scholarly journals Repertoire Sequencing of B Cells Elucidates the Role of UNG and Mismatch Repair Proteins in Somatic Hypermutation in Humans

2019 ◽  
Vol 10 ◽  
Author(s):  
Hanna IJspeert ◽  
Pauline A. van Schouwenburg ◽  
Ingrid Pico-Knijnenburg ◽  
Jan Loeffen ◽  
Laurence Brugieres ◽  
...  
Keyword(s):  
B Cells ◽  
Mismatch Repair ◽  
Somatic Hypermutation ◽  
Repertoire Sequencing ◽  
Mismatch Repair Proteins

Evaluation of immunohistochemical expression of mismatch repair proteins in endometrioid and seromucinous borderline ovarian tumors a 10-year experience in a large health care institution.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e17557-e17557
Author(s):  
Hector Chavarria ◽  
Marina Frimer ◽  
Noah D. Kauff ◽  
Veena S. John ◽  
Seema Khutti
Keyword(s):  
Mismatch Repair ◽  
Ovarian Tumors ◽  
Borderline Tumor ◽  
Nuclear Staining ◽  
Immunohistochemical Expression ◽  
Stromal Invasion ◽  
Borderline Tumors ◽  
Dna Mismatch ◽  
Mismatch Repair Proteins

e17557 Background: Borderline tumors (BT) are atypical proliferation of epithelium in the ovary in the absence of destructive stromal invasion, representing for 15% of all epithelial ovarian cancers. [1] Around 10% of the ovarian tumors are hereditary, and approximately 10% of all the hereditary forms of epithelial ovarian tumors are result of a loss of DNA mismatch repair (MMR). [2] Endometrioid borderline tumor (EBT) and Seromucinous borderline tumors (SMBT) are rare tumors in ovary and there is limited literature available on immunohistochemical (IHC) expression of Mismatch repair proteins(MMRP)in these tumors.[3, 4] The aim of this study is to evaluate IHC expression of MMRP in EBT and SMBT of ovary. Methods: Pathology database was searched for ovarian Endometrioid borderline tumor (EBT) and Seromucinous borderline tumor (SMBT) for a 10-year period (2010-2020). The cohort consisted of 10 EBT (6 of which had focal microinvasion or carcinoma) and 12 SMBT(2 of which had focal carcinoma ). For comparison, 1 borderline Brenner. 15 serous borderline tumors (SBT) and 15 mucinous borderline tumors (MBT) were also included. After reviewing slides, a block with adequate borderline tumor was selected for IHC stains. For the cases with carcinoma, two different blocks with each component were selected. In all selected blocks, IHC stains for four MMRP (MLH1, PMS2, MSH2, MSH6) were performed. The complete absence of nuclear staining in tumor cells was considered as “loss” of the MMRP expression. Any “weak” or “focal” nuclear staining was considered intact. Results: Total 53 cases were evaluated for MMRP IHC. All cases had intact MMRP expression. In cases with carcinoma, both components (BT and carcinoma) have intact MMR IHC expression. See table. Conclusions: Our study did not show loss of MMRP IHC expression in EMT or SMBT. However, our study consisted of a small number of cases. Multi Institutional study with a large number of cases can be helpful in future to further evaluate the role of MMRP IHC in EMT and SMBT. [Table: see text]

scholarly journals H2AX Is Required for Recombination Between Immunoglobulin Switch Regions but Not for Intra-Switch Region Recombination or Somatic Hypermutation

2003 ◽  
Vol 197 (12) ◽  
pp. 1767-1778 ◽  
Author(s):  
Bernardo Reina-San-Martin ◽  
Simone Difilippantonio ◽  
Leif Hanitsch ◽  
Revati F. Masilamani ◽  
André Nussenzweig ◽  
...  
Keyword(s):  
B Cells ◽  
Posttranslational Modifications ◽  
Somatic Hypermutation ◽  
Dna Lesions ◽  
Switch Region ◽  
Histone H2ax ◽  
Class Switch ◽  
Switch Regions ◽  
Precise Role

Changes in chromatin structure induced by posttranslational modifications of histones are important regulators of genomic function. Phosphorylation of histone H2AX promotes DNA repair and helps maintain genomic stability. Although B cells lacking H2AX show impaired class switch recombination (CSR), the precise role of H2AX in CSR and somatic hypermutation (SHM) has not been defined. We show that H2AX is not required for SHM, suggesting that the processing of DNA lesions leading to SHM is fundamentally different from CSR. Impaired CSR in H2AX−/− B cells is not due to alterations in switch region transcription, accessibility, or aberrant joining. In the absence of H2AX, short-range intra-switch region recombination proceeds normally while long-range inter-switch region recombination is impaired. Our results suggest a role for H2AX in regulating the higher order chromatin remodeling that facilitates switch region synapsis.

