Dataset Information

Cartilage destruction in early rheumatoid arthritis patients correlates with CD21^-/low double-negative B cells.

ABSTRACT:

Background

Involvement of B cells in the pathogenesis of rheumatoid arthritis (RA) is supported by the presence of disease-specific autoantibodies and the efficacy of treatment directed against B cells. B cells that express low levels of or lack the B cell receptor (BCR) co-receptor CD21, CD21^-/low B cells, have been linked to autoimmune diseases, including RA. In this study, we characterized the CD21⁺ and CD21^-/low B cell subsets in newly diagnosed, early RA (eRA) patients and investigated whether any of the B cell subsets were associated with autoantibody status, disease activity and/or joint destruction.

Methods

Seventy-six eRA patients and 28 age- and sex-matched healthy donors were recruited. Multiple clinical parameters were assessed, including disease activity and radiographic joint destruction. B cell subsets were analysed in peripheral blood (PB) and synovial fluid (SF) using flow cytometry.

Results

Compared to healthy donors, the eRA patients displayed an elevated frequency of naïve CD21⁺ B cells in PB. Amongst memory B cells, eRA patients had lower frequencies of the CD21⁺CD27⁺ subsets and CD21^-/low CD27⁺IgD⁺ subset. The only B cell subset found to associate with clinical factors was the CD21^-/low double-negative (DN, CD27^-IgD^-) cell population, linked with the joint space narrowing score, i.e. cartilage destruction. Moreover, in SF from patients with established RA, the CD21^-/low DN B cells were expanded and these cells expressed receptor activator of the nuclear factor κB ligand (RANKL).

Conclusions

Cartilage destruction in eRA patients was associated with an expanded proportion of CD21^-/low DN B cells in PB. The subset was also expanded in SF from established RA patients and expressed RANKL. Taken together, our results suggest a role for CD21^-/low DN in RA pathogenesis.

SUBMITTER: Thorarinsdottir K

PROVIDER: S-EPMC10789032 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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Publications

Cartilage destruction in early rheumatoid arthritis patients correlates with CD21<sup>-/low</sup> double-negative B cells.

Thorarinsdottir Katrin K McGrath Sarah S Forslind Kristina K Agelii Monica Leu ML Ekwall Anna-Karin Hultgård AH Jacobsson Lennart T H LTH Rudin Anna A Mårtensson Inga-Lill IL Gjertsson Inger I

Arthritis research & therapy 20240115 1

<h4>Background</h4>Involvement of B cells in the pathogenesis of rheumatoid arthritis (RA) is supported by the presence of disease-specific autoantibodies and the efficacy of treatment directed against B cells. B cells that express low levels of or lack the B cell receptor (BCR) co-receptor CD21, CD21<sup>-/low</sup> B cells, have been linked to autoimmune diseases, including RA. In this study, we characterized the CD21<sup>+</sup> and CD21<sup>-/low</sup> B cell subsets in newly diagnosed, earl ...[more]

