scholarly journals Upregulated Expression of Activation-Induced Cytidine Deaminase in Ocular Adnexal Marginal Zone Lymphoma with IgG4-Positive Cells

2021 ◽  
Vol 22 (8) ◽  
pp. 4083
Author(s):  
Asami Nishikori ◽  
Yoshito Nishimura ◽  
Rei Shibata ◽  
Koh-ichi Ohshima ◽  
Yuka Gion ◽  
...  

Immunoglobulin G4-related disease (IgG4-RD) is a systemic disorder characterized by tissue fibrosis and intense lymphoplasmacytic infiltration, causing progressive organ dysfunction. Activation-induced cytidine deaminase (AID), a deaminase normally expressed in activated B-cells in germinal centers, edits ribonucleotides to induce somatic hypermutation and class switching of immunoglobulin. While AID expression is strictly controlled under physiological conditions, chronic inflammation has been noted to induce its upregulation to propel oncogenesis. We examined AID expression in IgG4-related ophthalmic disease (IgG4-ROD; n = 16), marginal zone lymphoma with IgG4-positive cells (IgG4+ MZL; n = 11), and marginal zone lymphoma without IgG4-positive cells (IgG4- MZL; n = 12) of ocular adnexa using immunohistochemical staining. Immunohistochemistry revealed significantly higher AID-intensity index in IgG4-ROD and IgG4+ MZL than IgG4- MZL (p < 0.001 and = 0.001, respectively). The present results suggest that IgG4-RD has several specific causes of AID up-regulation in addition to inflammation, and AID may be a driver of oncogenesis in IgG4-ROD to IgG4+ MZL.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2397-2397
Author(s):  
Gabriel Brisou ◽  
Laurent Jallades ◽  
Alexandra Traverse-Glehen ◽  
Francoise Berger ◽  
Aurélie Verney ◽  
...  

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.


eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Jean-Marie Buerstedde ◽  
Noel Lowndes ◽  
David G Schatz

The activation induced cytidine deaminase (AID) protein is known to initiate somatic hypermutation, gene conversion or switch recombination by cytidine deamination within the immunoglobulin loci. Using chromosomally integrated fluorescence reporter transgenes, we demonstrate a new recombinogenic activity of AID leading to intra- and intergenic deletions via homologous recombination of sequence repeats. Repeat recombination occurs at high frequencies even when the homologous sequences are hundreds of bases away from the positions of AID-mediated cytidine deamination, suggesting DNA end resection before strand invasion. Analysis of recombinants between homeologous repeats yielded evidence for heteroduplex formation and preferential migration of the Holliday junctions to the boundaries of sequence homology. These findings broaden the target and off-target mutagenic potential of AID and establish a novel system to study induced homologous recombination in vertebrate cells.


Blood ◽  
2004 ◽  
Vol 103 (7) ◽  
pp. 2795-2798 ◽  
Author(s):  
Gavin Babbage ◽  
Richard Garand ◽  
Nelly Robillard ◽  
Niklas Zojer ◽  
Freda K. Stevenson ◽  
...  

Abstract Isotype switch commonly follows onset of somatic hypermutation in the germinal center (GC), with activation-induced cytidine deaminase (AID) as a prerequisite. Mantle cell lymphoma (MCL) with t(11;14) includes a subset with unmutated (UM) and a minor subset with mutated (MUT) VH genes. Here, we investigated whether switch events and AID expression occur in MCL. In 4 of 6 UM and 4 of 7 MUT MCLs, alternative tumor-derived Cγ,α,ϵ transcripts were identified. AID transcripts, including a splice variant, were common to both subsets. AID expression correlated with switch in 8 of 8 cases, but in 3 of 5 cases it occurred with switch absent. Circle transcripts (Iγ-Cμ/Iα-Cμ) were identified in 5 of 7 evaluated cases. In 1 of 12 cases, 12% of tumor cells expressed immunoglobulin L-restricted surface IgA. Ongoing switch recombination events appear to be a feature of MCL, likely restricted to a minor tumor subpopulation, with occasional variant sIg expression. UM MCLs implicate origins from pre-GC B cells and reveal switch events at ectopic sites. (Blood. 2004;103:2795-2798)


2005 ◽  
Vol 201 (4) ◽  
pp. 637-645 ◽  
Author(s):  
Teresa M. Wilson ◽  
Alexandra Vaisman ◽  
Stella A. Martomo ◽  
Patsa Sullivan ◽  
Li Lan ◽  
...  

Activation-induced cytidine deaminase deaminates cytosine to uracil (dU) in DNA, which leads to mutations at C:G basepairs in immunoglobulin genes during somatic hypermutation. The mechanism that generates mutations at A:T basepairs, however, remains unclear. It appears to require the MSH2–MSH6 mismatch repair heterodimer and DNA polymerase (pol) η, as mutations of A:T are decreased in mice and humans lacking these proteins. Here, we demonstrate that these proteins interact physically and functionally. First, we show that MSH2–MSH6 binds to a U:G mismatch but not to other DNA intermediates produced during base excision repair of dUs, including an abasic site and a deoxyribose phosphate group. Second, MSH2 binds to pol η in solution, and endogenous MSH2 associates with the pol in cell extracts. Third, MSH2–MSH6 stimulates the catalytic activity of pol η in vitro. These observations suggest that the interaction between MSH2–MSH6 and DNA pol η stimulates synthesis of mutations at bases located downstream of the initial dU lesion, including A:T pairs.


