scholarly journals Analysis of the human VH gene repertoire. Differential effects of selection and somatic hypermutation on human peripheral CD5(+)/IgM+ and CD5(-)/IgM+ B cells.

1997 ◽  
Vol 99 (10) ◽  
pp. 2488-2501 ◽  
Author(s):  
H P Brezinschek ◽  
S J Foster ◽  
R I Brezinschek ◽  
T Dörner ◽  
R Domiati-Saad ◽  
...  
Keyword(s):  
B Cells ◽  
Somatic Hypermutation ◽  
Gene Repertoire ◽  
Differential Effects ◽  
Vh Gene

scholarly journals Most peripheral B cells in mice are ligand selected.

1991 ◽  
Vol 173 (6) ◽  
pp. 1357-1371 ◽  
Author(s):  
H Gu ◽  
D Tarlinton ◽  
W Müller ◽  
K Rajewsky ◽  
I Förster
Keyword(s):  
B Cells ◽  
B Cell ◽  
Gene Selection ◽  
Somatic Hypermutation ◽  
Sequence Data ◽  
Gene Repertoire ◽  
Genomic Libraries ◽  
Vh Gene ◽  
Vh Genes ◽  
Peripheral B Cells

Using amplified cDNA and genomic libraries, we have analyzed the VH gene repertoire of pre-B cells and various B cell subsets of conventional mice at the level of VH genes belonging to the J558 VH gene family. The sequence data were evaluated on the basis of a newly established list of 67 J558 VH genes that comprise approximately two-thirds of the J558 VH genes of the murine IgHb haplotype. The results of the analysis demonstrate that VH gene utilization in pre-B cells, although biased to some extent by B cell autonomous VH gene selection, scatters over the whole range of J558 VH genes present in the germline. In contrast, in mature, peripheral B cells comprising long-lived mu + delta high B cells as well as Ly-1 B cells, small overlapping sets of germline VH genes are dominantly expressed. The data indicate that the recruitment of newly generated B cells into the long-lived peripheral B cell pool is mediated through positive selection by internal and/or external antigens. Because of the absence of immunoglobulin class switching and somatic hypermutation, this process is different from the selection of memory B cells in T cell-dependent immune responses.

scholarly journals Functional Heterogeneity of Marginal Zone B Cells Revealed by Their Ability to Generate Both Early Antibody-forming Cells and Germinal Centers with Hypermutation and Memory in Response to a T-dependent Antigen

2003 ◽  
Vol 198 (12) ◽  
pp. 1923-1935 ◽  
Author(s):  
Haifeng Song ◽  
Jan Cerny
Keyword(s):  
B Cells ◽  
Marginal Zone ◽  
Germinal Centers ◽  
Gene Repertoire ◽  
Immune Functions ◽  
First Line ◽  
Marginal Zone B Cells ◽  
A Cell ◽  
Vh Gene ◽  
Conventional Paradigm

Marginal zone (MZ) B cells play a major role in the first-line responses against blood-born T-independent bacterial antigens (TI), but the full scope of their immune functions is not known. Here we compare the responses of MZ and follicular (FO) B cells to a T-dependent antigen (TD), hapten–(4-hydroxy-3-nitrophenyl)acetyl (NP) coupled to chicken γ-globulin, in a cell transfer system. Consistent with the conventional paradigm, MZ B cells but not FO B cells rapidly generated the early burst of NP-specific antibody-forming cells (AFC), high levels of IgM Ab, and early IgG with relatively high affinity to NP. However, MZ B cells were also capable of forming germinal centers (GCs) albeit with a delay, compared with FO B cells. The early AFCs and the GCs originated from different MZ precursors, but the MZ- and FO-derived GCs were similar in VH gene repertoire, somatic mutation, and production of late AFC and IgG Ab. Surprisingly, the MZ but not the FO memory response included IgM Ab. We conclude that MZ B cells are heterogeneous, comprising cells for both early AFC response and GC/memory pathway against TD antigens.

scholarly journals Distinct clonal evolution of B-cells in HIV controllers with neutralizing antibody breadth

