Dataset Information

Effect of rituximab treatment on T and B cell subsets in lymph node biopsies of patients with rheumatoid arthritis.

ABSTRACT:

Objectives

The exact underlying mechanism of rituximab treatment in patients with RA is poorly defined and knowledge about the effect of B cell depletion on immune cells in secondary lymphoid organs is lacking. We analysed lymphoid tissue responses to rituximab in RA patients.

Methods

Fourteen RA patients received 2 × 1000 mg rituximab intravenously, and lymph node (LN) biopsies were obtained before and 4 weeks after the first infusion. Tissues were examined by flow cytometry, immunohistochemistry and quantitative PCR. LN biopsies from five healthy individuals (HC) served as controls.

Results

LN biopsies of RA patients showed increased frequencies of CD21+CD23+IgDhighIgMvariable follicular B cells and CD3+CD25+CD69+ early activated, tissue resident T cells when compared with HCs. After treatment, there was incomplete depletion of LN B cells. There was a significant decrease in CD27-IgD+ naïve B cells, and CD27+IgD+ unswitched memory B cells including the CD27+IgD+IgM+ subset and follicular B cells. Strikingly, CD27+IgD- switched memory B cells persisted in LN biopsies after rituximab treatment. In the T cell compartment, a significant decrease was observed in the frequency of early activated, tissue resident T cells after rituximab treatment, but late activated T cells persisted. B cell proliferation inducing cytokine IL-21 was higher expressed in LN biopsies of RA patients compared with HC and expression was not affected by rituximab treatment.

Conclusion

Rituximab does not cure RA, possibly due to persistence of switched memory B cells in lymphoid tissues suggesting that factors promoting B cell survival and differentiation need to be additionally targeted.

SUBMITTER: Ramwadhdoebe TH

PROVIDER: S-EPMC6532448 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Publications

Effect of rituximab treatment on T and B cell subsets in lymph node biopsies of patients with rheumatoid arthritis.

Ramwadhdoebe Tamara H TH van Baarsen Lisa G M LGM Boumans Maria J H MJH Bruijnen Stefan T G STG Safy Mary M Berger Ferco H FH Semmelink Johanna F JF van der Laken Conny J CJ Gerlag Danielle M DM Thurlings Rogier M RM Tak Paul P PP

Rheumatology (Oxford, England) 20190601 6

<h4>Objectives</h4>The exact underlying mechanism of rituximab treatment in patients with RA is poorly defined and knowledge about the effect of B cell depletion on immune cells in secondary lymphoid organs is lacking. We analysed lymphoid tissue responses to rituximab in RA patients.<h4>Methods</h4>Fourteen RA patients received 2 × 1000 mg rituximab intravenously, and lymph node (LN) biopsies were obtained before and 4 weeks after the first infusion. Tissues were examined by flow cytometry, imm ...[more]

PMID: 30649469

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Project description:Rheumatoid arthritis (RA) is a progressive, destructive autoimmune arthritis. Break of tolerance and formation of autoantibodies occur years before arthritis. Adaptive immunity is initiated in lymphoid tissue where lymph node stromal cells (LNSCs) play a crucial role in shaping the immune response and maintaining peripheral tolerance. Here we performed the first epigenomic characterization of LNSCs during health and early RA, by analyzing their transcriptome and DNA methylome in LNSCs isolated from lymph node needle biopsies obtained from healthy controls (HC), autoantibody positive RA-risk individuals and patients with established RA. Of interest, LNSCs from RA-risk individuals and RA patients revealed a common significantly differential expressed gene signature compared with HC LNSCs. Pathway analysis of this common signature showed, among others, significant enrichment of pathways affecting the extracellular matrix (ECM), cholesterol biosynthesis and immune system. In a gel contraction assay LNSCs from RA-risk individuals and RA patients showed impaired collagen contraction compared to healthy LNSCs. In RA LNSCs a significant enrichment was observed for genes involved in cytokine signaling, hemostasis and packaging of telomere ends. In contrast, in RA-risk LNSCs pathways in cancer (cell cycle related genes) were differentially expressed compared with HC, which could be validated in vitro using a proliferation assay, which indicated a slower proliferation rate. DNA methylation analyses revealed common and specific differentially methylated CpG sites (DMS) in LNSC from RA patients and RA-risk individuals compared with HC. Intriguingly, shared DMS were all associated with antigen processing and presentation. This data point toward alterations in cytoskeleton and antigen-processing and presentation in LNSC from RA-risk individuals and RA patients. Further studies are required to investigate the consequence of this LNSC abnormality on LNSC-mediated immunomodulation.

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Dataset Information

Effect of rituximab treatment on T and B cell subsets in lymph node biopsies of patients with rheumatoid arthritis.

Objectives

Methods

Results

Conclusion

Publications

Effect of rituximab treatment on T and B cell subsets in lymph node biopsies of patients with rheumatoid arthritis.

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