Immune Reconstitution after Hematopoietic Stem Cell Transplantation
Richard K. Burt, Alberto M. Marmont in Stem Cell Therapy for Autoimmune Disease, 2019
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
The Immunoglobulin Variable-Region Gene Repertoire and Its Analysis
Cliburn Chan, Michael G. Hudgens, Shein-Chung Chow in Quantitative Methods for HIV/AIDS Research, 2017
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].
VLP Vaccines
Paul Pumpens in Single-Stranded RNA Phages, 2020
Liao et al. (2017) developed methods to label and enrich the Qβ-VLP-specific B cells and followed these cells in immunized mice for 1 year. They found that, as expected for a T cell independent response, Qβ+ B cells expanded much more quickly after immunization than had been previously observed for the B cells specific for T cell-dependent antigens. The initiation of germinal center B cell differentiation was T cell-independent upon the Qβ VLP immunization. More interestingly, the Qβ-VLP-induced T cell-independent response generated memory B cells, some of which were class-switched and somatically hypermutated, indicating the efficient induction of activation-induced cytidine deaminase in the absence of T cells. Then, the T cell dependent response induced the long-lived Qβ-specific memory B cells, which were mainly IgG+. Although IgM+ memory cells were generated during the early immune response to the Qβ VLPs, they disappeared within a few months. This was quite different from previous reports for other T cell-dependent antigens, in which IgM+ and IgG+ memory cells were generated in similar numbers, and IgM+ memory cells were stably maintained for a very long time (Liao et al. 2017).
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.
Characterising acquired resistance to erlotinib in non-small cell lung cancer patients
Published in Expert Review of Respiratory Medicine, 2019
Niki Karachaliou, Jordi Codony-Servat, Jillian Wilhelmina Paulina Bracht, Masaoki Ito, Martyna Filipska, Carlos Pedraz, Imane Chaib, Jordi Bertran-Alamillo, Andres Felipe Cardona, Miguel Angel Molina, Rafael Rosell
All EGFR TKIs, including erlotinib or osimertinib, activate the NFĸB pathway. NFĸB subsequently induces the expression of the activation-induced cytidine deaminase (AICDA). AICDA is implicated in the development of the T790M mutation after treatment with EGFR TKIs of any generation (Figure 2) [34]. Specifically, AICDA methylates cytosine at position c.2369 and the deamination of 5-methylcytosine to thymine generates the T790M mutation [34]. In the PC9 cell line, there was a significant increase at the mRNA levels of AICDA upon treatment with any type of EGFR TKI [34]. AICDA is expressed in germinal center B lymphocytes and induced upon antigen exposure, causing cytosine deamination and point mutations in immunoglobulin genes. These acquired mutation processes are known as somatic hypermutations. Targeting AICDA activity directly (developing specific inhibitors) or indirectly with NFĸB inhibitors, or using DNA repair inhibitors, could delay the emergence of the T790M resistant mutation or fully prevent it (Table 1) [34].
Targeting transcription factors in multiple myeloma: evolving therapeutic strategies
Published in Expert Opinion on Investigational Drugs, 2019
Shirong Li, Sonia Vallet, Antonio Sacco, Aldo Roccaro, Suzanne Lentzsch, Klaus Podar
Advances of our knowledge on B cell differentiation processes which ultimately give rise to normal PCs have been crucial to understand, how these processes are deranged in MM cells. IgH gene rearrangement of germ-line variable (V), diversity (D), and joining (J) gene segments occurs in pro-B cells (DJH rearrangement) and in pre-B cells (VDJH rearrangement). Following IgH recombination, IgL loci are rearranged (either at the Ig kappa locus (IGK) or Ig lambda locus). Assembly of IgH-IgL protein complexes on the B cell surface (B cell receptor) prevents B cell apoptosis and enables further B cell differentiation. Immunocompetent, naïve B cells leave the BM, migrate through the mantle zone into GCs within secondary lymphoid organs where they bind their cognate antigens, and affinity maturation, somatic hypermutation (SHM) and class switch recombination (CSR) occur. B cells, which produce high-affinity antibodies, receive survival signals via BCR binding, while B cells, which produce low-affinity antibodies, undergo apoptosis. Activation-induced cytidine deaminase (AID) warrants clonal expansion of B cells, SHM and CSR of Igs [10].