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Deniz Cizmeci ◽  
Giuseppe Lofano ◽  
Evan Rossignol ◽  
Anne-Sophie Dugast ◽  
Dongkyoon Kim ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Somatic Hypermutation ◽  
Clonal Evolution ◽  
Neutralizing Antibody ◽  
Affinity Maturation ◽  
Gene Repertoire ◽  
Immunoglobulin Gene ◽  
Hiv Controllers ◽  
Hiv 1

A minor subset of individuals infected with HIV-1 develop antibody neutralization breadth during the natural course of the infection, often linked to chronic, high-level viremia. Despite significant efforts, vaccination strategies have been unable to induce similar neutralization breadth and the mechanisms underlying neutralizing antibody induction remain largely elusive. Broadly neutralizing antibody responses can also be found in individuals who control HIV to low and even undetectable plasma levels in the absence of antiretroviral therapy, suggesting that high antigen exposure is not a strict requirement for neutralization breadth. We therefore performed an analysis of paired heavy and light chain B-cell receptor (BCR) repertoires in 12,591 HIV-1 envelope-specific single memory B-cells to determine alterations in the BCR immunoglobulin gene repertoire and B-cell clonal expansions that associate with neutralizing antibody breadth in 22 HIV controllers. We found that the frequency of genomic mutations in IGHV and IGLV was directly correlated with serum neutralization breadth. The repertoire of the most mutated antibodies was dominated by a small number of large clones with evolutionary signatures suggesting that these clones had reached peak affinity maturation. These data demonstrate that even in the setting of low plasma HIV antigenemia, similar to what a vaccine can potentially achieve, BCR selection for extended somatic hypermutation and clonal evolution can occur in some individuals suggesting that host-specific factors might be involved that could be targeted with future vaccine strategies.

Relapsed MALT Lymphomas Are Associated with a Restricted VH3-30.3 Immunoglobulin VH Gene Repertoire and Are Targeted by Aberrant Somatic Hypermutation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2830-2830
Author(s):  
Alexander JA Deutsch ◽  
Ruth I Brezinschek ◽  
Hans-Peter Brezinschek ◽  
Christine Beham-Schmid ◽  
Peter Neumeister
Keyword(s):  
Salivary Gland ◽  
B Cell ◽  
Salivary Glands ◽  
Malt Lymphoma ◽  
Somatic Hypermutation ◽  
Gene Segment ◽  
Low Grade ◽  
Gene Repertoire ◽  
Mrna Levels ◽  
Vh Gene

