A Pilot Study of the Interferon Transcriptome in Children with Lyme Arthritis

Objectives Lyme arthritis (LA) results from dissemination of the causative organism of Lyme disease, Borreliaburgdorferi, to synovial joints. In our retrospective cohort of children with LA, 70% had resolution of arthritis after one course of antibiotics, 15% after ≥2 courses, and 15% had persistent arthritis after ≥2 courses of antibiotics, defined as post-infectious LA (PILA). As a part of a larger multi-omics project, which aims to understand the immune response on the hypothesized anti-infectious to chronic inflammatory/autoimmune continuum in children with LA and PILA, in this pilot study, we analyzed interferon (IFN) type I and II gene expression signatures between groups of children with LA based on clinical outcomes. Methods Study participants with LA were recruited prospectively from a pediatric rheumatology clinic in Halifax, NS. Clinical outcomes were divided into those with resolution of arthritis with 1-2 courses of antibiotics and PILA. Oligoarticular JIA and healthy volunteers served as comparator groups. Reverse-Transcription quantitative Polymerase Chain Reaction (RT-qPCR) of mRNA isolated from peripheral blood mononuclear cells was analyzed to evaluate the expression levels of Type I IFN (IFNA1) and Type I IFN responsive genes (ISG15, IFIT1, OAS1) to create a Type I IFN score, and IFNG as a representative Type II IFN. Standard housekeeping genes ACTINB and UBC were used as reference genes. Fold changes in gene expression within groups were analyzed using the Wilcoxon signed-rank test, and differences between groups with T-tests. Results Research cohorts included: 28 antibiotic responders (57%F, age 8.5y ± 3.4y), [19 had resolution after 1 course of antibiotics, 9 after 2 courses], 5 with PILA (75%F, age 10.4y± 1.3y), 5 with JIA (100%F, age 6.8y± 4.0y) and 18 healthy controls ( 43%F, 8.3y±4.9y). Significant expression of IFNA1, ISG15, IFIT1, and OAS1 (p<0.0001) and IFN score (p<0.0001) was observed within the antibiotic responder group, while PILA and JIA groups failed to demonstrate a measurable IFN response. Analysis between groups demonstrated significantly higher IFNA1 expression in the antibiotic responder group compared to PILA (p=0.015). Conclusion Our data suggest that robust IFN expression is associated with antibiotic response and disease resolution in children with LA; however, a low IFN signature after Borrelia exposure is associated with persistent joint inflammation despite antibiotics, similar to oligoarticular JIA. Our study is limited by the small number of patients in the PILA group, with sample collection ongoing.