scholarly journals Somatic Mutation of the Cd95 Gene in Human B Cells as a Side-Effect of the Germinal Center Reaction

2000 ◽  
Vol 192 (12) ◽  
pp. 1833-1840 ◽  
Author(s):  
Markus Müschen ◽  
Daniel Re ◽  
Berit Jungnickel ◽  
Volker Diehl ◽  
Klaus Rajewsky ◽  
...  
Keyword(s):  
B Cells ◽  
Germinal Center ◽  
Negative Selection ◽  
Somatic Mutations ◽  
Somatic Hypermutation ◽  
Suppressor Gene ◽  
Death Domain ◽  
Apoptosis Resistance ◽  
Germinal Center Reaction ◽  
Human B Cells

Somatic hypermutation specifically modifies rearranged immunoglobulin (Ig) genes in germinal center (GC) B cells. However, the bcl-6 gene can also acquire somatic mutations during the GC reaction, indicating that certain non-Ig genes can be targeted by the somatic hypermutation machinery. The CD95 gene, implicated in negative selection of B lymphocytes in GCs, is specifically expressed by GC B cells and was recently identified as a tumor suppressor gene being frequently mutated in (post) GC B cell lymphomas. In this study, the 5′ region (5′R) and/or the last exon coding for the death domain (DD) of the CD95 gene were investigated in naive, GC, and memory B cells from seven healthy donors. About 15% of GC and memory, but not naive, B cells carried mutations within the 5′R (mutation frequency 2.5 × 10−4 per basepair). Mutations within the DD were very rare but could be efficiently selected by inducing CD95-mediated apoptosis: in 22 apoptosis-resistant cells, 12 DD mutations were found. These results indicate that human B cells can acquire somatic mutations of the CD95 gene during the GC reaction, which potentially confers apoptosis resistance and may counteract negative selection through the CD95 pathway.

Analysis of IgVH, BCL-6, PIM, RHO/TTF and PAX5 Mutational Status in Splenic and Nodal Marginal Zone B Cell Lymphoma Suggests a Particular B Cell Origin.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 162-162 ◽  
Author(s):  
Alexandra Traverse-Glehen ◽  
Aurelie Verney ◽  
Lucille Baseggio ◽  
Pascale Felman ◽  
Evelyne Callet-Bauchu ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Somatic Mutations ◽  
Marginal Zone ◽  
Somatic Hypermutation ◽  
B Cell Lymphoma ◽  
Marginal Zone B Cells ◽  
Mutational Status ◽  
Frequent Absence

Abstract Background and Objectives Splenic and nodal marginal zone B cell lymphoma (SMZL and NMZL) have been recently identified as distinct clinicopathological entities in the WHO classification. These lymphomas entities may have a common origin in the marginal B-cell compartment of the lymphoid organs. However the precise cell of origin of marginal zone B cells, its status in the B cell differentiation pathway and the mechanisms involved in lymphomagenesis remain unclear. The most widely held view is that marginal zone B cells are mostly memory B cells. But the origin of these cells, especially the transit through germinal center pathway, remains contradictory. Somatically mutated variable-region of immunoglobulin genes and bcl-6 gene represent at this time faithful markers for exposure to the germinal center. In addition, aberrant somatic hypermutations have been suggested to contribute to the development of B-cell lymphomas, occurring in the 5′ sequence of several proto-oncogenes. Interestingly those mutation do not occur in normal germinal center B cells. Design and Methods: IgVH, BCL-6, PIM1, Rho/TTF and PAX 5 genes, highly mutated in DLBCL and other indolent lymphoma such as B-CLL, were analysed for the presence of somatic mutations from 50 marginal zone lymphoma tissue and blood samples (21 NMZL and 29 SMZL including 10 cases with numerous villous lymphoma cells in peripheral blood). According to the morphological and immunophenotypical analysis, the fraction of malignant cells in the specimen was 70% or more in all cases. Mutational analysis was restricted to the regions previously shown to contain more than 95% of mutations in DLBCL. PCR products were directly sequenced on both sides and perfomed in duplicate in two independent reactions. Results: Out of 18 NMZL cases analysed for IgVH mutational status (3 cases not analysed for IgVH) 15 cases were mutated and 21 out of 28 in SMZL cases. Mutation of BCL-6 was detected in only 1 NMZL patients (1/21) and 1 SMZL patients (1/29). For RhoH/TTF, PIM1, PAX5 the mutation average was also low with only 1 case mutated per group and per gene, with a different case mutated in each for each gene. Conclusion In summary, we demonstrate the low frequency of aberrant somatic mutations in SMZL and NMZL, suggesting that this process is probably not a major contributor to lymphomageneis. However the frequent absence of mutation in BCL6 suggest a particular differentiation pathway, as suggested before in normal marginal zone B cells, possibly without transit through the germinal center. Interestingly the relatively high frequency of VH mutated cases compared with the frequent absence of mutation of BCL6, considered as a specific germinal center tag, could suggest somatic hypermutation outside the germinal center. In addition the absence of hypermutation could be linked with the absence of recurrent translocation in SMZL and NMZL, the translocation process haveing been associated with somatic hypermutation dysfunction.