Abstract Mucosa associated lymphoid tissue (MALT) type lymphomas are B-cell neoplasms that develop out of a reactive infiltrate; Sjoegren syndrome, Hashimoto thyroiditis, and Helicobacter pylori gastritis provide the pathogenetic background. Direct antigen stimulation through surface immunoglobulin (Ig) molecules may be playing an important role in the development of MALT lymphomas. In rare cases MALT lymphomas may undergo transformation into extranodal diffuse large B-cell lymphomas (eDLBCL). Previous reports suggested salivary gland MALT lymphomas expressed a restricted Ig VH gene repertoire with over use of VH1-69 gene segments. Because knowledge about the VH gene used by MALT lymphoma of gastric and extragastric origin and by eDLBCL is limited, we sequenced the VH genes from 11 MALT lymphomas [5 of gastric and 6 of extragastric origin (3 salivary gland, 3 thyroid)] and from 10 eDLBCL, all arisen from MALT lymphoma and still exhibiting a low grade component [= so called “transformed MALT lymphoma”: 5 of gastric and 5 of extragastric origin (3 salivary gland and 2 thyroid)]. MALT lymphomas used gene segments of the VH1 (1–69: 2 salivary gland and 1 thyroid), VH3 (3–30.3: 1 thyroid), VH4 (4–34: 1 thyroid, 1 salivary gland and 2 gastric), VH5 (5–51: 2 gastric) and VH6 (6-1: 1 gastric) families. Extranodal DLBCLs used segments derived from VH1 (1–69: 1 gastric and 1 salivary gland), VH2 (2–70: 1 thyroid), VH3 (3–23: 1 gastric; 3–30: 1 gastric; 3–30.3: 1 gastric and 2 salivary glands) and VH4 (4–34: 1 gastric) families as shown in table 1. The VH1-69 gene segment was found in 3 of 6 extragastric MALT lymphomas (2 salivary glands and 1 thyroid), in one gastric and one salivary gland eDLBCL but in no gastric MALT lymphoma. Further, 4 of the 21 lymphomas relapsed, 3 eDLBCL and one MALT lymphoma – and remarkably, all of them used the VH3-30.3 gene segment. Comparing the frequency of somatic hypermutation (SHM) of the immunoglobuline locus and aberrant somatic hypermutation (ASHM) of the four proto-oncogenes PAX-5, PIM-1, Rho/TTF and c-MYC between the relapsed (n=4) and non relapsed lymphomas (n=17) a ~2.9 fold (5.8 vs 2.0 × 10−2/bp, p=0.017) and 2.1 fold (0.067 vs 0.032 × 10−2/bp, p=0.027) higher mutation rate for SHM and ASHM in relapsed lymphomas was observed. Also, the AID mRNA relative expression number was 1.7 fold higher in the group of relapsed lymphomas (4.66 vs 2.71, p=0.049). Performing immunohistochemical analysis for AID a significant positive correlation (p=0.01; correlation coefficient (Spearman rho) = 0.794) was observed when comparing protein expression with mRNA levels. These results are consistent with the model in which only certain B cells displaying specific patterns of VH immunoglobuline molecules binding to an as yet undefined antigen together with a highly aberrant somatic hypermutation process are preferentially selected for malignant transformation and determine the natural course of disease. Table1: VH gene sement used by MALT lymphomas and eDLBCL Case Type Origin V H gene Relapse GHM2 eDLBCL stomach 1–69 no GHM3 eDLBCL stomach 3–23 no GHM5 eDLBCL stomach 3-30-3 yes GHM7 eDLBCL stomach 4–34 no GHM8 eDLBCL stomach 3–30 no EHM12 eDLBCL thyroid 6–1 no EHM15 eDLBCL salivary gland 3-30-3 yes EHM16 eDLBCL salivary gland 3-30-3 yes EHM18 eDLBCL thyroid 2–70 no EHM19 eDLBCL salivary gland 1–69 no ENM14 MALT thyroid 3-30-3 yes ENM21 MALT salivary gland 1–69 no ENM29 MALT salivary gland 1–69 no ENM30 MALT salivary gland 4–34 no ENM33 MALT thyroid 1–69 no ENM35 MALT thyroid 4–34 no GNM36 MALT stomach 5–51 no GNM37 MALT stomach 4–34 no GNM38 MALT stomach 6–1 no GNM39 MALT stomach 5–51 no GNM41 MALT stomach 4–34 no

scholarly journals Relative contribution of T and B cells to hypermutation and selection of the antibody repertoire in germinal centers of aged mice.

1996 ◽  
Vol 183 (3) ◽  
pp. 959-970 ◽  
Author(s):  
X Yang ◽  
J Stedra ◽  
J Cerny
Keyword(s):  
T Cells ◽  
B Cells ◽  
Somatic Hypermutation ◽  
Variable Region ◽  
Germinal Centers ◽  
Antibody Repertoire ◽  
Gene Repertoire ◽  
Aged Mice ◽  
Relative Contribution ◽  
Adult Mice

