The expansion of activated naive DNA autoreactive B cells and its association with disease activity in systemic lupus erythematosus patients

Wangriatisak, Kittikorn; Thanadetsuntorn, Chokchai; Krittayapoositpot, Thamonwan; Leepiyasakulchai, Chaniya; Suangtamai, Thanitta; Ngamjanyaporn, Pintip; Khowawisetsut, Ladawan; Khaenam, Prasong; Setthaudom, Chavachol; Pisitkun, Prapaporn; Chootong, Patchanee

doi:10.1186/s13075-021-02557-0

Cited by 17 publications

(20 citation statements)

References 34 publications

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“…Previous reports showed that dysregulation of cTfh cells could help naïve B cells differentiate into plasmablasts to produce autoantibodies and was related to the development of SLE (10,29,30). Additionally, the frequencies of PD1 + ICOS + Tfh cells, B cells and plasmablasts were significantly increased in both thymus and spleen of MRL/ lpr mice, respectively, which were accorded with previous reports (27,28). These findings imply the relationship of these Tfh cells and the disease activity of SLE to some extent, and that Tfh cells and their subsets play important roles in the development of SLE.…”

Section: Discussionsupporting

confidence: 90%

“…Moreover, our results showed that the frequencies of plasmablasts were closely correlated with the frequencies of cTfh cells, ICOS + PD-1 + cTfh cells in CD4 + T cells, anti-ANA titers and SLEDAI scores in SLE patients (20,22). An increased plasmablast population can produce autoantibodies, including anti-ANA antibodies, and correlates with disease activity, which plays critical roles in the pathogenesis of SLE (27,28). Previous reports showed that dysregulation of cTfh cells could help naïve B cells differentiate into plasmablasts to produce autoantibodies and was related to the development of SLE (10,29,30).…”

Section: Discussionmentioning

confidence: 99%

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Aberrant expansion of follicular helper T cell subsets in patients with systemic lupus erythematosus

Jin

Chen²,

Wu³

et al. 2022

Front. Immunol.

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ObjectiveSystemic lupus erythematosus (SLE) is a chronic and complex autoimmune disease characterized by multiple autoantibodies, resulting in multiple organ and tissue damages. These pathogenic autoantibodies produced by B cells are closely correlated with follicular helper T (Tfh) cell subsets that play a fundamental role in the pathogenesis of SLE. The aim of the present study was to study the phenotype and role of circulating Tfh (cTfh) cell subsets and associated B cell subpopulations in active and inactive SLE patients.MethodsThirty SLE outpatients and 24 healthy controls (HCs) were enrolled in this study. The frequency of cTfh cell and B cell subsets in peripheral blood mononuclear cells (PBMCs) and the plasma levels of eight cytokines were determined by flow cytometry, and plasma IL-21 levels were measured by ELISA. Meanwhile, we used MRL/lpr mice as the model of SLE to research the alterations of Tfh cells in the thymus and spleen of mice.ResultsFrequencies of CD4+CXCR5+CD45RA-effector cTfh cells, PD1+cTfh, PD1+ICOS+cTfh, PD1+cTfh1, PD1+cTfh2, PD1+cTfh17, and PD1+ICOS+cTfh1 cells as well as plasmablasts showed significant differences among HC, active and inactive SLE patients. Moreover, cytokines typically associated with cTfh cells, including IL-6 and IL-21, were elevated in active SLE patients compared to inactive SLE patients and HCs. Additionally, a positive correlation was observed between PD1+ICOS+ cTfh or PD1+ICOS+ cTfh1 cell frequencies and plasmablasts or IL-21 levels, as well as between plasmablasts. We also found PD1+ICOS+ Tfh cells expansion in both thymus and spleen of MRL/lpr mice, accompanied by increased frequencies in B cells and plasmablasts, meanwhile, cTfh1which expressing IFN-γ was increased in the peripheral blood of MRL/lpr mice.ConclusionTfh cell subsets and plasmablasts may play a fundamental role in the pathogenesis of SLE and may provide potential targets for therapeutic interventions for SLE.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Aberrant expansion of follicular helper T cell subsets in patients with systemic lupus erythematosus

Jin

Chen²,

Wu³

et al. 2022

Front. Immunol.

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“…The phenotype shared by aNAV B and DN2 B cells (pre-ASCs) might be involved in autoantibody secretion. 18 20 Here, the upregulation of B-cell coreceptors (CD19, CD20 and FCRL5) on these cells and their increased expression involving B cell activation via BCR stimulatory signals was assessed. FCRL5 was significantly overexpressed on aNAV B cells from lupus patients versus HCs, whereas no significant difference was found with CD19 nor CD20 ( figure 2A ).…”

Section: Resultsmentioning

confidence: 99%

“…The total IgG and anti-DNA autoantibody levels were determined by ELISA as previously reported. 18 Briefly, 1 µg/mL anti-human IgG (Mabtech, Nacka, Stockholm, Sweden) or 10 µg/mL calf thymic DNA was coated on 96-well plates and blocked with phosphate buffered saline with 10% fetal bovine serum (10% FBS–PBS). Undiluted supernatants were added to wells followed by goat anti-human IgG conjugated to horseradish peroxidase (KPL, Milford, Massachusetts, USA).…”

