Background Recent genome-wide association studies (GWAS) have revealed numerous genetic associations between specific single-nucleotide polymorphisms (SNPs) and spondyloarthritis (SpA), a highly heritable arthropathy. These studies highlighted the importance of non-HLA genes, in particular of key components of the IL-23 signaling pathway such as IL23R and IL12B, as well as genes associated with other pathways such as ERAP1 and ANTXR2. However, the link between these genes and the disease mechanisms remained unknown.

Objectives The current challenge is to define associations between defined genetic variants and effector mechanisms implicated in disease pathogenesis. Here, we have investigated the link between genetic variants associated with spondyloarthritis (SpA) and the function of CD4⁺ effector T lymphocyte subsets, known mediators of chronic inflammatory disease.

Methods To assess if genetic variants at IL23R and other genes in the IL-23/IL-17 pathway affect CD4⁺ T cell functions, we isolated CD4⁺ T cells from the peripheral blood of 49 SpA patients and stimulated them through the T cell receptor in vitro. We then analyzed the expression of genes associated with development and function of Th1 and Th17 cells. Genotyping was performed using pre-developed TaqMan allelic discrimination assays and immunophenotyping using standard flow cytometry panels.

Results We found that selected disease-associated polymorphisms in genes involved in the IL-23 signaling pathway, such as IL23R, IL12B and CCR6, correlated with the expression levels of genes controlling differentiation and function of inflammatory Th1 and Th17 cells in SpA patients. In contrast, genetic variation at loci genetically linked to SpA, but not associated with the IL-23 pathway, had no measurable impact on the expression of inflammatory cytokines.

To assess the global effect of multiple SNPs on CD4 effector functions, we correlated the numbers of susceptibility or protective alleles at molecules in the IL-23 pathway that each patient carried with the expression levels of Th1 and Th17 cytokine genes. Patients carrying predominantly alleles associated with increased disease risk expressed overall higher levels of effector cytokines. In contrast, patients carrying the highest number of protective alleles expressed the lowest levels of these cytokine genes.

Conclusions Our data revealed a combinatorial control of T helper cell effector functions by SNPs at genes associated with the IL-23 signaling pathway in SpA patients and provide a framework to delineate the mechanisms by which genetic variants may contribute to SpA pathogenesis. We propose that genetic variation at genes in the IL-23/IL-17 axis tunes the homeostasis of CD4 effector cell populations, by affecting the frequencies of inflammatory T cell subsets.

Disclosure of Interest None Declared