The immune system of aged individuals often produces antibodies that have lower affinity and are less protective than antibodies from young individuals. Recent studies in mice suggested that antibodies produced by old individuals may be encoded by distinct immunoglobulin (Ig) genes and that the somatic hypermutation process in these individuals is compromised. The present study employed Ighb scid mice reconstituted with normal lymphocytes from young (2-3-mo-old) and aged (20-25-mo-old) donors and immunized with a protein conjugate of the hapten (4-hydroxy-3-nitrophenyl)acetyl (NP) to determine whether the molecular changes in antibody repertoire reflect senescence in the B cells or whether they are mediated by the aging helper T lymphocytes. The NP-reactive B cells from splenic germinal centers (GC) were recovered by microdissection of frozen tissue sections and their rearranged Ig heavy chain variable region (VH) genes of the V186.2/V3 families were sequenced. It was found that the VH gene repertoire of the GC B cells was strongly influenced by the source of the CD4+ T cells. When T cells were donated by young mice, the anti-NP response in GC was dominated by the canonical V186.2 gene, even if the responder B cells came from aged donors. However, when the mice were reconstituted with T cells from aged donors, the expression of the V186.2 gene by young B cells was diminished and the response was dominated by the C1H4 gene, another member of the V186.2/V3 family. In contrast, the somatic hypermutation process in the GC B cells followed a different pattern. The mutation frequencies in the animals that were reconstituted with both B and T cells from young donors (1/50 to 1/150 bp) were comparable to the frequencies previously reported for NP-immunized intact young/adult mice. However, when either lymphocyte subset was donated by the aged mice, the mutation frequencies declined. Thus, mice reconstituted with T cells from the aged and B cells from the young had severely compromised mutational mechanism. Likewise, the recipients of aged B and young T cells had diminished mutations even though the repertoire of their anti-NP response was dominated by the canonical V186.2 gene. It appears that the change in germine-encoded repertoire and the decrease of somatic hypermutation represent distinct mechanisms of immunosenescence and that the aging of helper T cells plays a pivotal role in both of these processes.

scholarly journals Distinct clonal evolution of B-cells in HIV controllers with neutralizing antibody breadth

2020 ◽  
Author(s):  
Deniz Cizmeci ◽  
Giuseppe Lofano ◽  
Anne-Sophie Dugast ◽  
Dongkyoon Kim ◽  
Guy Cavet ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Somatic Hypermutation ◽  
Clonal Evolution ◽  
Neutralizing Antibody ◽  
Affinity Maturation ◽  
Gene Repertoire ◽  
Immunoglobulin Gene ◽  
Hiv Controllers ◽  
Hiv 1

AbstractA minor subset of individuals infected with HIV-1 develop antibody neutralization breadth during the natural course of the infection, often linked to chronic, high level viremia. Despite significant efforts, vaccination strategies have been unable to induce similar neutralization breadth and the mechanisms underlying neutralizing antibody induction remain largely elusive. Broadly neutralizing antibody responses can also be found in individuals who control HIV to low and even undetectable plasma levels in the absence of antiretroviral therapy, suggesting that high antigen exposure is not a strict requirement for neutralization breadth. We therefore performed an analysis of paired heavy and light chain B-cell receptor repertoires in 12,591 HIV-1 Envelope-specific single memory B-cells to determine alterations in the BCR immunoglobulin gene repertoire and B-cell clonal expansions that associate with neutralizing antibody breadth in 22 HIV controllers. We found that the frequency of genomic mutations in IGHV and IGLV was directly correlated with serum neutralization breadth. The repertoire of the most mutated antibodies was dominated by a small number of large clones with evolutionary signatures suggesting that these clones had reached peak affinity maturation. These data demonstrate that even in the setting of low plasma HIV antigenemia, similar to what a vaccine can potentially achieve, BCR selection for extended somatic hypermutation and clonal evolution can occur in some individuals suggesting that host-specific factors might be involved that could be targeted with future vaccine strategies.

scholarly journals Genomic Uracil and Aberrant Profile of Demethylation Intermediates in Epigenetics and Hematologic Malignancies

2021 ◽  
Vol 22 (8) ◽  
pp. 4212
Author(s):  
Ryszard Olinski ◽  
Geir Slupphaug ◽  
Marek Foksinski ◽  
Hans Einar Krokan
Keyword(s):  
B Cells ◽  
Adaptive Immunity ◽  
Somatic Hypermutation ◽  
Hematologic Malignancies ◽  
Living Cells ◽  
Oxidation Products ◽  
Epigenetic Mark ◽  
Active Demethylation ◽  
Dna Base ◽  
Natural Modification

