Background: Immune-mediated polyarthritis (IMPA) causes severe lameness, joint effusions, pyrexia, and lethargy in affected dogs. Clinical features are caused by aberrant immune responses directed at joint antigens, but there is little understanding of the molecular mechanisms driving disease development. Hypothesis/
Objectives: To uncover molecular features of the aberrant immune response occurring in dogs with IMPA. Animals: Seventeen client-owned dogs with primary idiopathic IMPA evaluated at diagnosis and 2 weeks after commencing prednisolone therapy, and 6 healthy controls.
Methods: Total RNA was extracted from residual blood samples before bulk library preparation with depletion of ribosomal and hemoglobin transcripts. After sequencing, reads were aligned to the CanFam3.1 reference genome and quantified using Salmon. Differential expression among groups was evaluated with DESeq2 before gene set enrichment analysis and evaluation of transcription factor (TF) activity using the ChEA3 database.
Results: At diagnosis, dogs with IMPA had marked upregulation of inflammatory cytokine genes compared to controls (IL1B, IL6, TNF), as well as significant enrichment for pathways related to type I interferon signaling and TNF-mediated activation of NF-kB. Moreover, the NF-kB member RELB was upregulated and predicted to be among the most activated TFs. After treatment, TNF/NF-kB activity was no longer increased compared to controls, but interferon activity was persistently higher. Additionally, treated dogs showed significant increases in oxidative phosphorylation and reactive oxygen species responses, driven by genes like PRDX2 and ATOX1. Conclusions and Clinical Importance: Dogs with IMPA display dramatic inflammatory responses in peripheral blood, which appear to be incompletely controlled by conventional immunosuppressive therapy.
