scholarly journals Activation-induced cytidine deaminase in B cells of hepatits C virus-related cryoglobulinaemic vasculitis

2015 ◽  
Vol 182 (3) ◽  
pp. 323-331 ◽  
Author(s):  
S. Russi ◽  
F. Dammacco ◽  
S. Sansonno ◽  
F. Pavone ◽  
D. Sansonno
Keyword(s):  
B Cells ◽  
Cytidine Deaminase ◽  
Activation Induced Cytidine Deaminase ◽  
Hepatits C Virus ◽  
Cryoglobulinaemic Vasculitis

scholarly journals The Balance Between Pax5 and Id2 Activities Is the Key to AID Gene Expression

2003 ◽  
Vol 198 (9) ◽  
pp. 1427-1437 ◽  
Author(s):  
Hiroyuki Gonda ◽  
Manabu Sugai ◽  
Yukiko Nambu ◽  
Tomoya Katakai ◽  
Yasutoshi Agata ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cells ◽  
Cytidine Deaminase ◽  
Regulatory Region ◽  
Binding Activity ◽  
Class Switch ◽  
Dna Binding Activity ◽  
Activation Induced Cytidine Deaminase ◽  
Putative Regulatory Region ◽  
Kinetics Of

Pax5 activity is enhanced in activated B cells and is essential for class switch recombination (CSR). We show that inhibitor of differentiation (Id)2 suppresses CSR by repressing the gene expression of activation-induced cytidine deaminase (AID), which has been shown to be indispensable for CSR. Furthermore, a putative regulatory region of AID contains E2A- and Pax5-binding sites, and the latter site is indispensable for AID gene expression. Moreover, the DNA-binding activity of Pax5 is decreased in Id2-overexpressing B cells and enhanced in Id2−/− B cells. The kinetics of Pax5, but not E2A, occupancy to AID locus is the same as AID expression in primary B cells. Finally, enforced expression of Pax5 induces AID transcription in pro–B cell lines. Our results provide evidence that the balance between Pax5 and Id2 activities has a key role in AID gene expression.

scholarly journals miR-181b negatively regulates activation-induced cytidine deaminase in B cells

2008 ◽  
Vol 205 (10) ◽  
pp. 2199-2206 ◽  
Author(s):  
Virginia G. de Yébenes ◽  
Laura Belver ◽  
David G. Pisano ◽  
Susana González ◽  
Aranzazu Villasante ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Molecular Mechanisms ◽  
Bystander Effect ◽  
Somatic Hypermutation ◽  
Cytidine Deaminase ◽  
Fine Tuning ◽  
Functional Screening ◽  
Activation Induced Cytidine Deaminase ◽  
Activated B Cells

Activated B cells reshape their primary antibody repertoire after antigen encounter by two molecular mechanisms: somatic hypermutation (SHM) and class switch recombination (CSR). SHM and CSR are initiated by activation-induced cytidine deaminase (AID) through the deamination of cytosine residues on the immunoglobulin loci, which leads to the generation of DNA mutations or double-strand break intermediates. As a bystander effect, endogenous AID levels can also promote the generation of chromosome translocations, suggesting that the fine tuning of AID expression may be critical to restrict B cell lymphomagenesis. To determine whether microRNAs (miRNAs) play a role in the regulation of AID expression, we performed a functional screening of an miRNA library and identified miRNAs that regulate CSR. One such miRNA, miR-181b, impairs CSR when expressed in activated B cells, and results in the down-regulation of AID mRNA and protein levels. We found that the AID 3′ untranslated region contains multiple putative binding sequences for miR-181b and that these sequences can be directly targeted by miR-181b. Overall, our results provide evidence for a new regulatory mechanism that restricts AID activity and can therefore be relevant to prevent B cell malignant transformation.

scholarly journals Specific Expression of Activation-induced Cytidine Deaminase (AID), a Novel Member of the RNA-editing Deaminase Family in Germinal Center B Cells

1999 ◽  
Vol 274 (26) ◽  
pp. 18470-18476 ◽  
Author(s):  
Masamichi Muramatsu ◽  
V. S. Sankaranand ◽  
Shrikant Anant ◽  
Manabu Sugai ◽  
Kazuo Kinoshita ◽  
...  
Keyword(s):  
B Cells ◽  
Rna Editing ◽  
Germinal Center ◽  
Cytidine Deaminase ◽  
Specific Expression ◽  
Activation Induced Cytidine Deaminase ◽  
Germinal Center B Cells