scholarly journals Accurate Immune Repertoire Sequencing Reveals Malaria Infection Driven Antibody Lineage Diversification in Young Children

2017 ◽  
Author(s):  
Ben S. Wendel ◽  
Chenfeng He ◽  
Mingjuan Qu ◽  
Di Wu ◽  
Stefany M. Hernandez ◽  
...  
Keyword(s):  
B Cells ◽  
Somatic Hypermutation ◽  
Antibody Repertoire ◽  
Infants And Toddlers ◽  
High Coverage ◽  
Sequence Composition ◽  
Age Related ◽  
Sequencing Method ◽  
Repertoire Sequencing ◽  
Lineage Diversification

ABSTRACTAccurately measuring antibody repertoire sequence composition in a small amount of blood is challenging yet important to the understanding of the repertoire response to infections and vaccinations. Here, we describe an accurate and high-coverage repertoire sequencing method, MIDCIRS, which uses as few as 1,000 naïve B cells. Using it, we studied age-related antibody repertoire development and diversification before and during acute malaria in infants (< 12 months old) and toddlers (12 – 47 months old) with 4-8 ml of blood draws. Unexpectedly, we discovered high levels of somatic hypermutation (SHM) in infants as young as three months old. Antibody clonal lineage analysis revealed that both infants and toddlers increase SHM levels upon infection and memory B cells isolated from pre-malaria samples in malaria-experienced individuals continue to induce SHMs upon malaria rechallenge. These results highlight the vast potential of antibody repertoire diversification in infants and toddlers that has not been realized previously.

scholarly journals Local BLyS production by T follicular cells mediates retention of high affinity B cells during affinity maturation

2013 ◽  
Vol 211 (1) ◽  
pp. 45-56 ◽  
Author(s):  
Radhika Goenka ◽  
Andrew H. Matthews ◽  
Bochao Zhang ◽  
Patrick J. O’Neill ◽  
Jean L. Scholz ◽  
...  
Keyword(s):  
B Cells ◽  
B Lymphocyte ◽  
Somatic Hypermutation ◽  
Affinity Maturation ◽  
Local Source ◽  
High Affinity ◽  
Cell Clones ◽  
B Lymphocyte Stimulator ◽  
Efficient Selection

We have assessed the role of B lymphocyte stimulator (BLyS) and its receptors in the germinal center (GC) reaction and affinity maturation. Despite ample BLyS retention on B cells in follicular (FO) regions, the GC microenvironment lacks substantial BLyS. This reflects IL-21–mediated down-regulation of the BLyS receptor TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor) on GC B cells, thus limiting their capacity for BLyS binding and retention. Within the GC, FO helper T cells (TFH cells) provide a local source of BLyS. Whereas T cell–derived BLyS is dispensable for normal GC cellularity and somatic hypermutation, it is required for the efficient selection of high affinity GC B cell clones. These findings suggest that during affinity maturation, high affinity clones rely on TFH-derived BLyS for their persistence.

scholarly journals A/T mutagenesis in hypermutated immunoglobulin genes strongly depends on PCNAK164 modification

2007 ◽  
Vol 204 (8) ◽  
pp. 1989-1998 ◽  
Author(s):  
Petra Langerak ◽  
Anders O.H. Nygren ◽  
Peter H.L. Krijger ◽  
Paul C.M. van den Berk ◽  
Heinz Jacobs
Keyword(s):  
B Cells ◽  
Somatic Hypermutation ◽  
Cytidine Deaminase ◽  
Nuclear Antigen ◽  
Translesion Dna Synthesis ◽  
Class Switch ◽  
Activation Induced Cytidine Deaminase ◽  
Mismatch Recognition ◽  
Proliferating Cell

B cells use translesion DNA synthesis (TLS) to introduce somatic mutations around genetic lesions caused by activation-induced cytidine deaminase. Monoubiquitination at lysine164 of proliferating cell nuclear antigen (PCNAK164) stimulates TLS. To determine the role of PCNAK164 modifications in somatic hypermutation, PCNAK164R knock-in mice were generated. PCNAK164R/K164R mutants are born at a sub-Mendelian frequency. Although PCNAK164R/K164R B cells proliferate and class switch normally, the mutation spectrum of hypermutated immunoglobulin (Ig) genes alters dramatically. A strong reduction of mutations at template A/T is associated with a compensatory increase at G/C, which is a phenotype similar to polymerase η (Polη) and mismatch repair–deficient B cells. Mismatch recognition, monoubiquitinated PCNA, and Polη likely cooperate in establishing mutations at template A/T during replication of Ig genes.

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