scholarly journals Analysis of Somatic Hypermutation in the JH4 intron of Germinal Center B cells from Mouse Peyer's Patches

10.3791/61551 ◽  
2021 ◽  
Author(s):  
Emily Sible ◽  
Simin Zheng ◽  
Jee Eun Choi ◽  
Bao Q. Vuong
Keyword(s):  
B Cells ◽  
Germinal Center ◽  
Somatic Hypermutation ◽  
Peyer's Patches ◽  
Peyer’S Patches ◽  
Germinal Center B Cells

Nonimmunoglobulin Gene Hypermutation in Germinal Center B Cells

Blood ◽  
1999 ◽  
Vol 93 (7) ◽  
pp. 2167-2172 ◽  
Author(s):  
Huai-Zheng Peng ◽  
Ming-Qing Du ◽  
Athanasios Koulis ◽  
Antonella Aiello ◽  
Ahmet Dogan ◽  
...  
Keyword(s):  
B Cells ◽  
Germinal Center ◽  
Cell Lymphoma ◽  
Somatic Hypermutation ◽  
Mantle Zone ◽  
Germinal Center Reaction ◽  
Inherent Feature ◽  
Mantle Cell ◽  
Center Cell ◽  
Germinal Center B Cells

Somatic hypermutation is the most critical mechanism underlying the diversification of Ig genes. Although mutation occurs specifically in B cells during the germinal center reaction, it remains a matter of debate whether the mutation machinery also targets non-Ig genes. We have studied mutations in the 5′ noncoding region of the Bcl6 gene in different subtypes of lymphomas. We found frequent hypermutation in follicular lymphoma (25 of 59 = 42%) (germinal center cell origin) and mucosa-associated lymphoid tissue (MALT) lymphoma (19 of 45 = 42%) (postgerminal center), but only occasionally in mantle cell lymphoma (1 of 21 = 4.8%) (pregerminal center). Most mutations were outside the motifs potentially important for transcription, suggesting they were not important in lymphomagenesis but may, like Ig mutation, represent an inherent feature of the lymphoma precursor cells. Therefore, we investigated their normal cell counterparts microdissected from a reactive tonsil. Bcl6 mutation was found in 13 of 24 (54%) clones from the germinal centre but only in 1 of 24 (4%) clones from the naive B cells of the mantle zone. The frequency, distribution, and nature of these mutations were similar to those resulting from the Ig hypermutation process. The results show unequivocal evidence of non-Ig gene hypermutation in germinal center B cells and provide fresh insights into the process of hypermutation and lymphomagenesis.

scholarly journals WASp Is Crucial for the Unique Architecture of the Immunological Synapse in Germinal Center B-Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
Yanan Li ◽  
Anshuman Bhanja ◽  
Arpita Upadhyaya ◽  
Xiaodong Zhao ◽  
Wenxia Song
Keyword(s):  
B Cells ◽  
B Cell ◽  
Lipid Bilayers ◽  
Germinal Center ◽  
Actin Polymerization ◽  
Immunological Synapse ◽  
Somatic Hypermutation ◽  
Affinity Maturation ◽  
Membrane Protrusions ◽  
Germinal Center B Cells

B-cells undergo somatic hypermutation and affinity maturation in germinal centers. Somatic hypermutated germinal center B-cells (GCBs) compete to engage with and capture antigens on follicular dendritic cells. Recent studies show that when encountering membrane antigens, GCBs generate actin-rich pod-like structures with B-cell receptor (BCR) microclusters to facilitate affinity discrimination. While deficiencies in actin regulators, including the Wiskott-Aldrich syndrome protein (WASp), cause B-cell affinity maturation defects, the mechanism by which actin regulates BCR signaling in GBCs is not fully understood. Using WASp knockout (WKO) mice that express Lifeact-GFP and live-cell total internal reflection fluorescence imaging, this study examined the role of WASp-mediated branched actin polymerization in the GCB immunological synapse. After rapid spreading on antigen-coated planar lipid bilayers, GCBs formed microclusters of phosphorylated BCRs and proximal signaling molecules at the center and the outer edge of the contact zone. The centralized signaling clusters localized at actin-rich GCB membrane protrusions. WKO reduced the centralized micro-signaling clusters by decreasing the number and stability of F-actin foci supporting GCB membrane protrusions. The actin structures that support the spreading membrane also appeared less frequently and regularly in WKO than in WT GCBs, which led to reductions in both the level and rate of GCB spreading and antigen gathering. Our results reveal essential roles for WASp in the generation and maintenance of unique structures for GCB immunological synapses.

scholarly journals In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. III. The kinetics of V region mutation and selection in germinal center B cells.

