scholarly journals Impaired early B cell tolerance in patients with rheumatoid arthritis

2005 ◽  
Vol 201 (10) ◽  
pp. 1659-1667 ◽  
Author(s):  
Jonathan Samuels ◽  
Yen-Shing Ng ◽  
Claire Coupillaud ◽  
Daniel Paget ◽  
Eric Meffre
Keyword(s):  
Rheumatoid Arthritis ◽  
B Cells ◽  
B Cell ◽  
Cell Tolerance ◽  
B Cell Tolerance ◽  
Autoantibody Production ◽  
Autoreactive B Cells ◽  
Healthy Donors ◽  
Polyreactive Antibodies

Autoantibody production is a characteristic of most autoimmune diseases including rheumatoid arthritis (RA). The role of these autoantibodies in the pathogenesis of RA remains elusive, but they appear in the serum many years before the onset of clinical disease suggesting an early break in B cell tolerance. The stage of B cell development at which B cell tolerance is broken in RA remains unknown. We previously established in healthy donors that most polyreactive developing B cells are silenced in the bone marrow, and additional autoreactive B cells are removed in the periphery. B cell tolerance in untreated active RA patients was analyzed by testing the specificity of recombinant antibodies cloned from single B cells. We find that autoreactive B cells fail to be removed in all six RA patients and represent 35–52% of the mature naive B cell compartment compared with 20% in healthy donors. In some patients, RA B cells express an increased proportion of polyreactive antibodies that can recognize immunoglobulins and cyclic citrullinated peptides, suggesting early defects in central B cell tolerance. Thus, RA patients exhibit defective B cell tolerance checkpoints that may favor the development of autoimmunity.

scholarly journals Central human B cell tolerance manifests with a distinctive cell phenotype and is enforced via CXCR4 signaling in hu-mice

2021 ◽  
Vol 118 (16) ◽  
pp. e2021570118
Author(s):  
Thiago Alves da Costa ◽  
Jacob N. Peterson ◽  
Julie Lang ◽  
Jeremy Shulman ◽  
Xiayuan Liang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Immune System ◽  
B Cells ◽  
B Cell ◽  
Cell Tolerance ◽  
Human Immune System ◽  
B Cell Tolerance ◽  
Autoreactive B Cells ◽  
Cell Clones ◽  
Human Immune

Central B cell tolerance, the process restricting the development of many newly generated autoreactive B cells, has been intensely investigated in mouse cells while studies in humans have been hampered by the inability to phenotypically distinguish autoreactive and nonautoreactive immature B cell clones and the difficulty in accessing fresh human bone marrow samples. Using a human immune system mouse model in which all human Igκ+ B cells undergo central tolerance, we discovered that human autoreactive immature B cells exhibit a distinctive phenotype that includes lower activation of ERK and differential expression of CD69, CD81, CXCR4, and other glycoproteins. Human B cells exhibiting these characteristics were observed in fresh human bone marrow tissue biopsy specimens, although differences in marker expression were smaller than in the humanized mouse model. Furthermore, the expression of these markers was slightly altered in autoreactive B cells of humanized mice engrafted with some human immune systems genetically predisposed to autoimmunity. Finally, by treating mice and human immune system mice with a pharmacologic antagonist, we show that signaling by CXCR4 is necessary to prevent both human and mouse autoreactive B cell clones from egressing the bone marrow, indicating that CXCR4 functionally contributes to central B cell tolerance.

scholarly journals Active PI3K abrogates central tolerance in high-avidity autoreactive B cells

2019 ◽  
Vol 216 (5) ◽  
pp. 1135-1153 ◽  
Author(s):  
Sarah A. Greaves ◽  
Jacob N. Peterson ◽  
Pamela Strauch ◽  
Raul M. Torres ◽  
Roberta Pelanda
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Peripheral Tolerance ◽  
High Avidity ◽  
Cell Tolerance ◽  
B Cell Tolerance ◽  
Central Tolerance ◽  
Autoreactive B Cells ◽  
Self Antigen

