A close-up on the expanding landscape of CD21–/low B cells in humans

Gjertsson, Inger; McGrath, Sarah; Grimstad, Kristoffer; Jonsson, Charlotte; Camponeschi, Alessandro; Thorarinsdottir, Katrin; Mårtensson, Inga‐Lill

doi:10.1093/cei/uxac103

Cited by 28 publications

(14 citation statements)

References 97 publications

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“…We then carried out detailed profiling of PBMCs using two different well-established gating/classification strategies that allow to distinguish B cell populations based on IgD and CD27 and CD24 and CD38 expression [ 16 , 27 ]. This strategy enabled us to identify the following populations within the CD19 + B cell compartment: IgD + CD27 - naïve, IgD - CD27 + class-switched and IgD + CD27 + unswitched memory, IgD - CD27 - DN cells, CD24 hi CD38 hi transitional, CD24 int CD38 int mature, CD24 hi CD38 lo total memory, CD24 lo CD38 lo activated B cells, and CD24 int CD38 hi pre-plasmablasts.…”

Section: Resultsmentioning

confidence: 99%

Distinct B cell profiles characterise healthy weight and obesity pre- and post-bariatric surgery

et al. 2023

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Background/Objectives Obesity-associated metabolic dysfunction and inflammation can be ameliorated by bariatric surgery. While obesity is also linked to impaired B cell activation, differentiation, and persistence in response to infection and vaccination little is known about post-operative immune B cell compartment and to what extent dysregulation in B cell pathways can be reversed. To bridge this gap in knowledge, we carried out in-depth evaluation of B cell composition in individuals with obesity prior to and following bariatric surgery compared to lean controls. Subjects/Methods We recruited individuals with obesity (BMI at least 35 kg/m2) before bariatric surgery (n = 21) and followed them up 6 months post-operatively (n = 17). As controls we recruited age- and sex-matched lean (BMI < 25) individuals (n = 18). We carried out comprehensive immunophenotyping of peripheral blood B cells as well as interrogated their association with inflammatory and metabolic parameters. Results In obesity the balance of antigen-inexperienced and memory B cells in the peripheral blood is altered, with an expansion of naïve and a reduction in total memory B cells. 6 months following bariatric surgery this balance is restored. However, post-operative patients are uniquely characterised by an increase in B cell subsets associated with chronic inflammation – CD11c+CXCR5-IgD-CD27- double negative 2 (DN2) B cells and CD27+CD38++ plasmablasts. Correlations between B cells subsets, inflammatory and metabolic parameters were distinct in lean people and individuals with obesity pre- and post-bariatric surgery. Conclusions Bariatric surgery patients display a unique B cell profile 6 months post-operatively; this bears minimal resemblance to that of pre-operative patients and only partially overlaps with that of lean controls. Post-operative differences in the B cell compartment compared to lean controls are detected despite global amelioration of inflammation and restoration of metabolic health. Collectively, this indicates that bariatric surgery creates a specific immunometabolic state with potential implications for health outcomes.

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Section: Resultsmentioning

confidence: 99%

Distinct B cell profiles characterise healthy weight and obesity pre- and post-bariatric surgery

et al. 2023

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“…Amongst the relatively few studies regarding B cell subsets in patients with eRA, our current report is unique as it separates the B cell populations according to expression levels of the complement 2 receptor, CD21. Lack of or low levels of CD21 on B cells are characteristic of pathologies related to some chronic infections and autoimmunity [ 22 ]. We have both identified changes in the composition of the B cell population and additionally analysed those in relation to clinical outcomes.…”

Section: Discussionmentioning

confidence: 99%

“…Other studies have in addition to the DN subset also shown SWM to be a significant component of the SF B cell compartment [ 35 , 36 ]. CD21 −/low B cell subset in different chronic autoimmune and inflammatory conditions have been described using diverse markers, but a common characteristic of these subsets is the expression of CD11c and Tbet [ 22 ]. Indeed, our CD21 −/low DN SF subset is mainly CD11c + Tbet + .…”

Section: Discussionmentioning

confidence: 99%

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

Thorarinsdottir,

McGrath,

Forslind

et al. 2024

Arthritis Res Ther

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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.

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“…In contrast, the therapy with natalizumab, an antibody to α4 integrins, leads to a preferential expansion of the memory B-cell pool, which is attributable to a decreased retention of these cells within secondary lymphoid tissues [ 66 – 68 ]. At the same time, the proportion of CD21 −/low CD38 −/low B cells, which have been shown to be enriched with autoreactive unresponsive clones in some autoimmune diseases [ 47 , 69 ], was significantly lower in patients on IRTs but significantly higher in patients on natalizumab therapy. Further research on CNS-resident and antigen-specific B cells may provide deeper insights into the therapeutic mechanisms of action.…”

Section: Discussionmentioning

confidence: 99%

Transcriptome alterations in peripheral blood B cells of patients with multiple sclerosis receiving immune reconstitution therapy

Hecker

Fitzner

Boxberger

et al. 2023

J Neuroinflammation

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Background Multiple sclerosis (MS) is a chronic, inflammatory and neurodegenerative disease that leads to irreversible damage to the brain and spinal cord. The goal of so-called "immune reconstitution therapies" (IRTs) is to achieve long-term disease remission by eliminating a pathogenic immune repertoire through intense short-term immune cell depletion. B cells are major targets for effective immunotherapy in MS. Objectives The aim of this study was to analyze the gene expression pattern of B cells before and during IRT (i.e., before B-cell depletion and after B-cell repopulation) to better understand the therapeutic effects and to identify biomarker candidates of the clinical response to therapy. Methods B cells were obtained from blood samples of patients with relapsing–remitting MS (n = 50), patients with primary progressive MS (n = 13) as well as healthy controls (n = 28). The patients with relapsing MS received either monthly infusions of natalizumab (n = 29) or a pulsed IRT with alemtuzumab (n = 15) or cladribine (n = 6). B-cell subpopulation frequencies were determined by flow cytometry, and transcriptome profiling was performed using Clariom D arrays. Differentially expressed genes (DEGs) between the patient groups and controls were examined with regard to their functions and interactions. We also tested for differences in gene expression between patients with and without relapse following alemtuzumab administration. Results Patients treated with alemtuzumab or cladribine showed on average a > 20% lower proportion of memory B cells as compared to before IRT. This was paralleled by profound transcriptome shifts, with > 6000 significant DEGs after adjustment for multiple comparisons. The top DEGs were found to regulate apoptosis, cell adhesion and RNA processing, and the most highly connected nodes in the network of encoded proteins were ESR2, PHB and RC3H1. Higher mRNA levels of BCL2, IL13RA1 and SLC38A11 were seen in patients with relapse despite IRT, though these differences did not pass the false discovery rate correction. Conclusions We show that B cells circulating in the blood of patients with MS undergoing IRT present a distinct gene expression signature, and we delineated the associated biological processes and gene interactions. Moreover, we identified genes whose expression may be an indicator of relapse risk, but further studies are needed to verify their potential value as biomarkers.

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A close-up on the expanding landscape of CD21–/low B cells in humans

Cited by 28 publications

References 97 publications

Distinct B cell profiles characterise healthy weight and obesity pre- and post-bariatric surgery

Distinct B cell profiles characterise healthy weight and obesity pre- and post-bariatric surgery

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

Transcriptome alterations in peripheral blood B cells of patients with multiple sclerosis receiving immune reconstitution therapy

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