Mucosal B cells and their function
Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald in Principles of Mucosal Immunology, 2020
IgA switch factors initiate transcription through switch regions of Cα in cells expressing sIgM. The RNA produced is noncoding and may be referred to as a sterile transcript. Experimentally, the presence of sterile transcripts in a population of B cells reflects the potential for class-switch recombination. The function of sterile germline transcript production is to open up the DNA double helix in a transcription bubble, allowing the molecular mediators of class-switch recombination, including AID, access to single-stranded DNA substrate (see Figure 10.6). The switch regions are long DNA sequences composed largely of repeated nucleotide motifs that include the DNA target substrate for AID. Deamination of cytidine on both DNA strands generates uracil that can be removed by uracil glycosylase. The abasic site can then be recognized by apurinic/apyrimidinic endonuclease that generates nicks in the DNA. The subsequent repair (by a nonhomologous end-joining pathway related to repair of DNA strand breaks during RAG-mediated recombination) replaces the Cμ constant region with Cα, leaving a circular deleted episomal fragment (see Figure 10.6). RNA transcripts of the circular DNA fragment (noncoding circle transcripts) are produced for a short time after the recombination event. Circle transcript production is therefore a feature of class-switch recombination in the recent past history of a B cell—a feature that can be exploited experimentally when investigating class-switch recombination events.
Monocyte and lymphocyte membrane markers: Ontogeny and clinical significance
Gabriel Virella in Medical Immunology, 2019
Isotype switching and affinity maturation. Around birth, mature, resting B cells co-express sIgM and sIgD on their membranes. The sIgM and sIgD expressed on individual B-cell clones have the same antigenic specificity. These mature, naive B lymphocytes home to secondary lymphoid organs where, upon antigenic challenge, they downmodulate sIgD and, less constantly, sIgM. Activated B cells undergo subsequent heavy-chain constant region gene rearrangements or isotype switching by a process called class switch recombination (Figure 7.3). Hence, the same variable region can be associated with a different heavy-chain isotype (IgG, IgE, or IgA). The resultant sIg of different isotypes are expressed on nonoverlapping B-cell subsets, sometimes in association with sIgM. In addition to isotype switching, activated B cells undergo antibody affinity maturation by a process called somatic hypermutation, which results in the emergence and selection of B-cell clones producing antibodies of similar specificity but higher affinity, as discussed in Chapters 7 and 12.
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].
Double-edged effects of interferons on the regulation of cancer-immunity cycle
Published in OncoImmunology, 2021
Xiao Zhang, Song Wang, Yuanyuan Zhu, Minghui Zhang, Yan Zhao, Zhengbin Yan, Qiuxu Wang, Xiaobo Li
Both NK cells and macrophages also kill cancer cells through the mechanism of antibody-dependent cell-mediated cytotoxicity (ADCC), which mainly depends on the binding of the Fc fragment of IgG antibodies and their coordinated receptor FcγR located on effector cells.185 IFN-α has been reported to induce ADCC against B16 melanoma cells in vivo.186 IFN-β also contributes to enhancing the sensitivity of lung cancer cells to ADCC.187 IFN-γ is a predominant activator of macrophages,188 and thus promotes killing of cancer cells via ADCC.187 Mechanistically, type I IFNs and IFN-γ could promote antibody isotype switching into IgG.189,190 The regulation of class switch recombination is largely dependent on germline (GL) transcription, which means that distinct cytokines determine the isotypes of antibodies synthesized by B cells by inducing different transcription factors targeting various cytokine-responsive elements accompanied by GL promoters.191 STAT1 and T-bet, induced by IFN signaling,192,193 are both important transcriptional activators for IgG germline transcription.194–196 Additionally, IFN-γ has also been found to enhance the transcription of the Fc receptor for IgG,197,198 which may also contribute to ADCC.
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.
Integration of inflammation, fibrosis, and cancer induced by carbon nanotubes
Published in Nanotoxicology, 2019
Rapidly growing tumors create a hypoxic condition that activates cancer-associated fibroblasts (CAFs) through a hypoxia-inducible factor (HIF)-1-induced TGF-β signaling axis. In this scenario, TAMs may convert from type 1 (TAM1, pro-inflammatory) to type 2 macrophages (TAM2, anti-inflammatory and pro-fibrotic). TAM2 cells produce vascular endothelial growth factor (VEGF) to foster neoangiogenesis both surrounding and within the tumor tissue to support rapid tumor growth. Lymphocytes also play roles in tumor formation. CAFs secrete TGF-β and CXCL13 that recruit lymphotoxin-producing B2 lymphocytes to further support tumor growth, whereas chemokines produced in the tumor recruit tumor-promoting Th17 cells and immunosuppressive regulatory T cells (Tregs). Finally, tumor-infiltrating B cells may undergo class-switch recombination to induce an exhausted or anergic phenotype in cytotoxic T cells (Shalapour and Karin 2015). On the other hand, acute inflammatory reactions often stimulate dendritic cell maturation and antigen presentation that boost anti-tumor immunity, which may be targeted for immunotherapy against cancer. These findings indicate that chronic inflammation influences tumorigenesis and tumor progression and metastasis at several levels via multiple means.
Related Knowledge Centers
- Antibody
- B Cell
- Immunoglobulin Heavy Chain
- Immunoglobulin M
- Isotype
- Ligand
- Epitope
- Immunoglobulin G
- B-Cell Receptor
- V(D)J Recombination