed genes (DEGs), including type 1 interferon, B cell, and T cell-related genes, in the four cases compared to healthy skin margin controls. Additionally, we compared our results with existing CLE datasets from humans and mice and found that humans and canines share 49 DEGs, whereas humans and mice shared only 25 DEGs in our gene set. Immunohistochemistry of IFNG and CXCL10, two of the most highly upregulated inflammatory mediators, confirmed protein-level expression and revealed immune cells as the primary source of CXCL10 in dogs with SLE, whereas keratinocytes stained strongly for CXCL10 in dogs without SLE. We propose that gene expression analysis may aid the diagnosis of complex autoimmune skin diseases and that dogs may provide important insights into CLE and SLE pathogeneses, or more broadly, skin manifestations during systemic autoimmunity.

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Section: Discussionsupporting

confidence: 82%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Rna Isolationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Using Gene Expression Analysis to Understand Complex Autoimmune Skin Disease Patients: A Series of Four Canine Cutaneous Lupus Erythematosus Cases

et al. 2022

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Canine systemic immunologic diseases

Tizard

2024

The Immunology of the Dog

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Spatial characterization of interface dermatitis in cutaneous lupus reveals novel chemokine ligand-receptor pairs that drive disease

Shakiba,

Haddadi,

Afshari

et al. 2024

Preprint

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Chemokines play critical roles in the recruitment and activation of immune cells in both homeostatic and pathologic conditions. Here, we examined chemokine ligand-receptor pairs to better understand the immunopathogenesis of cutaneous lupus erythematosus (CLE), a complex autoimmune connective tissue disorder. We used suction blister biopsies to measure cellular infiltrates with spectral flow cytometry in the interface dermatitis reaction, as well as 184 protein analytes in interstitial skin fluid using Olink targeted proteomics. Flow and Olink data concordantly demonstrated significant increases in T cells and antigen presenting cells (APCs). We also performed spatial transcriptomics and spatial proteomics of punch biopsies using digital spatial profiling (DSP) technology on CLE skin and healthy margin controls to examine discreet locations within the tissue. Spatial and Olink data confirmed elevation of interferon (IFN) and IFN-inducible CXCR3 chemokine ligands. Comparing involved versus uninvolved keratinocytes in CLE samples revealed upregulation of essential inflammatory response genes in areas near interface dermatitis, includingAIM2. Our Olink data confirmed upregulation of Caspase 8, IL-18 which is the final product of AIM2 activation, and induced chemokines including CCL8 and CXCL6 in CLE lesional samples. Chemotaxis assays using PBMCs from healthy and CLE donors revealed that T cells are equally poised to respond to CXCR3 ligands, whereas CD14+CD16+ APC populations are more sensitive to CXCL6 via CXCR1 and CD14+ are more sensitive to CCL8 via CCR2. Taken together, our data map a pathway from keratinocyte injury to lymphocyte recruitment in CLE via AIM2-Casp8-IL-18-CXCL6/CXCR1 and CCL8/CCR2, and IFNG/IFNL1-CXCL9/CXCL11-CXCR3.One Sentence SummaryWe mapped chemokine orchestrators of interface dermatitis in lupus using spatial approaches on archival tissue and confirmed with fresh tissues.

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Shared inflammatory and skin-specific gene signatures reveal common drivers of discoid lupus erythematosus in canines, humans and mice

Cited by 10 publications

References 64 publications

Using Gene Expression Analysis to Understand Complex Autoimmune Skin Disease Patients: A Series of Four Canine Cutaneous Lupus Erythematosus Cases

Using Gene Expression Analysis to Understand Complex Autoimmune Skin Disease Patients: A Series of Four Canine Cutaneous Lupus Erythematosus Cases

Canine systemic immunologic diseases

Spatial characterization of interface dermatitis in cutaneous lupus reveals novel chemokine ligand-receptor pairs that drive disease

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