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Ankylosing spondylitis patients present a distinct CD8 T-cell subset with osteogenic and cytotoxic potential

ABSTRACT: Ankylosing Spondylitis (AS) is a chronic inflammatory rheumatic disease affecting mainly the axial skeleton. Peripheral involvement (arthritis, enthesitis and dactylitis) and extra-musculoskeletal manifestations including uveitis, psoriasis and bowel inflammation occur in a relevant proportion of patients. AS is responsible for chronic and severe back pain caused by local inflammation that can lead to osteoproliferation and ultimately spinal fusion. The association of AS with the Human Leukocyte Antigen (HLA)‑B27 gene, together with elevated levels of chemokines CCL17 and CCL22 in the sera of patients with AS, lead us to study the role of CCR4+ T-cells in the disease pathogenesis. Here we show that, CD8+ CCR4+ T-cells display a distinct effector phenotype and upregulate the inflammatory chemokine receptors CCR1, CCR5, CX3CR1 and the L‑selectin CD62L, indicating an altered migration ability. Functionally, CD8+CCR4+T‑cells expressing CX3CR1 present an enhanced cytotoxic profile, expressing both perforin and granzymeB. Of note, these cells, isolated from patients in the active state of the disease, upregulate genes promoting the ossification process. Our results shed light to a new molecular mechanism by which T-cells may promote new bone formation and contribute to the pathological ossification process observed in AS.

ORGANISM(S): Homo sapiens

PROVIDER: GSE243689 | GEO | 2024/02/13

REPOSITORIES: GEO

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Project description:We have compared synovial biopsies from ankylosing spondylitis and undifferentiated spondylitis patients with healthy controls and osteoarthritis patients Objective: In spondylarthropies, whole-genome gene expression profiling studies have been limited to peripheral blood to date. By undertaking a study in knee synovial biopsies from spondylarthropy (SpA) and ankylosing spondylitis (AS) patients we aimed to identified joint-specific candidate genes and pathways. These pathways may mediate systemic inflammation driven joint damaging processes and more specifically, the osteoproliferation that is characteristic of these conditions. Methods: RNA was extracted from six seronegative SpA, two AS, three osteoarthritis (OA) and four normal control knee synovial biopsies. Whole genome expression profiling was undertaken using the Illumina DASL system, which assays 24000 cDNA probes. Differentially expressed candidate genes were then validated using quantitative PCR and immunohistochemistry. Results: 416 differentially expressed genes were identified that clearly delineated between AS/SpA and control groups. Pathway analysis showed altered gene-expression in oxidoreductase activity, osteoblast activity, B-cell associated, matrix catabolic, and metabolic pathways. The inflammatory mediator, MMP3, was strongly upregulated in AS/SpA samples and the Wnt pathway inhibitors DKK3 and Kremen1 were downregulated. Conclusion: Pathways mediating both systemic inflammation as well as local tissue changes were identified. This suggests initial systemic inflammation in spondylarthropies transfers to and persists in the local joint environment, subsequently mediating changes in genes directly involved in the destructive tissue remodelling. Fifteen knee synovial biopsy tissue samples consisting of six seronegative spondyloarthropy (SpA), two ankylosing spondylitis (AS), three osteoarthritis (OA) and four normal control biopsies were obtained from the Synovial Tissue Bank at the Repatriation General Hospital in Adelaide, South Australia with the appropriate ethical approval (Supplementary Table 1). All patients provided informed written consent.

Project description:The hallmark of IgA nephropathy (IgAN) is gross hematuria (GH) coinciding with or immediately following an upper respiratory or gastrointestinal tract infection and can represent the disease triggering event. Therefore, a whole genomic screening of IgAN patients during the GH was done to clarify the link between mucosal encountered antigens and the occurrence of glomerular hematuria. The modulated genes during GH show a clear involvement of the interferon signalling, antigen presenting pathway, and the immuno-proteasome. The gene characterizing cytotoxic effector lymphocytes (CX3CR1) implicated in vascular endothelial damage, was found up-regulated at both mRNA and protein level. In vitro antigenic stimulation of PBMCs on an independent set of IgAN patients and healthy blood donors (HBS) demonstrated that patients upregulate specifically CX3CR1 in an enhanced and dose dependant manner, while an expected down-regulation occurred in HBD. This enhanced activation occurred in both patients characterized by recurrent GH and by permanent microscopic hematuria (MH). We then analyzed glomerular fractalkine (FKN) expression, since this ligand is involved in the vascular gateway for CX3CR1+ cells towards the inflamed tissues. A significantly higher FKN expression on the capillary vessels and podocytes was found in recurrent GH patients compared to permanent MH, suggesting a predisposition for cytotoxic cell extravasation in recurrent GH patients. Taken together, our findings demonstrate, for the first time, a defect in antigen handling in PBMCs of IgAN patients with a specific up-regulation of CX3CR1. Furthermore, the constitutive up regulation of glomerular FKN, suggests an involvement of the CX3CR1-FKN axis in the exacerbation of GH. Gene expression profile comparison 3 IgAN patients at two different clinical time points, the first sample during the gross hematuria episode and the second during the remission phase of the disease characterized by microscopic hematuria

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Ankylosing spondylitis patients present a distinct CD8 T-cell subset with osteogenic and cytotoxic potential

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