Section: Methodsmentioning

confidence: 99%

CD4⁺T-cell cooperation promoted pathogenic function of activated naïve B cells of patients with SLE

et al. 2022

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ObjectiveTo explore cooperation between activated naïve (aNAV) B cells and CD4+ T cells in the pathogenesis of SLE through autoantibody production, T-cell differentiation and inflammatory cytokine secretion.MethodsPeripheral blood mononuclear cell samples were obtained from 31 patients with SLE and used to characterise phenotype of aNAV B cells (n=14) and measured the phosphorylation of B-cell receptor (BCR) signalling molecules (n=5). Upregulation of T-cell costimulatory molecules after BCR and toll-like receptor (TLR)-7/TLR-8 stimulation was detected in cells from four subjects. To explore the role of these cells in SLE pathogenesis via T cell-dependent mechanisms, four subjects were analysed to detect the promotion of CD4+ T-cell activation and antibody-secreting cell (ASC) differentiation after CD4+ T-cell–B-cell cocultures. The aNAV B cells from four patients were used to assess cytokine secretion.ResultsThe aNAV B cells of patients with SLE had increased expression of surface CD40, HLA-DR and interleukin-21 receptor (IL-21R) and FCRL5 molecules. With BCR stimulation, these cells greatly increased PLCγ2 phosphorylation. Integrated BCR and TLR-7/TLR-8 signals induced overexpression of CD40, CD86, IL-21R and HLA-DR on lupus aNAV B cells. In T-cell–B-cell cocultures, lupus aNAV B cells (with upregulated costimulatory molecules) promoted CD4+ T-cell proliferation and polarisation toward effector Th2 and Th17 cells. Importantly, in this coculture system, CD4+ T-cell signals enhanced aNAV B-cell differentiation into auto-ASCs and produced anti-DNA antibodies. The interaction between CD4+ T cell and aNAV B cell increased production of inflammatory cytokines (IL-6, IL-8 and IL-23).ConclusionCooperation between aNAV B cells and CD4+ T cells contributed to SLE pathogenesis by promoting both differentiation of pathogenic T cells (Th2 and Th17) and autoantibody secretion.

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“…In a study conducted in a cohort of Asian patients with SLE, an expansion of aNAV and DN2 B cells was associated with disease activity ( 42 ). The similarity of their clinical associations in a population of patients with Asian ancestry, which also represents the third population in prevalence affected by SLE in the world, suggests a role of B cell extrafollicular differentiation pathway and a possible role in the pathophysiology of SLE, previously described in African-American patients, evidenced in Asian patients and confirmed in this study in Latin American patients.…”

Section: Discussionmentioning

confidence: 99%

Altered B cell phenotype and CD27+ memory B cells are associated with clinical features and environmental exposure in Colombian systemic lupus erythematosus patients

et al. 2022

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BackgroundB lymphocytes are dysregulated in Systemic Lupus Erythematosus (SLE) including the expansion of extrafollicular B cells in patients with SLE of African American ancestry, which is associated with disease activity and nephritis. The population of Colombia has a mixture of European, Native American, and African ancestry. It is not known if Colombian patients have the same B cell distributions described previously and if they are associated with disease activity, clinical manifestations, and environmental exposures.ObjectiveTo characterize B cell phenotype in a group of Colombian Systemic Lupus Erythematosus patients with mixed ancestry and determine possible associations with disease activity, clinical manifestations, the DNA methylation status of the IFI44L gene and environmental exposures.Materials and methodsForty SLE patients and 17 healthy controls were recruited. Cryopreserved peripheral B lymphocytes were analyzed by multiparameter flow cytometry, and the DNA methylation status of the gene IFI44L was evaluated in resting Naive B cells (rNAV).ResultsExtrafollicular active Naive (aNAV) and Double Negative type 2, DN2 (CD27− IgD− CD21− CD11c+) B cells were expanded in severe active patients and were associated with nephritis. Patients had hypomethylation of the IFI44L gene in rNAV cells. Regarding environmental exposure, patients occupationally exposed to organic solvents had increased memory CD27+ cells (SWM).ConclusionaNAV and DN2 extrafollicular cells showed significant clinical associations in Colombian SLE patients, suggesting a relevant role in the disease’s pathophysiology. Hypomethylation of the IFI44L gene in resting Naive B cells suggests that epigenetic changes are established at exceedingly early stages of B cell ontogeny. Also, an alteration in SWM memory cells was observed for the first time in patients exposed to organic solvents. This opens different clinical and basic research possibilities to corroborate these findings and deepen the knowledge of the relationship between environmental exposure and SLE.

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The expansion of activated naive DNA autoreactive B cells and its association with disease activity in systemic lupus erythematosus patients

Cited by 17 publications

References 34 publications

Aberrant expansion of follicular helper T cell subsets in patients with systemic lupus erythematosus

Aberrant expansion of follicular helper T cell subsets in patients with systemic lupus erythematosus

CD4⁺T-cell cooperation promoted pathogenic function of activated naïve B cells of patients with SLE

Altered B cell phenotype and CD27+ memory B cells are associated with clinical features and environmental exposure in Colombian systemic lupus erythematosus patients

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The expansion of activated naive DNA autoreactive B cells and its association with disease activity in systemic lupus erythematosus patients

Cited by 17 publications

References 34 publications

Aberrant expansion of follicular helper T cell subsets in patients with systemic lupus erythematosus

Aberrant expansion of follicular helper T cell subsets in patients with systemic lupus erythematosus

CD4+T-cell cooperation promoted pathogenic function of activated naïve B cells of patients with SLE

Altered B cell phenotype and CD27+ memory B cells are associated with clinical features and environmental exposure in Colombian systemic lupus erythematosus patients

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CD4⁺T-cell cooperation promoted pathogenic function of activated naïve B cells of patients with SLE