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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.
Immunology (primary Immunodeficiency Syndromes
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
Stephan Strobel, Alison M. Jones
A group of disorders affecting immunoglobulin class-switch recombination. All are rare, but the most frequent is the X-linked form; several autosomal recessive genes cause a similar syndrome. X-linked: caused by mutations in the CD40 ligand (CD154) gene, located at Xq26, causing defective expression of CD40 ligand on activated T-cells and endothelial cells.Autosomal recessive: mutations in (i) activationinduced cytidine deaminase (AID) gene; (ii) CD40 gene; (iii) UNG gene. All result in defective isotype switching.
Recent advances in delivering RNA-based therapeutics to mitochondria
Published in Expert Opinion on Biological Therapy, 2022
Yuma Yamada, Sen Ishizuka, Manae Arai, Minako Maruyama, Hideyoshi Harashima
In order to use DddA for mitochondrial genome editing, several challenges needed to be overcome. The most important of these was that cytidine deaminase is toxic to mammalian cells. Mok et al. split the toxin domain of DddA (DddAtox) into two inactive parts (split-DddAtox half), and then fused each DddAtox half with a TALE protein resulting in a preparation that binds to a specific DNA sequence. When the two TALEs bind to mtDNA, the two split-DddAtox half bound to produce an active form. They achieved this by modifying each construct with a targeting signal (Figure 2(b)) [65]. Another challenge arises from the fact that cytidine deaminase converts C to U rather than to thymine (T). The U base is normally replaced by C with the help of uracil glycosylase. Mok et al. fused an uracil glycosylase inhibitor (UGI) to the TALE-split-DddAtox half to prevent this conversion with the help of the enzyme (Figure 2(b)). They investigated the therapeutic potential of DdCBE by evaluating mitochondrial function in cells carrying the G11922A mutation in the mtDNA coding the ND4. Treatment with the DdCBE that recognizes ND4 resulted in mitochondrial gene editing [65].
Myelodysplastic syndromes: a review of therapeutic progress over the past 10 years
Published in Expert Review of Anticancer Therapy, 2020
Jonathan Feld, Abigail Belasen, Shyamala C Navada
Other formulations undergoing evaluation, including an oral formulation of azacitidine (CC-486) was described above in MDS-LR. A phase II study of CC-486 in patients who have failed an HMA is underway [#NCT02281084]. Cedazuridine, a novel cytidine deaminase inhibitor, increases the bioavailability of oral decitabine by inhibiting its gastrointestinal and hepatic degradation [165]. A phase I study comparing oral decitabine with cedazuridine (ASTX727) to traditional intravenous decitabine showed similar clinical and biological responses [165]. Preliminary data from a phase II study comparing these two therapies demonstrated similar safety profiles, with 8 CRs (16%) and clinical benefit in 31 (62%) patients [166]. Preliminary results from a phase III study of 133 patients showed an ORR of 64% with 12 CRs (11.9%) at a median follow up of 5.2 months. Sixteen of these patients underwent ASCT [167].
Emerging DNA methylation inhibitors for cancer therapy: challenges and prospects
Published in Expert Review of Precision Medicine and Drug Development, 2019
Aurora Gonzalez-Fierro, Alfonso Dueñas-González
Since DNA methylation is dynamic, mammalian cells also possess the ability to remove these marks. Passive DNA demethylation was the first to be described. As it is passive, it depends on DNA replication and cell division plus the subsequent lack of action of DNA methylation maintenance pathways. On the contrary, active DNA demethylation is replication-independent and occurs through the active enzymatic removal of the methylcytosine [27]. Among DNA demethylases, the enzyme activation-induced cytidine deaminase (AID) deaminate 5-mC yielding thymidine that is replaced by an unmethylated cytosine by the base-excision repair (BER) pathway. Thus, AID may promote aberrant gene expression by decreasing the promoter DNA methylation of specific genes [28,29]. The family of tet1, tet2, and tet3 (ten-eleven translocation) proteins are also considered active DNA demethylases. These enzymes carry out the hydroxylation of 5-mC to 5-hmC [30], 5-hmC, in turn, is replaced with an unmethylated cytosine by the BER pathway [31]. Recent data demonstrate that several proteins bind to 5-hmC, revealing the possibility that specific proteins may be able to interpret the 5-hmC epigenetic mark and subsequently influence chromatin structure and gene expression [32,33]. Taken together, the establishment and maintenance model of DNA methylation is likely an oversimplification of what actually occurs and all DNMTs in concert with tet enzymes, regulate DNA methylation levels through a dynamic equilibrium of site-specific gain and loss of methylation during development and health and disease conditions.