Altered BCR and TLR signals promote enhanced positive selection of autoreactive transitional B cells in Wiskott-Aldrich Syndrome

immuneACCESS ◽  
2018 ◽  
Author(s):  
NS Kolhatkar ◽  
A Brahmandam ◽  
CD Thouvenel ◽  
S Becker-Herman ◽  
HM Jacobs ◽  
...  
Keyword(s):  
B Cells ◽  
Positive Selection ◽  
Wiskott Aldrich Syndrome ◽  
Transitional B Cells ◽  
Selection Of

scholarly journals Altered BCR and TLR signals promote enhanced positive selection of autoreactive transitional B cells in Wiskott-Aldrich syndrome

2015 ◽  
Vol 212 (10) ◽  
pp. 1663-1677 ◽  
Author(s):  
Nikita S. Kolhatkar ◽  
Archana Brahmandam ◽  
Christopher D. Thouvenel ◽  
Shirly Becker-Herman ◽  
Holly M. Jacobs ◽  
...  
Keyword(s):  
B Cells ◽  
Positive Selection ◽  
B Cell ◽  
Heavy Chain ◽  
High Throughput Sequencing ◽  
Cell Stage ◽  
Wiskott Aldrich Syndrome ◽  
Transitional B Cells ◽  
Selection Of

Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency disorder frequently associated with systemic autoimmunity, including autoantibody-mediated cytopenias. WAS protein (WASp)–deficient B cells have increased B cell receptor (BCR) and Toll-like receptor (TLR) signaling, suggesting that these pathways might impact establishment of the mature, naive BCR repertoire. To directly investigate this possibility, we evaluated naive B cell specificity and composition in WASp-deficient mice and WAS subjects (n = 12). High-throughput sequencing and single-cell cloning analysis of the BCR repertoire revealed altered heavy chain usage and enrichment for low-affinity self-reactive specificities in murine marginal zone and human naive B cells. Although negative selection mechanisms including deletion, anergy, and receptor editing were relatively unperturbed, WASp-deficient transitional B cells showed enhanced proliferation in vivo mediated by antigen- and Myd88-dependent signals. Finally, using both BCR sequencing and cell surface analysis with a monoclonal antibody recognizing an intrinsically autoreactive heavy chain, we show enrichment in self-reactive cells specifically at the transitional to naive mature B cell stage in WAS subjects. Our combined data support a model wherein modest alterations in B cell–intrinsic, BCR, and TLR signals in WAS, and likely other autoimmune disorders, are sufficient to alter B cell tolerance via positive selection of self-reactive transitional B cells.

scholarly journals Positive Selection of Natural Poly-Reactive B Cells in the Periphery Occurs Independent of Heavy Chain Allelic Inclusion

PLoS ONE ◽  
2015 ◽  
Vol 10 (5) ◽  
pp. e0125747
Author(s):  
Ying Xing ◽  
Qiuhe Ji ◽  
Ying Lin ◽  
Meng Fu ◽  
Jixin Gao ◽  
...  
Keyword(s):  
B Cells ◽  
Positive Selection ◽  
Heavy Chain ◽  
Selection Of

scholarly journals Permissive selection followed by affinity-based proliferation of GC light zone B cells dictates cell fate and ensures clonal breadth

2021 ◽  
Vol 118 (2) ◽  
pp. e2016425118
Author(s):  
Rinako Nakagawa ◽  
Amparo Toboso-Navasa ◽  
Marta Schips ◽  
George Young ◽  
Leena Bhaw-Rosun ◽  
...  
Keyword(s):  
B Cells ◽  
Positive Selection ◽  
B Cell ◽  
Cell Fate ◽  
Clonal Diversity ◽  
Affinity Maturation ◽  
Cell Fates ◽  
Lower Affinity ◽  
Cell Subpopulations ◽  
Selection Of

Affinity maturation depends on how efficiently germinal centers (GCs) positively select B cells in the light zone (LZ). Positively selected GC B cells recirculate between LZs and dark zones (DZs) and ultimately differentiate into plasmablasts (PBs) and memory B cells (MBCs). Current understanding of the GC reaction presumes that cMyc-dependent positive selection of LZ B cells is a competitive affinity-dependent process; however, this cannot explain the production of GC-derived lower-affinity MBCs or retention of GC B cells with varied affinities. Here, by combining single-cell/bulk RNA sequencing and flow cytometry, we identified and characterized temporally and functionally distinct positively selected cMyc+ GC B cell subpopulations. cMyc+ LZ B cell subpopulations enriched with either higher- or lower-affinity cells diverged soon after permissive positive selection. The former subpopulation contained PB precursors, whereas the latter comprised less proliferative MBC precursors and future DZ entrants. The overall affinity of future DZ entrants was enhanced in the LZ through preferential proliferation of higher-affinity cells. Concurrently, lower-affinity cells were retained in GCs and protected from apoptosis. These findings redefine positive selection as a dynamic process generating three distinct B cell fates and elucidate how positive selection ensures clonal diversity for broad protection.

scholarly journals TLR4, TLR9 and MyD88 are not requiredfor the positive selection of autoreactive B cells intothe primary repertoire

2006 ◽  
Vol 36 (6) ◽  
pp. 1404-1412 ◽  
Author(s):  
Karlee Silver ◽  
Helen Ferry ◽  
Tanya Crockford ◽  
Richard J. Cornall
Keyword(s):  
B Cells ◽  
Positive Selection ◽  
Autoreactive B Cells ◽  
Selection Of
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