Activation Induced Cytidine Deaminase (AID) Is Required for Germinal-Center Derived Lymphomagenesis.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 223-223
Author(s):  
Laura Pasqualucci ◽  
Mara Compagno ◽  
Tongwei Mo ◽  
Paula Smith ◽  
Herbert C. Morse ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Somatic Hypermutation ◽  
Profile Analysis ◽  
Cytidine Deaminase ◽  
Receptor Gene ◽  
Activation Induced Cytidine Deaminase ◽  
Hodgkin's Lymphomas

Abstract Most B cell non-Hodgkin’s lymphomas (B-NHL) derive from germinal center (GC) B cells and their pathogenesis is associated with the accumulation of distinct genetic lesions, including chromosomal translocations and a more recently identified mechanism of genomic instability, termed aberrant somatic hypermutation. These alterations are thought to be due to mistakes occurring during two GC-associated immunoglobulin (Ig) genes remodeling processes: class switch recombination (CSR) and somatic hypermutation (SHM). However, this model has never been formally proven. To conclusively investigate the role of CSR and SHM in the pathogenesis of B-NHL, we examined whether lymphoma development in mice requires the function of activation induced cytidine deaminase (AID), a DNA editing enzyme expressed specifically in GC and activated B cells and essential for both processes. Three transgenic mouse models were generated by crossing lymphoma-prone mice (λMYC, λMYC/IμHABCL6 and IμHABCL6) with mice (AID−/−) that are unable to undergo both SHM and CSR. The λMYC mice develop a diffusely infiltrating monoclonal proliferation of pre-GC origin, with unmutated IgV genes and lack of BCL6 expression, and therefore presumably independent from AID-associated DNA remodeling events. Conversely, lymphomas in λMYC/IμHABCL6 and IμHABCL6 mice recapitulate GC/post GC-derived malignancies, in that the former display somatically mutated IgV genes and upregulation of post-GC markers (CD138) in most of the cases, while the latter develop a splenic lymphoproliferative syndrome that culminates, past 12 months of age, in clonal B cell lymphomas with DLBCL morphology and somatically mutated IgV genes (~70% of the animals) (Cattoretti et al., Cancer Cell 7:445–455, 2005). Mice were monitored for tumor incidence and survival, and a combination of histologic, immunophenotypic and gene expression profiling analysis was used for tumor characterization. As expected, no significant differences in event-free survival and lymphoma type were observed between AID-proficient and AID-deficient λMYC mice, in agreement with their pre-GC derivation. Conversely, a phenotypic shift of the tumor was observed in λMYC/IμHABCL6 mice when bred into an AID−/− background, with >80% of the cases (N=21/26) reverting to a pre-GC phenotype (loss of GC/post GC markers) undistinguishable from that of the λMYC and λMYC/AID−/− mice. Gene expression profile analysis on representative cases (N=10 λMYC/IμHABCL6 and 5 each for λMYC, λMYC/AIDKO, λMYC/IμHABCL6/AIDKO) confirmed significant phenotypic similarities between pre-GC derived λMYC lymphomas and the λMYC/IμHABCL6/AID −/− lymphomas, which co-segregated in a separate cluster from λMYC/IμHABCL6 tumors. Analogously, a significant reduction in DLBCL frequency was observed in the IμHABCL6/AIDKO cohort as compared to IμHABCL6 mice (N= 4/19, 21% vs 8/14, 57%; p=0.03). Taken together, these results indicate that GC-derived lymphomas cannot develop in the absence of AID, thereby providing direct support to the notion that AID-mediated mistakes in antigen receptor gene modification events (CSR and SHM) represent major contributors to B-NHL pathogenesis.

Expression of a Dysfunctional Activation Induced Cytidine Deaminase Is Correlated with Disease Progression in Splenic Marginal Zone Lymphoma.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2397-2397
Author(s):  
Gabriel Brisou ◽  
Laurent Jallades ◽  
Alexandra Traverse-Glehen ◽  
Francoise Berger ◽  
Aurélie Verney ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Marginal Zone ◽  
Cytidine Deaminase ◽  
Marginal Zone Lymphoma ◽  
Splenic Marginal Zone Lymphoma ◽  
Marginal Zone B Cells ◽  
Activation Induced Cytidine Deaminase ◽  
Splicing Variants