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 A novel human B cell subpopulation representing the initial germinal center population to express AID

Blood ◽  
2006 ◽  
Vol 109 (6) ◽  
pp. 2545-2552 ◽  
Author(s):  
Grant R. Kolar ◽  
Darshna Mehta ◽  
Rosana Pelayo ◽  
J. Donald Capra
Keyword(s):  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Somatic Hypermutation ◽  
Cytidine Deaminase ◽  
Cell Subpopulation ◽  
Human Tonsil ◽  
Germinal Center Reaction ◽  
Cell Subpopulations ◽  
Human B Cell

Abstract We have identified a novel mature human B-cell subpopulation in the human tonsil that has characteristics of both naive B cells and germinal center B cells including the expression of activation-induced cytidine deaminase (AID), which is essential for the process of immunoglobulin somatic hypermutation and class-switch recombination. These cells are clearly somatically hypermutated, albeit modestly. Their phenotype (IgD+CD38−CD23−FSChiCD71+) is unique and suggests they may be intermediate between both naive and germinal center cells. Morphologically they are also distinct from other B-cell subpopulations. The evidence presented suggests these cells may be the founder cells of the germinal center reaction (a pro-GC cell) and may be the normal counterpart of the mantle cell lymphoma cell.

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

Abstract 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 Original Antigenic Sin: the Downside of Immunological Memory and Implications for COVID-19

mSphere ◽  
2021 ◽  
Vol 6 (2) ◽  
Author(s):  
Eric L. Brown ◽  
Heather T. Essigmann
Keyword(s):  
B Cells ◽  
Germinal Center ◽  
Somatic Hypermutation ◽  
Memory B Cells ◽  
Antibody Responses ◽  
Germinal Center Reaction ◽  
Link Type ◽  
Class Switch ◽  
Human Coronaviruses ◽  
Original Antigenic Sin

ABSTRACT The concept of original antigenic sin (OAS) was put forth many years ago to explain how humoral memory responses generated against one set of antigens can affect the nature of antibody responses elicited to challenge infections or vaccinations containing a similar but not identical array of antigens. Here, we highlight the link between OAS and the germinal center reaction (GCR), a process unique to activated B cells undergoing somatic hypermutation and class switch recombination. It is the powerful response of activated memory B cells and the accompanying GCR that establish the foundations of OAS. We apply these concepts to the current COVID-19 pandemic and put forth several possible scenarios whereby OAS may result in either beneficial or harmful outcomes depending, hypothetically, on prior exposure to antigens shared between SARS-CoV-2 and seasonal human coronaviruses (hCoVs) that include betacoronaviruses (e.g., HCoV-OC43 and HCoV-HKU1) and alphacoronaviruses (e.g., HCoV-NL63 and HCoV-HKU1) (E. M. Anderson, E. C. Goodwin, A. Verma, C. P. Arevalo, et al., medRxiv, 2020, https://doi.org/10.1101/2020.11.06.20227215; S. M. Kissler, C. Tedijanto, E. Goldstein, Y. H. Grad, and M. Lipsitch, Science 368:860–868, 2020, https://doi.org/10.1126/science.abb5793).

scholarly journals Activation-Induced Cytidine Deaminase Acts as a Mutator in BCR-ABL1-Transformed Acute Lymphoblastic Leukemia Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 640-640
Author(s):  
Niklas Feldhahn ◽  
Florian Klein ◽  
Wolf-Karsten Hofmann ◽  
Janet D. Rowley ◽  
Hassan Jumaa ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
B Cells ◽  
Germinal Center ◽  
Somatic Mutations ◽  
Kinase Activity ◽  
Somatic Hypermutation ◽  
Lymphoblastic Leukemia ◽  
V Region ◽  
Germinal Center B Cells

