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 Reduced receptor editing in lupus-prone MRL/lpr mice

2007 ◽  
Vol 204 (12) ◽  
pp. 2853-2864 ◽  
Author(s):  
Jennifer L. Lamoureux ◽  
Lisa C. Watson ◽  
Marie Cherrier ◽  
Patrick Skog ◽  
David Nemazee ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Messenger Rna ◽  
Immunoglobulin M ◽  
Considerable Proportion ◽  
Receptor Editing ◽  
Cell Tolerance ◽  
B Cell Tolerance ◽  
Immature B Cells

The initial B cell repertoire contains a considerable proportion of autoreactive specificities. The first major B cell tolerance checkpoint is at the stage of the immature B cell, where receptor editing is the primary mode of eliminating self-reactivity. The cells that emigrate from the bone marrow have a second tolerance checkpoint in the transitional compartment in the spleen. Although it is known that the second checkpoint is defective in lupus, it is not clear whether there is any breakdown in central B cell tolerance in the bone marrow. We demonstrate that receptor editing is less efficient in the lupus-prone strain MRL/lpr. In an in vitro system, when receptor-editing signals are given to bone marrow immature B cells by antiidiotype antibody or after in vivo exposure to membrane-bound self-antigen, MRL/lpr 3-83 transgenic immature B cells undergo less endogenous rearrangement and up-regulate recombination activating gene messenger RNA to a lesser extent than B10 transgenic cells. CD19, along with immunoglobulin M, is down-regulated in the bone marrow upon receptor editing, but the extent of down-regulation is fivefold less in MRL/lpr mice. Less efficient receptor editing could allow some autoreactive cells to escape from the bone marrow in lupus-prone mice, thus predisposing to autoimmunity.

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 Efficient Acquisition of Fully Human Antibody Genes against Self-Proteins by Sorting Single B Cells Stimulated with Vaccines Based on Nitrated T Helper Cell Epitopes

2019 ◽  
Vol 2019 ◽  
pp. 1-16
Author(s):  
Liangliang Jiang ◽  
Tao Jiang ◽  
Jianhua Luo ◽  
Yanliang Kang ◽  
Yue Tong ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
B Cells ◽  
B Cell ◽  
Immune Tolerance ◽  
Human Antibody ◽  
T Helper ◽  
Human Immune System ◽  
Helper Epitope ◽  
Human Immune

Single B cell antibody technology is a method for isolating antigen-specific B cells from human peripheral blood and obtaining antibody genes in developing antibody drugs. However, owing to immune tolerance to autoantigen, human autoantigen-specific B cells are difficult to acquire by conventional single B cell technology. In this study, we constructed a nitrated T-cell epitope named NitraTh by incorporating p-nitrophenylalanine into a universal T helper epitope. NitraTh had enhanced ability to activate CD4+ T cells and can be recognized by CD4+ T cells with different HLA class II haplotypes. This NitraTh can also break immune tolerance to autoantigens, such as human epidermal growth factor receptor 2 (HER2) and cannabinoid receptor 1, and induce strong specific IgM+ B cell responses in vitro. HER2-NitraTh vaccine can also stimulate the generation of HER2-specific IgG+ B cells in human immune system mice, which was established by cotransplanting lymphocytes and autologous dendritic cells in immunodeficient mice. We obtained 30 fully human IgG antibody genes by sorting single B cells from the human immune system mice immunized with HER2-NitraTh vaccine. The analysis of antibody genes showed that sorted B cells underwent the extensive somatic mutation of the antibody genes. We randomly selected eight genes for cloning, six of which expressed antibodies that can bind to HER2. Hence, we provided a convenient and effective method in acquiring fully human antibody genes against self-proteins, which can be used in developing therapeutic antibody drugs.

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 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 Accumulation of peripheral autoreactive B cells in the absence of functional human regulatory T cells

Blood ◽  
2013 ◽  
Vol 121 (9) ◽  
pp. 1595-1603 ◽  
Author(s):  
Tuure Kinnunen ◽  
Nicolas Chamberlain ◽  
Henner Morbach ◽  
Jinyoung Choi ◽  
Sangtaek Kim ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Regulatory T Cells ◽  
B Cell ◽  
Cell Tolerance ◽  
B Cell Tolerance ◽  
Autoreactive B Cells ◽  
Key Points

Key Points Peripheral B-cell tolerance is defective in IPEX patients, suggesting that Tregs are involved in the maintenance of B-cell tolerance. T cells, including Tregs, display an activated phenotype in IPEX patients that may favor the accumulation of autoreactive B cells.

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