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

Abstract

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.

Case report of canine discoid lupus erythematosus in Guatemala

“…In chronic DLE, inflammatory proteins have been identified as a primary cause of the disease. Recent studies suggest that the skin lesion transcriptomes of both canine and human CLEs are similar, with both showing activation of the innate immune system, interferon and JAK (Janus Kinase)‐STAT (Amudzi et al., 2022 ; Harvey et al., 2023 ). An experimental study has shown excellent responses in the treatment of FDLE cases, with improvement observed within the first 2 weeks of using oclacitinib at 1.8 mg/kg twice daily.…”

Cytotoxic dermatitis: Review of the interface dermatitis pattern in veterinary skin diseases

“…6 While infiltrating lymphocytes were identified as the main source of CXCL10 in dogs with associated systemic signs, keratinocytes were the main source in dogs without systemic signs. 6…”

“…Targeted transcriptomic analysis of skin lesions from 4 dogs with CLE demonstrated upregulation of IFNG and interferon-related chemokine CXCL10. 6 While infiltrating lymphocytes were identified as the main source of CXCL10 in dogs with associated systemic signs, keratinocytes were the main source in dogs without systemic signs. 6 In general, B lymphocytes are not major players in cytotoxic dermatitis.…”

“…6 While infiltrating lymphocytes were identified as the main source of CXCL10 in dogs with associated systemic signs, keratinocytes were the main source in dogs without systemic signs. 6 In general, B lymphocytes are not major players in cytotoxic dermatitis. B-cell-enriched lesions of DLE in humans suggest a link to systemic disease.…”

“…66 While it is important not to extrapolate between species, a recent retrospective study comparing gene expression in DLE lesions found that people and dogs shared 49 differentially expressed genes. 6 As mice only share 25 genes, it is possible that the dog may be a better model for the human disease than the mouse. 36 A second group of immune-mediated skin diseases that present with a cytotoxic interface reaction pattern fall under the category of cADR.…”