Abstract Acute lymphoblastic leukemia (ALL) cells are derived from B and T cell precursors and typically carry rearranged immunglobulin (Ig) or T cell receptor (TCR) variable (V) region genes devoid of somatic mutations. The Philadelphia chromsome (Ph) encoding the oncogenic BCR-ABL1 kinase defines a subset of ALL with a particularly unfavorable prognosis. Here we show that oncogenic BCR-ABL1 kinase activity induces aberrant somatic hypermutation in Ph-positive ALL cells. Under physiological conditions, somatic hypermutation is restricted to mature germinal center B cells and depends on expression of the DNA-deaminating enzyme AID. Comparing Ph-positive and Ph-negative ALL cells, AID expression was found in 24 of 28 Ph-positive but only 3 of 80 Ph-negative ALLs. As shown by RT-PCR and Western blot, expression of AID in Ph-positive ALL cells reached similar levels as in germinal center B cells. Forced expression of BCR-ABL1 in Ph-negative ALL cells and usage of the BCR-ABL1-kinase inhibitor STI571 revealed that BCR-ABL1 kinase activity is required and sufficient to induce aberrant expression of AID in Ph-positive ALL. Consistent with aberrant AID expression in Ph-positive ALL, Ig VH region genes were mutated in most Ph-positive but unmutated in Ph-negative cases. Of note, also non-Ig genes including BCL6 and MYC harbored somatic mutations in Ph-positive but not Ph-negative ALL cells. Likewise, Ph-positive T cell lineage ALL cells express AID and carry somatically mutated TCRβ V region genes. As demonstrated by ligation-mediated PCR, AID introduced DNA-single-strand breaks also within the tumor suppressor gene CDKN2B in Ph-positive ALL cells, which was sensitive to both inhibition of BCR-ABL1 kinase activity and silencing of AID expression by RNA interference. These findings identify AID as a BCR-ABL1-induced mutator in Ph-positive ALL cells, which may be relevant with respect to the particularly unfavorable prognosis of this leukemia subset.

The Pattern of Immunoglobulin Variable Genes Indicates That Most Post-Transplant Lymphoproliferative Disorders Derive from B-Cells That Have Failed the Germinal Center Reaction.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 702-702 ◽  
Author(s):  
Daniela Capello ◽  
Michaela Cerri ◽  
Eva Berra ◽  
Davide Rossi ◽  
Enrica Morra ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Survival ◽  
Germinal Center ◽  
Mutation Frequency ◽  
Somatic Hypermutation ◽  
B Cell Lymphoma ◽  
Lymphoproliferative Disorders ◽  
Antigen Binding ◽  
Germinal Center Reaction

Abstract Monoclonal posttransplant lymphoproliferative disorders (PTLD) comprise polymorphic PTLD (P-PTLD), diffuse large B cell lymphoma (DLBCL) and Burkitt/Burkitt-like lymphoma (BL/BLL). Recent studies have elucidated the germinal center-origin (GC) of PTLD, yet a detailed analysis of IgVH and IgVL chain genes is lacking. We investigated 54 PTLD, including 16 P-PTLD, 35 DLBCL and 3 BL/BLL for usage, mutation frequency and mutation pattern of clonal IgVH and IgVL rearrangements. A functional IgVH rearrangement was identified in 47/54 (87.0%) cases. Four cases yeilded only an out of frame IgVH rearrangement or a rearrangement rendered nonfunctional by crippling mutations. Three cases showed hybrid Ig VDJ rearrangements: two cases with a V-V fusion rearrangement and one case with a J-J fusion rearrangement, suggesting a failed attempt of heavy chain receptor revision in GC reaction. Despite extensive investigation by multiple PCR strategies, a functional IgVL rearrangement was found in only 25/54 (46.3%) cases. Eleven out of 25 (44.0%) cases harbored IgV kappa rearrangements and 12/25 (48.0%) cases harbored functional IgV lambda rearrangements. Two cases showed the presence of both IgV kappa and IgV lambda functional rearrangements. Among PTLD carrying solely nonfunctional IgVL rearrangements, 7/54 (13.0%) cases showed a crippled rearrangement and 11/54 (20.4%) cases harbored only an out of frame and/or inactivated IgV kappa gene. Inactivation occurred by rearrangement involving the kappa-deleting element (KDE). In 11/54 (20.4%) cases, no IgVL rearrangement was identified. Overall, only 23/54 (42.6%) PTLD displayed both a functional IgVH and a functional IgVL rearrangement. Analysis of somatic hypermutation showed the presence of somatically hypermutated IgVH and/or IgVL genes in 45/54 PTLD (83.3%). Conversely, IgV rearrangements of 9/54 (16.6%) PTLD were in germline configuration, suggesting a derivation from B-cells that have not experienced the GC-reaction. Among mutated cases, the average mutation frequency was 8.83% (median 8.43%, range 2.10%–24.1%) for IgVH genes and 7.37% (median 6.71%, range 2.30%–26.0%) for IgVL genes. Thirty-two cases (71.1%) showed highly mutated (mutation frequency >6%) IgVH and/or IgVL genes, a condition that, in normal B-cell, results in lower affinity for antigen and apoptosis. Analysis of the distribution of replacement and silent mutations in functional IgVH and/or IgVL sequences showed tendency to conserve FR sequences and maintain antigen binding in 20/34 (58.8%) cases. Selection for high affinity antigen binding occurred in 14/34 (41.2%) cases. Our data suggest that most PTLD arise from B-cells that have experienced the GC-reaction and frequently display impaired B-cell receptors (BCR). Since a functional receptor is required for normal B-cell survival during GC transit, PTLD development may implicate rescue from apoptosis and expansion of B-cells that have failed the GC-reaction. Notably, virtually all PTLD with nonfunctional IgVH and/or IgVL rearrangements carried EBV infection, which may promote cell survival.

