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Ankylosing spondylitis (AS) is a common spondyloarthropathy primarily affecting the axial skeleton and strongly associated with HLA-B*27 carriage. Genetic evidence implicates both autoinflammatory processes and autoimmunity against a HLA-B*27-restricted autoantigen in immunopathology. Additional to articular symptoms, up to 70% of AS patients present with concurrent bowel inflammation, suggesting that adverse interactions between a genetically-primed host immune system and the gut microbiome contributes to disease. Accordingly, this study aimed to characterise adaptive immune responses to antigenic stimuli in AS. We profiled the peripheral CD4 and CD8 T-cell receptor (TCR) repertoire of AS patients (n=47) and HLA-B*27 matched controls (n=38). We estimated repertoire diversity and employed univariate and multivariate statistical techniques to characterise AS-associated clonal signatures. We further investigated T-cell proliferation and cytokine production in response to immunogenic antigen exposure in vitro using AS patient (n=19) and control (n=14) peripheral blood mononuclear cells. AS patients showed increased TCR diversity (CD4 P=7.8x10 , CD8 P=9.3x10 ), attributed to a significant reduction in the magnitude of peripheral T-cell expansions globally, and fewer patient T-cells expressed IFNγ (CD8 P=0.03) and TNFα (CD4 P=0.01, CD8 P=0.002) upon in vitro stimulation. Additionally, the CD8 TCR signature was altered, with significantly expanded EBV (P=0.03) and CMV-specific (P=0.02) clonotypes and increased incidence of public CD8 TCRs in HLA-B*27+ AS relative to controls, including homologous clonotypes matching those previously isolated from individuals with bacterial-induced reactive arthritis (ReA). The dynamics of peripheral T-cell responses in AS patients are altered, suggesting that differential antigen exposure and disrupted adaptive immunity are underlying features of disease pathology.

Free to read Objective To use high-density genotyping to investigate the genetic associations of acute anterior uveitis (AAU) in patients with and those without ankylosing spondylitis (AS). Methods We genotyped samples from 1,711 patients with AAU (either primary or combined with AS), 2,339 AS patients without AAU, and 10,000 control subjects on an Illumina Immunochip Infinium microarray. We also used data for AS patients from previous genome-wide association studies to investigate the AS risk locus ANTXR2 for its putative effect in AAU. ANTXR2 expression in mouse eyes was investigated by real-time quantitative reverse transcription–polymerase chain reaction. Results A comparison between all patients with AAU and healthy control subjects showed strong association over HLA–B, corresponding to the HLA–B27 tag single-nucleotide polymorphism rs116488202. The association of 3 non–major histocompatibility complex loci, IL23R, the intergenic region 2p15, and ERAP1, reached genome-wide significance (P < 5 × 10−8). Five loci harboring the immune-related genes IL10–IL19, IL18R1–IL1R1, IL6R, the chromosome 1q32 locus harboring KIF21B, as well as the eye-related gene EYS, were also associated, reaching a suggestive level of significance (P < 5 × 10−6). Several previously confirmed AS associations demonstrated significant differences in effect size between AS patients with AAU and AS patients without AAU. ANTXR2 expression varied across eye compartments. Conclusion These findings of both novel AAU-specific associations and associations shared with AS demonstrate overlapping but also distinct genetic susceptibility loci for AAU and AS. The associations in IL10 and IL18R1 are shared with inflammatory bowel disease, suggesting common etiologic pathways.