Comparative Transcriptomic Analysis of Gene Expression Patterns in Neutrophils from Rheumatoid Arthritis and COVID-19

Abstract

Background: Rheumatoid arthritis (RA) is an autoimmune disorder characterised by chronic inflammation and immune dysregulation, and neutrophils play a key role in its progression. COVID-19 also involves neutrophil hyperactivation that contributes to severe immune responses. Emerging evidence links COVID-19 to increased incidence or exacerbation of RA, potentially through overlapping immune mechanisms. Objective: To compare neutrophil transcriptomic profiles in RA and COVID-19 and identify shared immune pathways and disease-specific features. Methods: Publicly available neutrophil RNA-seq count data from the Gene Expression Omnibus were analysed: RA versus healthy controls (GSE116899) and COVID-19 versus healthy controls (GSE212041). A second COVID-19 comparison (severe versus convalescent) was assembled from GSE272381 and GSE227116. Differential expression was analysed with DESeq2, pathway enrichment with fgsea (Hallmark gene sets) and topGO (Gene Ontology biological process and molecular function). Differentially expressed genes (DEGs) were compared between diseases by direction of change. Results: In RA neutrophils, 11,355 DEGs were identified, of which 90 had an absolute log2 fold change of at least 2 with p<0.05 (70 upregulated, 20 downregulated). Twenty-four Hallmark gene sets were positively enriched at adjusted p<0.05, led by interferon alpha and interferon gamma responses, and Gene Ontology analysis highlighted type I interferon, antiviral and double-stranded RNA terms. In COVID-19 neutrophils, 420 DEGs were identified (37 upregulated, 383 downregulated), and no Hallmark gene set reached adjusted p<0.05. Of the 90 RA DEGs, 46 changed in the same direction in COVID-19 without reaching significance, and 27 changed significantly in the opposite direction, including CAMK1G, SIGLEC1, OAS1 and OAS3. In the second COVID-19 comparison, several of these genes, including OAS1, OAS3 and SIGLEC1, changed in the same direction as in RA. Conclusions: RA neutrophils show a transcriptional programme enriched for interferon and antiviral-response pathways. Part of the RA signature is shared with COVID-19 neutrophils, while a subset of genes diverges, and this divergence depended on the COVID-19 comparison used. These findings are hypothesis-generating and provide candidate genes for experimental validation.