2008 ◽  
Vol 205 (10) ◽  
pp. 2199-2206 ◽  
Author(s):  
Virginia G. de Yébenes ◽  
Laura Belver ◽  
David G. Pisano ◽  
Susana González ◽  
Aranzazu Villasante ◽  
...  

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.


Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 223-223
Author(s):  
Laura Pasqualucci ◽  
Mara Compagno ◽  
Tongwei Mo ◽  
Paula Smith ◽  
Herbert C. Morse ◽  
...  

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.


Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1538-1538
Author(s):  
Aliki Xochelli ◽  
Fotini Marantidou ◽  
Evangelia Stalika ◽  
Lesley-Ann Sutton ◽  
Alba Navarro ◽  
...  

Abstract Abstract 1538 According to the WHO 2008 Classification, the cellular origin of mantle cell lymphoma (MCL) is traced to a peripheral B cell of the inner mantle zone, mostly of naïve pre-germinal center type. This notion, however, is seriously challenged by both the remarkable restrictions of the immunoglobulin gene repertoire in MCL and, furthermore, by the fact that the great majority of cases exhibit imprints of somatic hypermutation (SHM) in rearranged IGHV genes, ranging from (mostly) minimal to pronounced. These findings support an antigen-driven origin for MCL, at least for a substantial fraction of the entire cohort. Activation-induced cytidine deaminase (AID) is induced in B cells following contact with antigen and is critically implicated in both somatic hypermutation (SHM) and class switch recombination (CSR). Although the available information about AID expression and in vivo CSR in MCL is limited and contradictory, at least some MCL cases have been reported to express AID and undergo ongoing CSR. With this in mind, here we investigated AID-mRNA isoform expression and isotype switch events in a large series of MCL cases and explored possible associations with IGHV gene repertoire and SHM status. Overall, 107 cases were included in the study and tumor-involved diagnostic tissue samples of different types were evaluated, including: fresh-frozen lymph nodes (LN, n=53), peripheral blood (PB, n=42), spleen (n=5), bone marrow biopsies (n=3) and other (n=4). The neoplastic lymphocytic infiltration ranged from 52–98% (median 80%). Thirty-five of 107 cases (32.7%) carried IGHV genes with 100% identity to the germline (GI) whereas the remaining 72 cases bore some imprint of SHM: in particular, 48/107 cases (44.9%) carried IGHV genes with 97–99.9% GI and, finally, 24/107 cases (22.4%) carried IGHV genes with <97% GI. In keeping with the literature, the IGHV gene repertoire of the present cohort was remarkably biased, with the IGHV3–21, IGHV4–34, IGHV3–23 and IGHV1–8 genes accounting for 55.1% of cases. Profiling of AID mRNA expression was performed by RQ-PCR for the full-length AID (AID-FL) as well as the most frequent splice variants, namely AID-ΔE4a (lacking the first 30 nucleotides from exon 4), and AID-ΔE4 (loss of the entire exon 4). AID transcript levels were calculated as the percentage of AID copy number divided by the copy number of the reference transcript (c-ABL). AID-FL transcripts were detected in 104/107 (97%) cases whereas the AID-ΔE4a and AID-ΔE4 splice variants were detected in 72/107 (67.3%) and 107/107 cases (100%), respectively. The median values for AID-FL, AID-ΔE4a and AID-ΔE4 transcripts were 4.45%, 0.133% and 0.918%, respectively. AID transcript levels varied between different cases by up to 5-log for AID-FL transcripts and 4-log for splice variants. Not unexpectedly, the median transcript levels in LN samples were higher (up to 1-log) compared to PB samples. A highly significant (p<0.001) association was noted between medium-to-high AID-FL transcript levels (AID-FL/ABL○1%) and IGHV GI 100%. Given the difference in tissue origin of our samples, we also performed a separate analysis for LN samples only and found that cases with 100% IGHV GI expressed high AID-FL transcript levels (AID-FL/ABL○10%) significantly (p=0.04) more frequently than cases carrying mutated IGHV genes. Isotype switch events were investigated in 41 cases: overall, 4 cases (9.7%), all with GI<100%, carried alternative tumor-derived Cγ (n=1) or Cα (n=3) transcripts. In conclusion, the present analysis documents AID expression in the vast majority of MCL, thus corroborating our previous hypothesis for antigen involvement in MCL ontogeny. Ongoing CSR events appear to be a feature of MCL, further supporting an activated status, at least for subset of cases. Disclosures: No relevant conflicts of interest to declare.


Blood ◽  
2009 ◽  
Vol 113 (16) ◽  
pp. 3706-3715 ◽  
Author(s):  
Nancy S. Longo ◽  
Patricia L. Lugar ◽  
Sule Yavuz ◽  
Wen Zhang ◽  
Peter H. L. Krijger ◽  
...  

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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