Autoreactive B cells that bind self-antigen with high avidity in the bone marrow undergo mechanisms of central tolerance that prevent their entry into the peripheral B cell population. These mechanisms are breached in many autoimmune patients, increasing their risk of B cell–mediated autoimmune diseases. Resolving the molecular pathways that can break central B cell tolerance could therefore provide avenues to diminish autoimmunity. Here, we show that B cell–intrinsic expression of a constitutively active form of PI3K-P110α by high-avidity autoreactive B cells of mice completely abrogates central B cell tolerance and further promotes these cells to escape from the bone marrow, differentiate in peripheral tissue, and undergo activation in response to self-antigen. Upon stimulation with T cell help factors, these B cells secrete antibodies in vitro but remain unable to secrete autoantibodies in vivo. Overall, our data demonstrate that activation of the PI3K pathway leads high-avidity autoreactive B cells to breach central, but not late, stages of peripheral tolerance.

scholarly journals CXCR5+PD-1+ follicular helper CD8 T cells control B cell tolerance

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Yuhong Chen ◽  
Mei Yu ◽  
Yongwei Zheng ◽  
Guoping Fu ◽  
Gang Xin ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Cd8 T Cells ◽  
T Cell Subsets ◽  
Cell Tolerance ◽  
B Cell Tolerance ◽  
Autoantibody Production ◽  
Tfh Cells ◽  
Follicular Helper

Abstract Many autoimmune diseases are characterized by the production of autoantibodies. The current view is that CD4+ T follicular helper (Tfh) cells are the main subset regulating autoreactive B cells. Here we report a CXCR5+PD1+ Tfh subset of CD8+ T cells whose development and function are negatively modulated by Stat5. These CD8+ Tfh cells regulate the germinal center B cell response and control autoantibody production, as deficiency of Stat5 in CD8 T cells leads to an increase of CD8+ Tfh cells, resulting in the breakdown of B cell tolerance and concomitant autoantibody production. CD8+ Tfh cells share similar gene signatures with CD4+ Tfh, and require CD40L/CD40 and TCR/MHCI interactions to deliver help to B cells. Our study thus highlights the diversity of follicular T cell subsets that contribute to the breakdown of B-cell tolerance.

scholarly journals B cell tolerance and antibody production to the celiac disease autoantigen transglutaminase 2

2019 ◽  
Vol 217 (2) ◽  
Author(s):  
M. Fleur du Pré ◽  
Jana Blazevski ◽  
Alisa E. Dewan ◽  
Jorunn Stamnaes ◽  
Chakravarthi Kanduri ◽  
...  
Keyword(s):  
Celiac Disease ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Transglutaminase 2 ◽  
General Mechanism ◽  
Cell Tolerance ◽  
B Cell Tolerance ◽  
Autoreactive B Cells ◽  
T Cell Help

Autoantibodies to transglutaminase 2 (TG2) are hallmarks of celiac disease. To address B cell tolerance and autoantibody formation to TG2, we generated immunoglobulin knock-in (Ig KI) mice that express a prototypical celiac patient–derived anti-TG2 B cell receptor equally reactive to human and mouse TG2. We studied B cell development in the presence/absence of autoantigen by crossing the Ig KI mice to Tgm2−/− mice. Autoreactive B cells in Tgm2+/+ mice were indistinguishable from their naive counterparts in Tgm2−/− mice with no signs of clonal deletion, receptor editing, or B cell anergy. The autoreactive B cells appeared ignorant to their antigen, and they produced autoantibodies when provided T cell help. The findings lend credence to a model of celiac disease where gluten-reactive T cells provide help to autoreactive TG2-specific B cells by involvement of gluten–TG2 complexes, and they outline a general mechanism of autoimmunity with autoantibodies being produced by ignorant B cells on provision of T cell help.

