Epigenetic and gene expression analysis of ankylosing spondylitis-associated loci implicate immune cells and the gut in the disease pathogenesis

Abstract

Ankylosing spondylitis (AS) is a common immune-mediated arthropathy primarily affecting the spine and pelvis. Most AS patients have subclinical intestinal inflammation, suggesting the gut microbiome and the immune response play a role in pathogenesis. Susceptibility to AS is primarily genetic, and at least 114 susceptibility variants have been identified to date. We applied bioinformatic methods utilizing epigenetic and gene and protein expression data to identify the cell types through which AS-associated variants operate. Variants were enriched in transcriptionally regulated regions in monocytes, CD4 and CD8 T cells, natural killer cells, regulatory T cells and B cells and mucosa from the small intestine, sigmoid colon and rectum. Weak signals were detected in bone cells, consistent with bone disease being a secondary manifestation. RNA sequencing of blood cells from AS patients and controls identified differentially expressed genes. Interrogation of expression databases showed that the upregulated genes were enriched in monocytes and downregulated genes were enriched in CD8 T cells and natural killer cells. Gene Ontology term enrichment analysis identified microbes and the gut in the aetiology of AS. These findings identify the key immune cell types that drive the disease, and further highlight the involvement of the gut microbiome in the pathogenesis of AS.

HLA associations in inflammatory arthritis: emerging mechanisms and clinical implications

“…In SpA, inflammation of the sacroiliac and intervertebral joints is associated with both erosive bone changes and new bone formation at the entheses. HLA-B27 does not directly affect bone formation in transgenic mice or osteoblast differentiation by mouse or human bone precursor cells in vitro 80 ; rather, epigenetic and gene expression analyses suggest that new bone formation occurs in SpA owing to HLA-B27-driven inflammation 103,104 . The mechanistic hypotheses proposed to account for these findings are depicted in Fig.…”

IL-17 in the immunopathogenesis of spondyloarthritis

“…In addition to the HLA region, variants in the ERAP1/2 loci (which encode enzymes required for HLA class I peptide trimming [43][44][45], and the RUNX3 locus, which encodes runt-related transcription factor 3, a transcription factor essential for CD8+ T cell development and differentiation [46][47][48] , are associated with AS and PsA as well as psoriasis [49][50][51][52] . The location of susceptibility variants associated with PsA has been shown to overlap with epigenetic marks of transcription (histone H3 lysine 4 trimethylation (H3K4me3), a histone modification and epigenetic marker of active promoters) in memory CD8+ T cells 52 ; in AS, susceptibility variants overlap with H3K4me3 marks across a range of immune cell types, including CD4+ and CD8+ T cells 53 . Furthermore, risk and protective variants in the RUNX3 region correlate with variations in CD8+ T cell counts 49,54 and transcription factor (interferon regulatory factor 4, IRF4) binding 55 , respectively.…”

Shotgun metagenomics reveals an enrichment of potentially cross-reactive bacterial epitopes in ankylosing spondylitis patients, as well as the effects of TNFi therapy upon microbiome composition

“…There is considerable overlap in the overall heritability of AS and IBD,4 the two diseases are often cofamilial5 and many shared genetic associations have been identified 6. A bioinformatic study showed that AS susceptibility genes specifically enriched in gut cells are also enriched in ‘response to bacterium’ GO term pathway and that AS-associated genetic loci are found disproportionately to lie within epigenetic marks of gene activity in gut tissue and cells 7. Germ-free HLA-B27 -transgenic rats and SKG mice are disease-free 8 9.…”