1993 ◽  
Vol 178 (4) ◽  
pp. 1293-1307 ◽  
Author(s):  
J Jacob ◽  
J Przylepa ◽  
C Miller ◽  
G Kelsoe
Keyword(s):  
B Cells ◽  
Germinal Center ◽  
Somatic Hypermutation ◽  
Point Mutations ◽  
Variable Region ◽  
Germinal Centers ◽  
Primary Immune Response ◽  
Kinetics Of ◽  
Mutation And Selection ◽  
Germinal Center B Cells

In the murine spleen, germinal centers are the anatomic sites for antigen-driven hypermutation and selection of immunoglobulin (Ig) genes. To detail the kinetics of Ig mutation and selection, 178 VDJ sequences from 16 antigen-induced germinal centers were analyzed. Although germinal centers appeared by day 4, mutation was not observed in germinal center B cells until day 8 postimmunization; thereafter, point mutations favoring asymmetrical transversions accumulated until day 14. During this period, strong phenotypic selection on the mutant B lymphocytes was inferred from progressively biased distributions of mutations within the Ig variable region, the loss of crippling mutations, decreased relative clonal diversity, and increasingly restricted use of canonical gene segments. The period of most intense selection on germinal center B cell populations preceded significant levels of mutation and may represent a physiologically determined restriction on B cells permitted to enter the memory pathway. Noncanonical Ig genes recovered from germinal centers were mostly unmutated although they probably came from antigen-reactive cells. Together, these observations demonstrate that the germinal center microenvironment is rich and temporally complex but may not be constitutive for somatic hypermutation.

scholarly journals Integrity of immunoglobulin variable regions is supported by GANP during AID-induced somatic hypermutation in germinal center B cells

2017 ◽  
Vol 29 (5) ◽  
pp. 211-220 ◽  
Author(s):  
Mohammed Mansour Abbas Eid ◽  
Mayuko Shimoda ◽  
Shailendra Kumar Singh ◽  
Sarah Ameen Almofty ◽  
Phuong Pham ◽  
...  
Keyword(s):  
B Cells ◽  
Germinal Center ◽  
Somatic Hypermutation ◽  
Variable Regions ◽  
Germinal Center B Cells

DNA Breaks in Hypermutating Immunoglobulin Genes: Evidence for a Break-and-Repair Pathway of Somatic Hypermutation

Genetics ◽  
2001 ◽  
Vol 158 (1) ◽  
pp. 369-378 ◽  
Author(s):  
Qingzhong Kong ◽  
Nancy Maizels
Keyword(s):  
B Cells ◽  
Germinal Center ◽  
Somatic Hypermutation ◽  
Sequence Motif ◽  
Immunoglobulin Gene ◽  
Sequence Motifs ◽  
Dna Breaks ◽  
Dna Strands ◽  
Germinal Center B Cells

Abstract To test the hypothesis that immunoglobulin gene hypermutation in vivo employs a pathway in which DNA breaks are introduced and subsequently repaired to produce mutations, we have used a PCR-based assay to detect and identify single-strand DNA breaks in λ1 genes of actively hypermutating primary murine germinal center B cells. We find that there is a two- to threefold excess of breaks in λ1 genes of hypermutating B cells, relative to nonhypermutating B cells, and that 1.3% of germinal center B cells contain breaks in the λ1 gene that are associated with hypermutation. Breaks were found in both top and bottom DNA strands and were localized to the region of λ1 that actively hypermutates, but duplex breaks accounted for only a subset of breaks identified. Almost half of the breaks in hypermutating B cells occurred at hotspots, sites at which two or more independent breaks were identified. Breaksite hotspots were associated with characteristic sequence motifs: a pyrimidine-rich motif, either RCTYT or CCYC; and RGYW, a sequence motif associated with hypermutation hotspots. The sequence motifs identified at breaksite hotspots should inform the design of substrates for characterization of activities that participate in the hypermutation pathway.

scholarly journals BCL-6 mutations in normal germinal center B cells: Evidence of somatic hypermutation acting outside Ig loci

1998 ◽  
Vol 95 (20) ◽  
pp. 11816-11821 ◽  
Author(s):  
L. Pasqualucci ◽  
A. Migliazza ◽  
N. Fracchiolla ◽  
C. William ◽  
A. Neri ◽  
...  
Keyword(s):  
B Cells ◽  
Germinal Center ◽  
Somatic Hypermutation ◽  
Germinal Center B Cells
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