DNA of all living cells undergoes continuous structural and chemical alterations resulting from fundamental cellular metabolic processes and reactivity of normal cellular metabolites and constituents. Examples include enzymatically oxidized bases, aberrantly methylated bases, and deaminated bases, the latter largely uracil from deaminated cytosine. In addition, the non-canonical DNA base uracil may result from misincorporated dUMP. Furthermore, uracil generated by deamination of cytosine in DNA is not always damage as it is also an intermediate in normal somatic hypermutation (SHM) and class shift recombination (CSR) at the Ig locus of B-cells in adaptive immunity. Many of the modifications alter base-pairing properties and may thus cause replicative and transcriptional mutagenesis. The best known and most studied epigenetic mark in DNA is 5-methylcytosine (5mC), generated by a methyltransferase that uses SAM as methyl donor, usually in CpG contexts. Oxidation products of 5mC are now thought to be intermediates in active demethylation as well as epigenetic marks in their own rights. The aim of this review is to describe the endogenous processes that surround the generation and removal of the most common types of DNA nucleobase modifications, namely, uracil and certain epigenetic modifications, together with their role in the development of hematological malignances. We also discuss what dictates whether the presence of an altered nucleobase is defined as damage or a natural modification.

Inactivating SOCS1 mutations are caused by aberrant somatic hypermutation and restricted to a subset of B-cell lymphoma entities

Blood ◽  
2009 ◽  
Vol 114 (20) ◽  
pp. 4503-4506 ◽  
Author(s):  
Anja Mottok ◽  
Christoph Renné ◽  
Marc Seifert ◽  
Elsie Oppermann ◽  
Wolf Bechstein ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Lymphoma ◽  
Somatic Hypermutation ◽  
B Cell Lymphoma ◽  
Rare Mutations ◽  
Large B Cell Lymphoma ◽  
Mantle Cell ◽  
Follicular Lymphomas ◽  
Large B Cell

Abstract STATs are constitutively activated in several malignancies. In primary mediastinal large B-cell lymphoma and Hodgkin lymphoma (HL), inactivating mutations in SOCS1, an inhibitor of JAK/STAT signaling, contribute to deregulated STAT activity. Based on indications that the SOCS1 mutations are caused by the B cell–specific somatic hypermutation (SHM) process, we analyzed B-cell non-HL and normal B cells for mutations in SOCS1. One-fourth of diffuse large B-cell lymphoma and follicular lymphomas carried SOCS1 mutations, which were preferentially targeted to SHM hotspot motifs and frequently obviously inactivating. Rare mutations were observed in Burkitt lymphoma, plasmacytoma, and mantle cell lymphoma but not in tumors of a non–B-cell origin. Mutations in single-sorted germinal center B cells were infrequent relative to other genes mutated as byproducts of normal SHM, indicating that SOCS1 inactivation in primary mediastinal large B-cell lymphoma, HL, diffuse large B-cell lymphoma, and follicular lymphoma is frequently the result of aberrant SHM.

scholarly journals Constitutive Expression of AID Leads to Tumorigenesis

2003 ◽  
Vol 197 (9) ◽  
pp. 1173-1181 ◽  
Author(s):  
Il-mi Okazaki ◽  
Hiroshi Hiai ◽  
Naoki Kakazu ◽  
Shuichi Yamada ◽  
Masamichi Muramatsu ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Genome Stability ◽  
Somatic Hypermutation ◽  
Cytidine Deaminase ◽  
Point Mutations ◽  
Constitutive Expression ◽  
Cell Receptor ◽  
Genetic Alterations ◽  
Artificial Substrates

Genome stability is regulated by the balance between efficiencies of the repair machinery and genetic alterations such as mutations and chromosomal rearrangements. It has been postulated that deregulation of class switch recombination (CSR) and somatic hypermutation (SHM), which modify the immunoglobulin (Ig) genes in activated B cells, may be responsible for aberrant chromosomal translocations and mutations of non-Ig genes that lead to lymphocyte malignancy. However, the molecular basis for these genetic instabilities is not clearly understood. Activation-induced cytidine deaminase (AID) is shown to be essential and sufficient to induce both CSR and SHM in artificial substrates in fibroblasts as well as B cells. Here we show that constitutive and ubiquitous expression of AID in transgenic mice caused both T cell lymphomas and dysgenetic lesions of epithelium of respiratory bronchioles (micro-adenomas) in all individual mice. Point mutations, but not translocations, were massively introduced in expressed T cell receptor (TCR) and c-myc genes in T lymphoma cells. The results indicate that AID can mutate non-Ig genes including oncogenes, implying that aberrant AID expression could be a cause of human malignancy.

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