Defective early B cell tolerance checkpoints in patients with systemic sclerosis allow the production of self‐antigen‐specific clones

2021 ◽  
Author(s):  
Salome Glauzy ◽  
Brennan Olson ◽  
Christopher K. May ◽  
Daniele Parisi ◽  
Christopher Massad ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
B Cell ◽  
Cell Tolerance ◽  
B Cell Tolerance ◽  
Self Antigen

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.

Protein kinase Cδ controls self-antigen-induced B-cell tolerance

Nature ◽  
2002 ◽  
Vol 416 (6883) ◽  
pp. 860-865 ◽  
Author(s):  
Ingrid Mecklenbräuker ◽  
Kaoru Saijo ◽  
Nai-Ying Zheng ◽  
Michael Leitges ◽  
Alexander Tarakhovsky
Keyword(s):  
Protein Kinase ◽  
B Cell ◽  
Cell Tolerance ◽  
B Cell Tolerance ◽  
Self Antigen ◽  
Protein Kinase Cδ

scholarly journals Deletion and anergy of polyclonal B cells specific for ubiquitous membrane-bound self-antigen

2012 ◽  
Vol 209 (11) ◽  
pp. 2065-2077 ◽  
Author(s):  
Justin J. Taylor ◽  
Ryan J. Martinez ◽  
Philip J. Titcombe ◽  
Laura O. Barsness ◽  
Stephanie R. Thomas ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Transgenic Animals ◽  
B Cell Antigen Receptor ◽  
Cell Tolerance ◽  
B Cell Tolerance ◽  
Membrane Bound ◽  
T Cell Help ◽  
Self Antigen ◽  
Enrichment Strategy

B cell tolerance to self-antigen is critical to preventing antibody-mediated autoimmunity. Previous work using B cell antigen receptor transgenic animals suggested that self-antigen–specific B cells are either deleted from the repertoire, enter a state of diminished function termed anergy, or are ignorant to the presence of self-antigen. These mechanisms have not been assessed in a normal polyclonal repertoire because of an inability to detect rare antigen-specific B cells. Using a novel detection and enrichment strategy to assess polyclonal self-antigen–specific B cells, we find no evidence of deletion or anergy of cells specific for antigen not bound to membrane, and tolerance to these types of antigens appears to be largely maintained by the absence of T cell help. In contrast, a combination of deleting cells expressing receptors with high affinity for antigen with anergy of the undeleted lower affinity cells maintains tolerance to ubiquitous membrane-bound self-antigens.

scholarly journals The Cellular Location of Self-antigen Determines the Positive and Negative Selection of Autoreactive B Cells

2003 ◽  
Vol 198 (9) ◽  
pp. 1415-1425 ◽  
Author(s):  
Helen Ferry ◽  
Margaret Jones ◽  
David J. Vaux ◽  
Ian S.D. Roberts ◽  
Richard J. Cornall
Keyword(s):  
B Cells ◽  
Cell Surface ◽  
B Cell ◽  
Surface Antigen ◽  
Cell Surface Antigen ◽  
Cell Tolerance ◽  
B Cell Tolerance ◽  
Autoreactive B Cells ◽  
Self Antigen ◽  
Self Antigens

Systemic autoimmune disease is frequently characterized by the production of autoantibodies against widely expressed intracellular self-antigens, whereas B cell tolerance to ubiquitous and highly expressed extracellular antigens is strictly enforced. To test for differences in the B cell response to intracellular and extracellular self-antigens, we sequestered a tolerogenic cell surface antigen intracellularly by addition of a two amino acid endoplasmic reticulum (ER) retention signal. In contrast to cell surface antigen, which causes the deletion of autoreactive B cells, the intracellularly sequestered self-antigen failed to induce B cell tolerance and was instead autoimmunogenic. The intracellular antigen positively selected antigen-binding B cells to differentiate into B1 cells and induced large numbers of IgM autoantibody-secreting plasma cells in a T-independent manner. By analyzing the impact of differences in subcellular distribution independently from other variables, such as B cell receptor affinity, antigen type, or tissue distribution, we have established that intracellular localization of autoantigen predisposes for autoantibody production. These findings help explain why intracellular antigens are targeted in systemic autoimmune diseases.

scholarly journals The periphery is the dominant site of B-cell deletion in a polyclonal repertoire

2020 ◽  
Author(s):  
Jeremy F. Brooks ◽  
Raymond J. Steptoe
Keyword(s):  
B Cells ◽  
B Cell ◽  
Antigen Expression ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Peripheral Tolerance ◽  
Cell Tolerance ◽  
B Cell Tolerance ◽  
T Cell Help ◽  
Self Antigen

AbstractThe concerted actions of multiple tolerance checkpoints limit the possibility of immune attack against self-antigens. For B cells, purging of autoreactivity from the developing repertoire has been almost exclusively studied using B-cell receptor transgenic models. Analyses have generally agreed that central and peripheral tolerance occurs in the form of deletion, receptor editing and anergy. However, when and where these processes occur in a normal polyclonal repertoire devoid of B-cell receptor engineering remain unclear. Here, employing sensitive tools that alleviate the need for B-cell receptor engineering, we track the development of self-reactive B cells and challenge whether deletion plays a meaningful role in B-cell tolerance. We find self-reactive B cells can mature unperturbed by ubiquitous self-antigen expression but, even in the presence of T-cell help, are robustly anergic in the periphery. These studies query the prominence attributed to central and peripheral deletion by most BCR transgenic studies and suggest that other mechanisms predominantly govern B cell tolerance.

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