Switched Memory B Cells Are Increased in Oligoarticular and Polyarticular Juvenile Idiopathic Arthritis and Their Change Over Time Is Related to Response to Tumor Necrosis Factor Inhibitors

Marasco, Emiliano; Aquilani, Angela; Cascioli, Simona; Moneta, Gian Marco; Caiello, Ivan; Farroni, Chiara; Giorda, Ezio; D’Oria, Valentina; Marafon, Denise Pires; Magni‐Manzoni, Silvia; Carsetti, Rita; Benedetti, Fabrizio

doi:10.1002/art.40410

Cited by 27 publications

(22 citation statements)

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“…Although age-related and disease course associated changes in memory B cells have been reported ( 29 , 30 ) we did not observe a correlation between memory or naïve B cell population and age or disease duration ( Supplementary Figure S2 ). We observed a relatively higher estimated memory B cell fraction in JIA cases with late-onset uveitis, but this difference was not statistically significant ( P = 0.08) ( Supplementary Figure S3 ).…”

Section: Resultscontrasting

confidence: 59%

“…Some cases in this study used methotrexate. Although previous studies have shown that IgG-positive memory B cell frequency is increased in JIA patients treated with methotrexate, the absolute numbers of memory B cells are not affected (38), nor did methotrexate halt the progressive increase of memory B cells in early onset JIA (29). Also here, we would like to emphasize that conclusive data on changes in the composition of B cell subsets warrants further in-depth cytometry analysis ideally at different time points in cohorts of JIA cases with significant ophthalmological follow-up.…”

Section: Discussionmentioning

confidence: 71%

“…In contrast, expansion of switched memory B cells has been linked to early onset of JIA presenting before age 6 years, which persisted throughout the disease course in these cases (29). The early onset of JIA is also a risk factor for uveitis, which would make it tempting to speculate that the early onset associated expansion of memory B cells is linked to uveitis development.…”

Section: Discussionmentioning

confidence: 95%

“…Using this strategy, we identified a previously underappreciated heterogeneity among cases with uveitis that is characterized by increased proportion of memory B cells, most likely switched memory B cell populations. This is of interest, because in young patients with early onset oligoarticular JIA (a risk factor for uveitis) switched memory (CD27+ IgM-IgD-) B cells are expanded in blood and associated with the production of anti-nuclear antibodies (ANAs) (29). B-cell memory subsets that express relatively lower CCR7 are also increased in synovial fluid from oligoarticular JIA patients, suggesting that these cells also play a role in arthritis (34).…”

Section: Discussionmentioning

confidence: 99%

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Whole Transcriptome Analysis Reveals Heterogeneity in B Cell Memory Populations in Patients With Juvenile Idiopathic Arthritis-Associated Uveitis

et al. 2020

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Purpose: Patients with juvenile idiopathic arthritis (JIA) are prone to developing chronic anterior uveitis (JIA-U+). Although several risk factors for JIA-U+ have been identified, the underlying etiology is poorly understood. Histopathological studies demonstrate B cell infiltrates in eye tissues of patients with JIA-U+. Methods: We performed transcriptome profiling of peripheral blood CD19-positive B cells taken from 14 cases with JIA-U+, 13 JIA cases without uveitis (JIA-U−), and five healthy controls. Deconvolution-based estimation was used to determine the immune cell fractions for each sample. Results: Deconvolution results revealed that naive B cells made up on average 71% of the CD19-positive cell fractions analyzed. Differential expression analysis identified 614 differentially expressed genes (DEGs) between the groups at nominal significance and six genes at a false discovery rate of 5% (FDR < 0.05). Head-to-head comparison of all JIA-U− versus JIA-U+ revealed no DEGs in the CD19+ B cell pool (FDR < 0.05). However, principal component analysis based on a panel of key genes for B cell subsets revealed that JIA-U+ cases bifurcate into distinct clusters, characterized by markedly disparate expression for genes associated with specific memory B cell populations. CIBERSORT analysis of the overall transcriptome of the new uveitis cluster identified an increased proportion of memory B cells. Conclusion: These data show that JIA-U− and JIA-U+ have a globally similar transcriptome considering the global peripheral CD19-positive B cell pool. However, heterogeneity in B cell memory genes among cases with uveitis suggests a role for specific memory B cell subsets in the etiology of JIA-U+.

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Section: Resultscontrasting

confidence: 59%

Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

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Whole Transcriptome Analysis Reveals Heterogeneity in B Cell Memory Populations in Patients With Juvenile Idiopathic Arthritis-Associated Uveitis

et al. 2020

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“…Recent studies have suggested that B cells may have a role in these disorders. For example, B cell-related genes were up-regulated in JIA patients [ 4 ], and memory B cells were increased in oligoarticular and polyarticular JIA patients [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Frequency of CD19+CD24hiCD38hi regulatory B cells is decreased in peripheral blood and synovial fluid of patients with juvenile idiopathic arthritis: a preliminary study

