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Immune Reconstitution after Hematopoietic Stem Cell Transplantation
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Andreas Thiel, Tobias Alexander, Christian A. Schmidt, Falk Hiepe, Renate Arnold, Andreas Radbruch, Larissa Verda, Richard K. Burt
B cells undergo further affinity maturation within lymph node germinal centers by a process of somatic hypermutation (SHM), gene conversion, and class switching recombination (CSR) (Fig. 4). SHM is the term for insertion of point mutations in the vicinity of the variable region exon (Fig. 4) and results in generation of antigen specific high affinity antibodies. Gene conversion is the transfer of a pseudovariable (ipV)gene sequence into the variable region exon (Fig. 4). Both SHM and gene conversion alters the antigen binding site of the immunoglobulin.71-72 CSR involves switching the constant region heavy change (e.g., IgM to IgG) that alters the effector function of the antibody (Fig. 4). The mechanisms involved in DNA SHM, gene conversion, and CSR although incompletely understood probably involve common mechanisms of DNA recognition, targeting, cleavage, and repair.73 The enzyme activation-induced cytidine deaminase (AID) is involved in all three reactions by helping to create the DNA cut or cleavage.65,74-75
Genetics of immunoglobulins: Ontogenic, biological, and clinical implications
Published in Gabriel Virella, Medical Immunology, 2019
The discovery of the enzyme activation-induced cytidine deaminase (AID) has revolutionized research aimed at delineating the molecular mechanisms underlying various processes that amplify genomic information. AID appears to be an essential catalyst for somatic hypermutation, class switch recombination, and gene conversion, and thus a unifier at the molecular level of three apparently disparate mechanisms of antibody diversity. Its mode of action is under active investigation.
The Immunoglobulin Variable-Region Gene Repertoire and Its Analysis
Published in Cliburn Chan, Michael G. Hudgens, Shein-Chung Chow, Quantitative Methods for HIV/AIDS Research, 2017
Thomas B. Kepler, Kaitlin Sawatzki
Centroblasts undergo somatic hypermutation (SHM) of their IgVRG, accumulating point mutations at a rate of 10−4–10−3 mutations per nucleotide per cell division (orders of magnitude higher than is observed in typical genome replication) [29–31]. The enzyme activation-induced cytidine deaminase (AID) is responsible for the initial lesions in the DNA, which are followed by error-prone repair by the enzyme polymerase eta (polη). Centroblasts eventually differentiate into centrocytes and migrate to the light zone, where they interact with FDC and T cells and receive signals to survive, divide, or differentiate. Some surviving cells leave the GC as memory B cells, while others return to the dark zone and undergo further rounds of proliferation and mutation. At this stage, B cells may also undergo class switch recombination, which swaps out the constant region genes (IGHC) encoding the Fc portion of the antibody, changing the effector function of the antibody [29,30].
Dysregulated translational factors and epigenetic regulations orchestrate in B cells contributing to autoimmune diseases
Published in International Reviews of Immunology, 2023
Ming Yang, Ping Yi, Jiao Jiang, Ming Zhao, Haijing Wu, Qianjin Lu
The antigen-induced activation of B cell and interaction of T-B cells contribute to the entry of IgD and IgM-co-expressing mature B cells into GC. Proliferating cells (also centroblasts) and nonproliferating cells (also centrocytes) localize in dark zones and light zones of GC, respectively. The proliferation of B cells and Ig somatic hypermutation (SHM) occur in dark zones, while the activation programs of CSR, affinity maturation and plasma-cell differentiation emerge in light zones [7, 67]. In GC, activation-induced cytidine deaminase (AID)-mediated CSR of Ig gene happens in activated BN cells, turning the antibody class from IgM and IgD into IgG, IgA and IgE, and their antigenic specificity stay the same featuring altered constant region of Igh and same variable regions [68].
Expression and clinical significance of RAG1 in myelodysplastic syndromes
Published in Hematology, 2022
Xiaoke Huang, Xiaolin Liang, Shanhu Zhu, Qiongni Xie, Yibin Yao, Zeyan Shi, Zhenfang Liu
RAGs also can cleave cryptic RSSs (cRSSs) that are abundant in the genome. Various lines of evidence reveal that RAGs can cleave at non-B DNA structures resulting in cell death or chromosomal translocations and cancer, including leukemia and lymphoma[8]. Gazumyan, et al. reported that DNA breaks caused by RAG1 and activation-induced cytidine deaminase (AID) induce c-myc/immunoglobulin (Ig) heavy chain chromosomal translocations and thereby stimulated mice lymphomagenesis[9]. Mice, lacking the RAG1 protein, showed signs of earlier transformation to acute leukemia and reduced survival rates[10]. Hunter ZR, et al. performed next-generation transcriptional profiling in 57 Waldenström macroglobulinemia (WM) patients, compared with healthy donors, WM patient samples showed greatly enhanced expression of RAG1, its aberrant expression was associated with specific somatic mutation patterns such as deletions in BTG1 and ETV6[11]. Ting Kang, et al. showed that RAG1 was down-regulated in gastric cancer, low RAG1 expression correlated with poor survival of gastric cancer patients[12]. Harriet E Gee, et al. proved that low RAG1 expression significantly correlated with local recurrence of Early Breast Cancer[13]. These studies suggest that RAG1 may play an important role in the occurrence and development of cancer. However, the effects of RAG1 on the treatment and prognosis of MDS patients have not been extensively studied.
Unfolding the Role of Splicing Factors and RNA Debranching in AID Mediated Antibody Diversification
Published in International Reviews of Immunology, 2021
Ankit Jaiswal, Amit Kumar Singh, Anubhav Tamrakar, Prashant Kodgire
Humans are surrounded by millions of pathogens that have the potential to cause various types of disease. To combat against these pathogens or antigens our immune cells produce a diverse range of antibodies. Antibody diversity is an exceptional feature of B-cells that produced millions of different antibodies from just a handful number of immunoglobulin genes [1]. B-cells diversify its antibody archive even before it had encountered an antigen via the process of V(D)J recombination. V(D)J recombination increases antibody repository by rearrangements of the variable (V), diversity (D) and joining (J) gene segments mediated by RAG recombinase [2]. In contrast to V(D)J recombination, Somatic Hypermutation (SHM) and Class Switch Recombination (CSR) further diversify antibody upon antigenic stimulation of B-cell. SHM and CSR are mediated by a key genome mutator enzyme widely known as activation-induced cytidine deaminase (AID) encoded by the AICDA locus [3–5]. SHM is confined to the variable regions of light and heavy chain, where AID induced point mutations are unfaithfully repaired giving rise to antibody, having either higher or lower affinity against an antigen, and subsequently, the higher affinity antibodies are selected in the process of clonal selection. CSR is a DNA deletion event taking place in the constant region of IgH. AID mediated SHM and CSR required the transcription of the target genes and AID is found to be localized with splicing factors. This review unfolds the potential role of splicing factors in AID mediated antibody diversification.