scholarly journals OP0073 SINGLE-CELL TRANSCRIPTOMICS UNCOVERS DEFECTIVE BONE MARROW EARLY B CELL DEVELOPMENT IN A SUBSET OF LUPUS PATIENTS ASSOCIATED WITH AGGRAVATED INFLAMMATION

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 39.2-39
Author(s):  
C. Dong ◽  
X. Gu ◽  
J. Ji ◽  
X. Zhang ◽  
Z. Gu
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Cell Development ◽  
B Cell Development ◽  
Cell Tolerance ◽  
Systemic Lupus ◽  
B Cell Tolerance ◽  
Healthy Donors

Background:Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that occurs when the body’s immune system attacks own tissues and organs. B cells play a central role in SLE pathogenesis by producing autoantibodies as well as antibody-independent functions. Peripheral B cell abnormality is well known in lupus patients such as expansions of plasmablasts and atypical memory B cells, which are associated with active diseases. However, little is known about the B cell development in the bone marrow of lupus patients.Objectives:We conduct this survey to explore the disorder of the B cell development in the bone marrow of lupus patients.Methods:In this study, we have performed the scRNASeq to profile the bone marrow B cell compartment in lupus patients and healthy donors.Results:We identified that in a subset of lupus patients, the early B cells (proB and preB cells) were strongly decreased, which were confirmed by flow cytometry in an expanded cohort. Furthermore, bone marrow B cells from these patients showed a strong proinflammatory signature revealed by pathway analysis. Interestingly, BCR repertoire analysis showed that the IGHV-4-34 was highly enriched in these patients, indicating an enhanced B cell tolerance defect. Finally, a panel of proinflammatory cytokines (TNF-a, IL-1a, IL-12p70, IFN-g, et al.) were strongly increased in the bone marrow plasma of these patients compared with early B normal patients and healthy donors, confirming a localized proinflammatory microenvironment.Conclusion:Altogether, the current study has revealed that a defective early B cell development in lupus patients is associated with a more severe B cell tolerance defect and aggravated inflammation, which may shed new light on developing novel therapies by targeting relevant pathways.References:[1]Min Wang, Hua Chen, Jia Qiu, et al. Antagonizing miR-7 suppresses B cell hyperresponsiveness and inhibits lupus development. J Autoimmun 2020.[2]A M Jacobi, D M Goldenberg, F Hiepe, et al. Differential effects of epratuzumab on peripheral blood B cells of patients with systemic lupus erythematosus versus normal controls. Ann Rheum Dis, 2008.Acknowledgements:This work was funded by Special project of clinical medicine of Nantong University (Grant/Award number: 2019LQ001), National Natural Science Foundation of China (Grant/Award number: 81671616, 81871278 and 82071838).Disclosure of Interests:None declared

scholarly journals Recent Advances in Lupus B Cell Biology: PI3K, IFNγ, and Chromatin

2021 ◽  
Vol 11 ◽  
Author(s):  
Maria A. Bacalao ◽  
Anne B. Satterthwaite
Keyword(s):  
B Cells ◽  
Autoimmune Disease ◽  
B Cell ◽  
Cell Biology ◽  
Chromatin Accessibility ◽  
Cell Tolerance ◽  
B Cell Tolerance ◽  
Murine Lupus ◽  
The Past

