Marginal-Zone B-Cells Are Main Producers of IgM in Humans, and Are Reduced in Patients With Autoimmune Vasculitis

Söderberg, Daniel; Eriksson, Per; Ernerudh, Jan; Segelmark, Mårten

doi:10.3389/fimmu.2018.02242

Cited by 46 publications

(39 citation statements)

References 45 publications

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“…Moreover the correlation of unswitched memory B-cells and serum IgM levels were consistent with a previous study (41). In this study marginal zone (MZ)-like B-cells (CD19 + CD27 + IgD + IgM high , comparable with unswitched memory B-cells in our study), negatively correlated with MPO-and PR3-ANCA levels, whereas we found a positive significant correlation of the changes in MPO-and PR3-ANCA levels with the changes in unswitched memory B-cells.…”

Section: Discussionsupporting

confidence: 92%

Highly Sensitive Flow Cytometric Detection of Residual B-Cells After Rituximab in Anti-Neutrophil Cytoplasmic Antibodies-Associated Vasculitis Patients

et al. 2020

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BackgroundB-cell depletion with rituximab (RTX) is an effective treatment for anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) patients. Nevertheless, relapses are frequent after RTX, often preceded by B-cell repopulation suggesting that residual autoreactive B-cells persist despite therapy. Therefore, this study aimed to identify minimal residual autoimmunity (MRA) in the B-cell compartment of AAV patients treated with RTX.MethodsEuroFlow-based highly-sensitive flow cytometry (HSFC) was employed to study B-cell and plasma cell (PC) subsets in-depth in AAV patients before and after RTX treatment. Additionally, peripheral blood mononuclear cells (PBMCs) of these RTX-treated AAV patients were cultured and in vitro stimulated with CpG, IL-2, and IL-21 to induce antibody-secreting cells (ASC). (ANCA)-IgG was measured in these supernatants by ELISA.ResultsBy employing EuroFlow-based HSFC, we detected circulating CD19+ B-cells at all timepoints after RTX treatment, in contrast to conventional low-sensitive flow cytometry. Pre-germinal center (Pre-GC) B-cells, memory B-cells and CD20+CD138− plasmablasts (PBs) were rapidly and strongly reduced, while CD20−CD138− PrePC and CD20-CD138+ mature (m)PCs were reduced slower and remained detectable. Both memory B-cells and CD20− PCs remained detectable after RTX. Serum ANCA-IgG decreased significantly upon RTX. Changes in ANCA levels strongly correlated with changes in naive, switched CD27+ and CD27− (double-negative) memory B-cells, but not with plasma cells. Lastly, we demonstrated in vitro ANCA production by AAV PBMCs, 24 and 48 weeks after RTX treatment reflecting MRA in the memory compartment of AAV patients.ConclusionWe demonstrated that RTX induced strong reductions in circulating B-cells, but never resulted in complete B-cell depletion. Despite strongly reduced B-cell numbers after RTX, ANCA-specific memory B-cells were still detectable in AAV patients. Thus, MRA is identifiable in AAV and can provide a potential novel approach in personalizing RTX treatment in AAV patients.

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Section: Discussionsupporting

confidence: 92%

Highly Sensitive Flow Cytometric Detection of Residual B-Cells After Rituximab in Anti-Neutrophil Cytoplasmic Antibodies-Associated Vasculitis Patients

et al. 2020

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“…53,54 Others reported that marginal zone (MZ) B cells also contribute to natural antibody production in both humans and mice. 55,56 Serum concentrations of natural IgM are similar between mice held under standard housing conditions and those kept free of microbiota or even solid food antigens. 57 The CD5+ B-1 cells in spleen and body cavities of germfree, as well as SPF-housed, mice also showed very similar Ig-VH gene repertoires, supporting the long-held concept of "natural" IgM production, that is, production of IgM that is independent of foreign antigen.…”

Section: Natural Igm Production: Two Sides To a Coinmentioning

confidence: 97%

“…Early adoptive transfer studies showed that much of the circulating IgM was produced by these cells and subsequent studies using transfer of B‐1 cells into neonatal B cell‐depleted mice showed that amount to be more than 90% . Others reported that marginal zone (MZ) B cells also contribute to natural antibody production in both humans and mice …”

