Co-expression of CD21L and IL17A defines a subset of rheumatoid synovia, characterised by large lymphoid aggregates and high inflammation

McKelvey, Kelly; Millier, Melanie J; Doyle, Terence; Stamp, Lisa K.; Highton, John; Hessian, Paul A.

doi:10.1371/journal.pone.0202135

Cited by 6 publications

(5 citation statements)

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“…and their presence and function have been associated with lymphoid pathology [ 31 , 40 – 42 ]. CD68 is a pan macrophage marker, which we used to identify macrophages and macrophage-like synoviocytes (MLS), while CD138 identifies plasma cells, also shown to associate with lymphoid pathology and auto-antibody production in RA [ 43 ]. To identify and characterise cell types expressing the Δ133p53β protein isoform, we performed triple immunofluorescence (IF) labelling to distinguish CD55 + lining fibroblasts, CD90 + fibroblasts, CD68 + macrophage subpopulations and CD138 + plasma cells.…”

Section: Resultsmentioning

confidence: 99%

“…Typically, the heightened immune cell infiltrate associated with synovial Δ133p53β expression includes B cells and is well organised, generally featuring prominent ELS that define a synovial follicular subtype. Previously, we have linked the co-expression of CD21L and IL17A to the number and size of B cell clusters in synovial tissue and high inflammation [ 43 ]. However, we find no links between CD21L or IL17A expression in synovial tissue and any of the TP53 isoforms.…”

Section: Discussionmentioning

confidence: 99%

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Activated CD90/Thy-1 fibroblasts co-express the Δ133p53β isoform and are associated with highly inflamed rheumatoid arthritis

et al. 2023

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Background The p53 isoform Δ133p53β is known to be associated with cancers driven by inflammation. Many of the features associated with the development of inflammation in rheumatoid arthritis (RA) parallel those evident in cancer progression. However, the role of this isoform in RA has not yet been explored. The aim of this study was to determine whether Δ133p53β is driving aggressive disease in RA. Methods Using RA patient synovia, we carried out RT-qPCR and RNAScope-ISH to determine both protein and mRNA levels of Δ133p53 and p53. We also used IHC to determine the location and type of cells with elevated levels of Δ133p53β. Plasma cytokines were also measured using a BioPlex cytokine panel and data analysed by the Milliplex Analyst software. Results Elevated levels of pro-inflammatory plasma cytokines were associated with synovia from RA patients displaying extensive tissue inflammation, increased immune cell infiltration and the highest levels of Δ133TP53 and TP53β mRNA. Located in perivascular regions of synovial sub-lining and surrounding ectopic lymphoid structures (ELS) were a subset of cells with high levels of CD90, a marker of ‘activated fibroblasts’ together with elevated levels of Δ133p53β. Conclusions Induction of Δ133p53β in CD90+ synovial fibroblasts leads to an increase in cytokine and chemokine expression and the recruitment of proinflammatory cells into the synovial joint, creating a persistently inflamed environment. Our results show that dysregulated expression of Δ133p53β could represent one of the early triggers in the immunopathogenesis of RA and actively perpetuates chronic synovial inflammation. Therefore, Δ133p53β could be used as a biomarker to identify RA patients more likely to develop aggressive disease who might benefit from targeted therapy to cytokines such as IL-6.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Activated CD90/Thy-1 fibroblasts co-express the Δ133p53β isoform and are associated with highly inflamed rheumatoid arthritis

et al. 2023

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“…The presence of IL-23 might “simply” reflect the outcome of a pathological process, as exemplified by the IL-1β-dependent induction of IL-23 p19 in fibroblast-like synoviocytes [ 34 ]. More likely, IL-23 is involved in multiple, independent but parallel processes as indicated by activation of the IL-23 pathway, which is strongly associated with synovial ectopic lymphoid neogenesis (ELN) in human RA, yet is seemingly independent of the IL-17A expression necessary for ELN development [ 6 , 35 ]. Conceivably, the situation might also reflect a temporal effect from IL-23, consistent with evidence suggesting the IL-23/Th17 cell-cytokine(s) axis may not have a constant influence throughout the disease course in RA [ 36 – 38 ].…”

Section: Discussionmentioning

confidence: 99%

“…Consequently, treatment and its efficacy are similarly heterogeneous and unpredictable [ 1 , 2 ]. Sub-types of RA inflammation may be distinguished by histologic features and signature expression profiles of synovial tissue — knowledge which may hold promise for guiding treatment options [ 2 – 6 ].…”