In the autoimmune disease Systemic Lupus Erythematosus (SLE), autoantibodies are formed that promote inflammation and tissue damage. There has been significant interest in understanding the B cell derangements involved in SLE pathogenesis. The past few years have been particularly fruitful in three domains: the role of PI3K signaling in loss of B cell tolerance, the role of IFNγ signaling in the development of autoimmunity, and the characterization of changes in chromatin accessibility in SLE B cells. The PI3K pathway coordinates various downstream signaling molecules involved in B cell development and activation. It is governed by the phosphatases PTEN and SHIP-1. Murine models lacking either of these phosphatases in B cells develop autoimmune disease and exhibit defects in B cell tolerance. Limited studies of human SLE B cells demonstrate reduced expression of PTEN or increased signaling events downstream of PI3K in some patients. IFNγ has long been known to be elevated in both SLE patients and mouse models of lupus. New data suggests that IFNγR expression on B cells is required to develop autoreactive germinal centers (GC) and autoantibodies in murine lupus. Furthermore, IFNγ promotes increased transcription of BCL6, IL-6 and T-bet in B cells, which also promote GC and autoantibody formation. IFNγ also induces epigenetic changes in human B cells. SLE B cells demonstrate significant epigenetic reprogramming, including enhanced chromatin accessibility at transcription factor motifs involved in B cell activation and plasma cell (PC) differentiation as well as alterations in DNA methylation and histone modifications. Histone deacetylase inhibitors limit disease development in murine lupus models, at least in part via their ability to prevent B cell class switching and differentiation into plasma cells. This review will discuss relevant discoveries of the past several years pertaining to these areas of SLE B cell biology.

scholarly journals Macrophages prevent the differentiation of autoreactive B cells by secreting CD40 ligand and interleukin-6

Blood ◽  
2007 ◽  
Vol 110 (5) ◽  
pp. 1595-1602 ◽  
Author(s):  
Michelle A. Kilmon ◽  
Nikki J. Wagner ◽  
Alaina L. Garland ◽  
Li Lin ◽  
Katja Aviszus ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Interleukin 6 ◽  
Cd40 Ligand ◽  
Innate Immune ◽  
Cell Tolerance ◽  
B Cell Tolerance ◽  
Soluble Cd40 Ligand ◽  
Autoreactive B Cells ◽  
Antibody Secretion

Abstract Activation of the innate immune system promotes polyclonal antibody secretion to eliminate invading pathogens. Inherent in this process is the potential to activate autoreactive B cells and induce autoimmunity. We showed previously that TLR-stimulated dendritic cells and macrophages regulate B cell tolerance to Smith antigen, in part through the secretion of interleukin-6 (IL-6). In this manuscript, we show that neutralization of IL-6 fails to abrogate macrophage-mediated repression and identify soluble CD40 ligand (CD40L) as a second repressive factor secreted by macrophages. CD40L selectively repressed Ig secretion by chronically antigen-experienced (anergic) immunoglobulin transgenic and nontransgenic B cells but not by transiently stimulated B cells. The importance of macrophages in maintaining B cell tolerance was apparent in lupus-prone MRL/lpr mice. Compared with C57BL/6 mice, macrophages from MRL/lpr mice were significantly less efficient at repressing immunoglobulin secretion coincident with diminished IL-6 and CD40 ligand production. These data indicate that macrophages regulate autoreactive B cells by secreting repressive factors that prohibit terminal differentiation of B cells. The regulation of autoreactive B cells by macrophages is diminished in lupus-prone mice suggesting a role in autoimmunity.

scholarly journals Receptor editing: How B cells stay tolerant

2007 ◽  
Vol 204 (8) ◽  
pp. 1735-1735
Author(s):  
Hema Bashyam
Keyword(s):  
B Cells ◽  
B Cell ◽  
Main Mechanism ◽  
Receptor Editing ◽  
Cell Tolerance ◽  
B Cell Tolerance ◽  
Autoreactive B Cells

In 1993, David Nemazee and Martin Weigert independently showed that autoreactive B cells could proofread, alter, and reexpress modified receptors to become nonautoreactive. This process, called “receptor editing,” has since gained prominence as the main mechanism of B cell tolerance.

scholarly journals CARD19, a Novel Negative Regulator of B-Cell Tolerance

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 997-997
Author(s):  
Yongwei Zheng ◽  
Mei Yu ◽  
Yuhong Chen ◽  
Liquan Xue ◽  
Wen Zhu ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Biology ◽  
Negative Regulator ◽  
Sequencing Analysis ◽  
Cell Tolerance ◽  
B Cell Tolerance ◽  
Clonal Deletion ◽  
Autoantibody Production ◽  
Induced Expression