Section: Natural Igm Production: Two Sides To a Coinmentioning

confidence: 99%

Secreted IgM: New tricks for an old molecule

Blandino

Baumgarth

2019

Journal of Leukocyte Biology

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Secreted IgM (sIgM) is a multifunctional evolutionary conserved antibody that is critical for the maintenance of tissue homeostasis as well as the development of fully protective humoral responses to pathogens. Constitutive secretion of self‐ and polyreactive natural IgM, produced mainly by B‐1 cells, provides a circulating antibody that engages with autoantigens as well as invading pathogens, removing apoptotic and other cell debris and initiating strong immune responses. Pathogen‐induced IgM production by B‐1 and conventional B‐2 cells strengthens this early, passive layer of IgM‐mediated immune defense and regulates subsequent IgG production. The varied effects of secreted IgM on immune homeostasis and immune defense are facilitated through its binding to numerous different cell types via different receptors. Recent studies identified a novel function for pentameric IgM, namely as a transporter for the effector protein ″apoptosis‐inhibitor of macrophages″ (AIM/CD5L). This review aims to provide a summary of the known functions and effects of sIgM on immune homeostasis and immune defense, and its interaction with its various receptors, and to highlight the many critical immune regulatory functions of this ancient and fascinating immunoglobulin.

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“…Variables investigated included serum levels of BAFF, which are increased in people with MS ( 42 ), and anti-EBV antibodies, since EBV has been implicated in the pathogenesis of MS ( 14 ). In addition, total non-specific IgM levels were compared with CD32b expression levels on cells, since MZ-like B cells are the main producers of serum IgM ( 43 ). Serum levels of other Ig, including IgA, total IgG and IgG subclasses were also included for comparison.…”

Section: Resultsmentioning

confidence: 99%

FcγRIIb Expression Is Decreased on Naive and Marginal Zone-Like B Cells From Females With Multiple Sclerosis

et al. 2021

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B cells are critical to the development of multiple sclerosis (MS), but the mechanisms by which they contribute to the disease are poorly defined. We hypothesised that the expression of CD32b (FcγRIIb), a receptor for the Fc region of IgG with inhibitory activities in B cells, is lower on B cell subsets from people with clinically isolated syndrome (CIS) or MS. CD32b expression was highest on post-naive IgM+ B cell subsets in healthy controls. For females with MS or CIS, significantly lower CD32b expression was identified on IgM+ B cell subsets, including naive and IgMhi MZ-like B cells, when compared with control females. Lower CD32b expression on these B cell subsets was associated with detectable anti-Epstein Barr Virus viral capsid antigen IgM antibodies, and higher serum levels of B cell activating factor. To investigate the effects of lower CD32b expression, B cells were polyclonally activated in the presence of IgG immune complexes, with or without a CD32b blocking antibody, and the expression of TNF and IL-10 in B cell subsets was assessed. The reduction of TNF but not IL-10 expression in controls mediated by IgG immune complexes was reversed by CD32b blockade in naive and IgMhi MZ-like B cells only. However, no consequence of lower CD32b expression on these cells from females with CIS or MS was detected. Our findings highlight a potential role for naive and marginal zone-like B cells in the immunopathogenesis of MS in females, which requires further investigation.

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Marginal-Zone B-Cells Are Main Producers of IgM in Humans, and Are Reduced in Patients With Autoimmune Vasculitis

Cited by 46 publications

References 45 publications

Highly Sensitive Flow Cytometric Detection of Residual B-Cells After Rituximab in Anti-Neutrophil Cytoplasmic Antibodies-Associated Vasculitis Patients

Highly Sensitive Flow Cytometric Detection of Residual B-Cells After Rituximab in Anti-Neutrophil Cytoplasmic Antibodies-Associated Vasculitis Patients

Secreted IgM: New tricks for an old molecule

FcγRIIb Expression Is Decreased on Naive and Marginal Zone-Like B Cells From Females With Multiple Sclerosis

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