Section: Introductionmentioning

confidence: 99%

Plasma interleukin-23 and circulating IL-17A+IFNγ+ ex-Th17 cells predict opposing outcomes of anti-TNF therapy in rheumatoid arthritis

et al. 2022

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Objectives TNF-α inhibitors are widely used in rheumatoid arthritis (RA) with varying success. Response to TNF-α inhibition may reflect the evolution of rheumatoid inflammation through fluctuating stages of TNF-α dependence. Our aim was to assess plasma concentrations of Th-17-related cytokines and the presence of circulating effector T-cells to identify predictors of response to TNF-α inhibitors. Methods Ninety-three people with RA were seen prior to and 4–6 months after commencing etanercept or adalimumab. Plasma concentrations of Th17-related cytokines, circulating effector T-cells, their production of relevant transcription factors and intracellular cytokines were measured at baseline. EULAR response criteria were used to define poor (ΔDAS28 ≤ 1.2 and/or DAS28 > 3.2) and good (ΔDAS28 > 1.2 and DAS28 ≤ 3.2) responders. Multivariate logistic regression was used to identify predictors of response. Results Participants with plasma IL-23 present at baseline were more likely to be poor responders [15/20 (75%) of IL-23+ versus 36/73 (49.3%) of IL-23−; p = 0.041]. While frequencies of Th1, Th17, ex-Th17 and Treg cell populations were similar between good and poor responders to anti-TNF therapy, IL-17A+IFNγ+ ex-Th17 cells were more prevalent in good responders (0.83% of ex-TH17 cells) compared to poor responders (0.24% of ex-Th17 cells), p = 0.023. Both plasma IL-23 cytokine status (OR = 0.17 (95% CI 0.04–0.73)) and IL-17A+IFNγ+ ex-Th17 cell frequency (OR = 1.64 (95% CI 1.06 to 2.54)) were independently associated with a good response to anti-TNF therapy. Receiver operator characteristic (ROC) analysis, including both parameters, demonstrated an area under the ROC curve (AUC) of 0.70 (95% CI 0.60–0.82; p = 0.001). Conclusions Plasma IL-23 and circulating IL-17A+IFNγ+ ex-Th17 cells are independently associated with response to anti-TNF therapy. In combination, plasma IL-23 and circulating IL-17A+IFNγ+ ex-Th17 cells provide additive value to the prediction of response to anti-TNF therapy in RA.

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“…The mature B cells express the short CD21 (CD21S) lacking exon 10a, and follicular dendritic cells selectively express long isoforms of CD21 (CD21L) containing exon 10a [ 66 ]. In clinic, CD21S+ expression was proposed to be used as a prognostic factor for better survival of the patients of diffuse large B-cell lymphoma, and CD21L+ in rheumatoid synovia indicated high inflammation [ 67 , 68 ], while the regulatory mechanism for the splicing isoforms has not been reported.…”

Section: Abnormally Spliced Isoforms In Immune-associated Diseasesmentioning

confidence: 99%

Alternative Splicing of Pre-mRNA in the Control of Immune Activity

Huang

2021

Genes

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The human immune response is a complex process that responds to numerous exogenous antigens in preventing infection by microorganisms, as well as to endogenous components in the surveillance of tumors and autoimmune diseases, and a great number of molecules are necessary to carry the functional complexity of immune activity. Alternative splicing of pre-mRNA plays an important role in immune cell development and regulation of immune activity through yielding diverse transcriptional isoforms to supplement the function of limited genes associated with the immune reaction. In addition, multiple factors have been identified as being involved in the control of alternative splicing at the cis, trans, or co-transcriptional level, and the aberrant splicing of RNA leads to the abnormal modulation of immune activity in infections, immune diseases, and tumors. In this review, we summarize the recent discoveries on the generation of immune-associated alternative splice variants, clinical disorders, and possible regulatory mechanisms. We also discuss the immune responses to the neoantigens produced by alternative splicing, and finally, we issue some alternative splicing and immunity correlated questions based on our knowledge.

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Co-expression of CD21L and IL17A defines a subset of rheumatoid synovia, characterised by large lymphoid aggregates and high inflammation

Cited by 6 publications

References 47 publications

Activated CD90/Thy-1 fibroblasts co-express the Δ133p53β isoform and are associated with highly inflamed rheumatoid arthritis

Activated CD90/Thy-1 fibroblasts co-express the Δ133p53β isoform and are associated with highly inflamed rheumatoid arthritis

Plasma interleukin-23 and circulating IL-17A+IFNγ+ ex-Th17 cells predict opposing outcomes of anti-TNF therapy in rheumatoid arthritis

Alternative Splicing of Pre-mRNA in the Control of Immune Activity

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