PMID: 38225658

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Project description:BackgroundRheumatoid arthritis (RA) is a chronic, inflammatory and systemic autoimmune disease that leads to progressive cartilage destruction. Advances in the treatment of RA-related destruction of cartilage require profound insights into the molecular mechanisms involved in cartilage degradation. Until now, comprehensive data about the molecular RA-related dysfunction of chondrocytes have been limited. Hence, the objective of this study was to establish a standardized in vitro model to profile the key regulatory molecules of RA-related destruction of cartilage that are expressed by human chondrocytes.MethodsHuman chondrocytes were cultured three-dimensionally for 14 days in alginate beads and subsequently stimulated for 48 hours with supernatants from SV40 T-antigen immortalized human synovial fibroblasts (SF) derived from a normal donor (NDSF) and from a patient with RA (RASF), respectively. To identify RA-related factors released from SF, supernatants of RASF and NDSF were analyzed with antibody-based protein membrane arrays. Stimulated cartilage-like cultures were used for subsequent gene expression profiling with oligonucleotide microarrays. Affymetrix GeneChip Operating Software and Robust Multi-array Analysis (RMA) were used to identify differentially expressed genes. Expression of selected genes was verified by real-time RT-PCR.ResultsAntibody-based protein membrane arrays of synovial fibroblast supernatants identified RA-related soluble mediators (IL-6, CCL2, CXCL1-3, CXCL8) released from RASF. Genome-wide microarray analysis of RASF-stimulated chondrocytes disclosed a distinct expression profile related to cartilage destruction involving marker genes of inflammation (adenosine A2A receptor, cyclooxygenase-2), the NF-kappaB signaling pathway (toll-like receptor 2, spermine synthase, receptor-interacting serine-threonine kinase 2), cytokines/chemokines and receptors (CXCL1-3, CXCL8, CCL20, CXCR4, IL-1beta, IL-6), cartilage degradation (matrix metalloproteinase (MMP)-10, MMP-12) and suppressed matrix synthesis (cartilage oligomeric matrix protein, chondroitin sulfate proteoglycan 2).ConclusionDifferential transcriptome profiling of stimulated human chondrocytes revealed a disturbed catabolic-anabolic homeostasis of chondrocyte function and disclosed relevant pharmacological target genes of cartilage destruction. This study provides comprehensive insight into molecular regulatory processes induced in human chondrocytes during RA-related destruction of cartilage. The established model may serve as a human in vitro disease model of RA-related destruction of cartilage and may help to elucidate the molecular effects of anti-rheumatic drugs on human chondrocyte gene expression.

Project description:We investigated the expression and localization of the receptor activator nuclear factor κB ligand (RANKL) in cartilage from patients with rheumatoid arthritis (RA) of relevance to cartilage degeneration. We also examined the role of exogenous lymphotoxin (LT)-α on RANKL expression in human chondrocytes and its effect on in vitro osteoclast differentiation. Cartilage and synovial fluid samples were obtained from 45 patients undergoing total joint replacement surgery or joint puncture, including 24 patients with osteoarthritis (OA) and 21 patients with RA. RANKL expression in articular cartilage was examined by immunohistochemistry. LT-α concentrations in synovial fluid were measured using an enzyme-linked immunosorbent assay (ELISA). Normal human chondrocytes were stimulated with LT-α, and the relative mRNA levels of RANKL, osteoprotegerin (OPG), matrix metalloproteinase-9, and vascular endothelial growth factor were examined by real-time polymerase chain reaction. Soluble RANKL protein in culture media was measured using ELISA, and membrane-bound RANKL protein in cells was examined by western blotting. Co-cultures of human chondrocytes with peripheral blood mononuclear cells (PBMCs) were stimulated with macrophage-colony stimulating factor and LT-α, and osteoclast differentiation was evaluated by staining for tartrate-resistant acid phosphatase. LT-α concentrations were higher in RA synovial fluid than in OA samples. The population of RANKL-positive chondrocytes of RA cartilage was higher than that of OA cartilage, and correlated with cartilage degeneration. Stimulation of cultured human chondrocytes by LT-α increased RANKL expression, the RANKL/OPG ratio, and angiogenic factors. Membrane-bound RANKL in chondrocytes was up-regulated after stimulation of LT-α, whereas soluble RANKL in culture medium did not increase. Co-cultures of human chondrocytes and PBMCs demonstrated that LT-α stimulated human chondrocytes to produce RANKL and induced osteoclastic differentiation of PBMCs. RANKL produced by chondrocytes may contribute to cartilage destruction during RA and LT-α could promote the expression of RANKL in human chondrocytes.

Dataset Information

Cartilage destruction in early rheumatoid arthritis patients correlates with CD21^-/low double-negative B cells.

Background

Methods

Results

Conclusions

Publications

Cartilage destruction in early rheumatoid arthritis patients correlates with CD21<sup>-/low</sup> double-negative B cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Cartilage destruction in early rheumatoid arthritis patients correlates with CD21-/low double-negative B cells.

Background

Methods

Results

Conclusions

Publications

Cartilage destruction in early rheumatoid arthritis patients correlates with CD21<sup>-/low</sup> double-negative B cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Cartilage destruction in early rheumatoid arthritis patients correlates with CD21^-/low double-negative B cells.