Zhao

Jung

2018

Pediatr Rheumatol

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BackgroundTo understand the relationship between regulatory B cells (Bregs) and juvenile idiopathic arthritis (JIA), we analyzed the percentages of Bregs and their function in peripheral blood (PB) and synovial fluid (SF) of JIA patients.MethodsTwenty-one JIA patients and 11 children with growing pain but without known rheumatic diseases as controls were included. The B cell phenotype and intracellular production of IL-10 of Bregs were assessed by flow cytometry. Mononuclear cells from PB and SF were stimulated to produce IL-10 in vitro for the identification of IL-10- producing regulatory B cells.ResultsThe percentage of CD24hiCD38hi Bregs in the PB of JIA patients was significantly decreased compared to that in controls, and it was even lower in the SF of JIA patients compared to that in the PB. CD24hiCD38hi Bregs frequency was significantly lower in the PB of RF-positive patients than in RF-negative patients. Frequency of IL-10-producing regulatory B cells (B10 cells) was significantly lower in active JIA patients than that in inactive patients.ConclusionsThe inability of the host to produce enough regulatory B cells in PB and especially in SF of JIA patients may contribute to the disease, especially the local inflammation.

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Effect of Clonally Expanded PD‐1^highCXCR5–CD4+ Peripheral T Helper Cells on B Cell Differentiation in the Joints of Patients With Antinuclear Antibody–Positive Juvenile Idiopathic Arthritis

Fischer

Dirks

Klaussner

et al. 2021

Arthritis & Rheumatology

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Objective. Antinuclear antibody (ANA)-positive juvenile idiopathic arthritis (JIA) is characterized by synovial B cell hyperactivity, but the precise role of CD4+ T cells in promoting local B cell activation is unknown. This study was undertaken to determine the phenotype and function of synovial CD4+ T cells that promote aberrant B cell activation in JIA.Methods. Flow cytometry was performed to compare the phenotype and cytokine patterns of PD-1 high CD4+ T cells in the synovial fluid (SF) of patients with JIA and T follicular helper cells in the tonsils of control individuals. TCRVB next-generation sequencing was used to analyze T cell subsets for signs of clonal expansion. The functional impact of these T cell subsets on B cells was examined in cocultures in vitro.Results. Multidimensional flow cytometry revealed the expansion of interleukin-21 (IL-21) and interferon-γ (IFNγ)coexpressing PD-1 high CXCR5-HLA-DR+CD4+ T cells that accumulate in the joints of ANA-positive JIA patients. These T cells exhibited signs of clonal expansion with restricted T cell receptor clonotypes. The phenotype resembled peripheral T helper (Tph) cells with an extrafollicular chemokine receptor pattern and high T-bet and B lymphocyteinduced maturation protein 1 expression, but low B cell lymphoma 6 expression. SF Tph cells, by provision of IL-21 and IFNy, skewed B cell differentiation toward a CD21 low/-CD11c+ phenotype in vitro. Additionally, SF Tph cell frequencies correlated with the appearance of SF CD21 low/-CD11c+CD27-IgM-double-negative (DN) B cells in situ.Conclusion. Clonally expanded CD4+ Tph cells accumulate in the joints of ANA-positive JIA patients and, in particular, promote CD21 low/-CD11c+ DN B cell differentiation. The expansion of Tph cells and DN B cells might reflect the autoimmune response in the joints of ANA-positive JIA patients.

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Switched Memory B Cells Are Increased in Oligoarticular and Polyarticular Juvenile Idiopathic Arthritis and Their Change Over Time Is Related to Response to Tumor Necrosis Factor Inhibitors

Cited by 27 publications

References 27 publications

Whole Transcriptome Analysis Reveals Heterogeneity in B Cell Memory Populations in Patients With Juvenile Idiopathic Arthritis-Associated Uveitis

Whole Transcriptome Analysis Reveals Heterogeneity in B Cell Memory Populations in Patients With Juvenile Idiopathic Arthritis-Associated Uveitis

Frequency of CD19+CD24hiCD38hi regulatory B cells is decreased in peripheral blood and synovial fluid of patients with juvenile idiopathic arthritis: a preliminary study

Effect of Clonally Expanded PD‐1^highCXCR5–CD4+ Peripheral T Helper Cells on B Cell Differentiation in the Joints of Patients With Antinuclear Antibody–Positive Juvenile Idiopathic Arthritis

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Switched Memory B Cells Are Increased in Oligoarticular and Polyarticular Juvenile Idiopathic Arthritis and Their Change Over Time Is Related to Response to Tumor Necrosis Factor Inhibitors

Cited by 27 publications

References 27 publications

Whole Transcriptome Analysis Reveals Heterogeneity in B Cell Memory Populations in Patients With Juvenile Idiopathic Arthritis-Associated Uveitis

Whole Transcriptome Analysis Reveals Heterogeneity in B Cell Memory Populations in Patients With Juvenile Idiopathic Arthritis-Associated Uveitis

Frequency of CD19+CD24hiCD38hi regulatory B cells is decreased in peripheral blood and synovial fluid of patients with juvenile idiopathic arthritis: a preliminary study

Effect of Clonally Expanded PD‐1highCXCR5–CD4+ Peripheral T Helper Cells on B Cell Differentiation in the Joints of Patients With Antinuclear Antibody–Positive Juvenile Idiopathic Arthritis

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Effect of Clonally Expanded PD‐1^highCXCR5–CD4+ Peripheral T Helper Cells on B Cell Differentiation in the Joints of Patients With Antinuclear Antibody–Positive Juvenile Idiopathic Arthritis