Abstract Abstract 2397 B cells can undergo at least two differentiation pathways, dependent of T cells or not, starting from follicular or marginal zone B cells respectively. The T-independent response, less understood than the germinal center reaction, is triggered by specific antigens and arises from marginal zone B cells. During this development, some B cells undergo somatic hypermutation (SHM) and class switch recombination (CSR), triggered by the same DNA editing enzyme called Activation Induced Cytidine Deaminase (AID). The splenic marginal zone lymphoma (SMZL) is a rare lymphoproliferative disorder characterized by a clonal expansion of B cells in the marginal zone of the spleen. These B-cells underwent SHM in roughly 60% of the cases but nearly none underwent CSR. These observations suggest that tumor clones originate from a particular activated B cell subset not transiting through the germinal center. In order to confirm this hypothesis, we focused our work on the status and impact of AID in this disease and worked on purified B cells extracted from spleen of well-characterized SMZL cases. We determined AID status by quantitative RT-PCR analysis on 27 SMZL samples and compared it with 5 controls. In the SMZL group the relative level of expression of AID is heterogeneous but two subgroups could be distinguished: one considered as expressing AID (14 cases out of the 27 analyzed), the remaining considered as not expressing AID. When we compared AID expression rate with occurrence of SHM and CSR, no clear correlation between AID expression and presence of SHM or CSR could be observed suggesting that AID, when expressed, is dysfunctional. To address this hypothesis, we first analyzed AID protein by immunohistochemistry and a good correlation between IHC signal and AID mRNA expression level has been observed. As AID gene was not mutated, we next focused our work on AID mRNA splicing variants as these variants exhibit different functions according to the domain of the protein they contain in a murine model. We found that SMZL B cells express various splicing variants of AID mRNA, some of those variants corresponding to the full length isoform (n = 6/17), and other variants corresponding to AID-ΔE4a (n = 2/17) or AID-ΔE4 (n = 7/17) isoforms known to be expressed in normal germinal center B cells as well as in Chronic Lymphocytic and Acute Lymphoblastic Leukemia. These findings indicate that although expressed at the mRNA and protein levels, AID may not be fully functional in SMZL cases. Finally we addressed the potential clinical significance of AID expression. We identified for that purpose a group of “progressive SMZL” patients that had received immuno-chemotherapy after splenectomy because of a significant risk of progression or transformation into aggressive large B cell lymphoma (n = 8/27) pre-empting outcome differences. We found a higher proportion of AID expressing patients in the defined “progressive SMZL” group (n = 7/8) as compared to the proportion found in the “indolent SMZL” group (n = 5/14, p = 0,03). Altogether, this data suggest that the B cell clone leading to SMZL originate from the marginal zone and support the hypothesis of a lymphoproliferative disorder affecting the T-independent response. AID expression in SMZL may reflect an advanced stage of the disease and could be correlated with the evolution of the lymphoma into a more clinically or pathologically aggressive form. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Analysis of somatic hypermutation in X-linked hyper-IgM syndrome shows specific deficiencies in mutational targeting

Blood ◽  
2009 ◽  
Vol 113 (16) ◽  
pp. 3706-3715 ◽  
Author(s):  
Nancy S. Longo ◽  
Patricia L. Lugar ◽  
Sule Yavuz ◽  
Wen Zhang ◽  
Peter H. L. Krijger ◽  
...  
Keyword(s):  
B Cells ◽  
Somatic Hypermutation ◽  
Cytidine Deaminase ◽  
Cd40 Ligation ◽  
Uracil Dna Glycosylase ◽  
Hyper Igm Syndrome ◽  
Reduced Frequency ◽  
Activation Induced Cytidine Deaminase ◽  
Hyper Igm ◽  
Ig Heavy Chain

Abstract Subjects with X-linked hyper-IgM syndrome (X-HIgM) have a markedly reduced frequency of CD27+ memory B cells, and their Ig genes have a low level of somatic hypermutation (SHM). To analyze the nature of SHM in X-HIgM, we sequenced 209 nonproductive and 926 productive Ig heavy chain genes. In nonproductive rearrangements that were not subjected to selection, as well as productive rearrangements, most of the mutations were within targeted RGYW, WRCY, WA, or TW motifs (R = purine, Y = pyrimidine, and W = A or T). However, there was significantly decreased targeting of the hypermutable G in RGYW motifs. Moreover, the ratio of transitions to transversions was markedly increased compared with normal. Microarray analysis documented that specific genes involved in SHM, including activation-induced cytidine deaminase (AICDA) and uracil-DNA glycosylase (UNG2), were up-regulated in normal germinal center (GC) B cells, but not induced by CD40 ligation. Similar results were obtained from light chain rearrangements. These results indicate that in the absence of CD40-CD154 interactions, there is a marked reduction in SHM and, specifically, mutations of AICDA-targeted G residues in RGYW motifs along with a decrease in transversions normally related to UNG2 activity.

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