Somatic hypermutation in normal and transformed human B cells

1998 ◽  
Vol 162 (1) ◽  
pp. 261-280 ◽  
Author(s):  
Ulf Klien ◽  
Tina Goasens ◽  
Motthias Fischer ◽  
Holger Kanzler ◽  
Andreas Braeuninger ◽  
...  
Keyword(s):  
B Cells ◽  
Somatic Hypermutation ◽  
Human B Cells

scholarly journals Germinal centers in human lymph nodes contain reactivated memory B cells

2007 ◽  
Vol 204 (11) ◽  
pp. 2655-2665 ◽  
Author(s):  
Richard J. Bende ◽  
Febe van Maldegem ◽  
Martijn Triesscheijn ◽  
Thera A.M. Wormhoudt ◽  
Richard Guijt ◽  
...  
Keyword(s):  
B Cells ◽  
Lymph Nodes ◽  
Germinal Center ◽  
Lymphoid Tissue ◽  
Somatic Hypermutation ◽  
Germinal Centers ◽  
Memory B Cells ◽  
Cell Clones ◽  
Clonal Origin ◽  
Successive Recall

To reveal migration trails of antigen-responsive B cells in lymphoid tissue, we analyzed immunoglobulin (Ig)M-VH and IgG-VH transcripts of germinal center (GC) samples microdissected from three reactive human lymph nodes. Single B cell clones were found in multiple GCs, one clone even in as many as 19 GCs. In several GCs, IgM and IgG variants of the same clonal origin were identified. The offspring of individual hypermutated IgG memory clones were traced in multiple GCs, indicating repeated engagement of memory B cells in GC reactions. These findings imply that recurring somatic hypermutation progressively drives the Ig repertoire of memory B cells to higher affinities and infer that transforming genetic hits in non-Ig genes during lymphomagenesis do not have to arise during a single GC passage, but can be collected during successive recall responses.

scholarly journals Cbl and Cbl-b control the germinal center reaction by facilitating naive B cell antigen processing

2020 ◽  
Vol 217 (9) ◽  
Author(s):  
Xin Li ◽  
Liying Gong ◽  
Alexandre P. Meli ◽  
Danielle Karo-Atar ◽  
Weili Sun ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Antigen Processing ◽  
Cell Interaction ◽  
Affinity Maturation ◽  
Antigen Uptake ◽  
Cell Antigen ◽  
Germinal Center Reaction ◽  
Follicular Helper

Antigen uptake and presentation by naive and germinal center (GC) B cells are different, with the former expressing even low-affinity BCRs efficiently capture and present sufficient antigen to T cells, whereas the latter do so more efficiently after acquiring high-affinity BCRs. We show here that antigen uptake and processing by naive but not GC B cells depend on Cbl and Cbl-b (Cbls), which consequently control naive B and cognate T follicular helper (Tfh) cell interaction and initiation of the GC reaction. Cbls mediate CD79A and CD79B ubiquitination, which is required for BCR-mediated antigen endocytosis and postendocytic sorting to lysosomes, respectively. Blockade of CD79A or CD79B ubiquitination or Cbls ligase activity is sufficient to impede BCR-mediated antigen processing and GC development. Thus, Cbls act at the entry checkpoint of the GC reaction by promoting naive B cell antigen presentation. This regulation may facilitate recruitment of naive B cells with a low-affinity BCR into GCs to initiate the process of affinity maturation.

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