Abstract The CARD11-Bcl10-Malt1 (CBM) signalosome controls TAK1 activation to regulate B-cell receptor (BCR)-induced NF-κB activation and B cell biology. The biological function of caspase recruitment domain family member 19 (CARD19), originally identified as a BCL10-interacting CARD protein (BinCARD), is not known. Here we found CARD19 strongly interacted with TAK1 but not BCL10 or other CBM components and prevented TAK1's association with TAB2, thereby inhibiting TAB2-mediated TAK1 ubiquitination and activation and subsequent NF-κB activation. CARD19 was ubiquitously expressed in hematopoietic lineages but its deficiency in mice had no effect on hematopoiesis, including B cell development and humoral immune response. CARD19 deficiency enhanced clonal deletion, receptor editing and anergy of self-reactive B cells, thus reducing autoantibody production in vivo. Mechanistically, CARD19 deficiency led to an increase of BCR/TAK1-mediated NF-κB activation. Activation of NF-κB, such as c-Rel, was responsible for the up-regulation of BCR-induced expression of the transcription factor early growth response genes 2 and 3 (Egr2, Egr3) and the E3 ubiquitin ligases, c-Cbl and Cbl-b, the important inducers of B-cell tolerance in B cells. Further, high-throughput RNA sequencing analysis revealed that CARD19 deficiency did not affect the overall antigen-induced gene expression in naïve B cells but suppressed BCR signaling to increase hyporesponsiveness of self-reactive B cells. Consequently, CARD19 deficiency prevented Bm12-induced experimental systemic lupus erythematosus (SLE) and autoimmunity in a B cell-intrinsic manner. Taken together, CARD19 negatively regulates BCR-induced NF-κB activation via blocking TAK1/TAB2 interaction and its deficiency leads to NF-κB-induced expression of Egr2/3 and c-Cbl/Cbl-b in self-reactive B cells, which enhances B-cell tolerance and thus prevents autoimmunity. Disclosures No relevant conflicts of interest to declare.

scholarly journals Rheumatoid arthritis patients display B-cell dysregulation already in the naïve repertoire consistent with defects in B-cell tolerance

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Yan Wang ◽  
Katy A. Lloyd ◽  
Ioannis Melas ◽  
Diana Zhou ◽  
Radha Thyagarajan ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
B Cells ◽  
B Cell ◽  
Somatic Hypermutation ◽  
Total Serum ◽  
Double Negative ◽  
Cell Tolerance ◽  
Cell Repertoire ◽  
B Cell Tolerance ◽  
Cell Markers

AbstractB cells are postulated to be central in seropositive rheumatoid arthritis (RA). Here, we use exploratory mass cytometry (n = 23) and next-generation sequencing (n = 19) to study B-cell repertoire shifts in RA patients. Expression of several B-cell markers were significantly different in ACPA+ RA compared to healthy controls, including an increase in HLA-DR across subsets, CD22 in clusters of IgM+ B cells and CD11c in IgA+ memory. Moreover, both IgA+ and IgG+ double negative (IgD− CD27−) CD11c+ B cells were increased in ACPA+ RA, and there was a trend for elevation in a CXCR5/CCR6high transitional B-cell cluster. In the RA BCR repertoire, there were significant differences in subclass distribution and, notably, the frequency of VH with low somatic hypermutation (SHM) was strikingly higher, especially in IgG1 (p < 0.0001). Furthermore, both ACPA+ and ACPA− RA patients had significantly higher total serum IgA and IgM compared to controls, based on serology of larger cohorts (n = 3494 IgA; n = 397 IgM). The observed elevated Ig-levels, distortion in IgM+ B cells, increase in double negative B cells, change in B-cell markers, and elevation of unmutated IgG+ B cells suggests defects in B-cell tolerance in RA. This may represent an underlying cause of increased polyreactivity and autoimmunity in RA.

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