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Mucosal B cells and their function
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Jo Spencer, Edward N. Janoff, Per Brandtzaeg
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
Published in Gabriel Virella, Medical Immunology, 2019
Scott Sugden, Damien Montamat-Sicotte, Karen K. Yam, Joseph Murphy, Bader Yassine Diab, Virginia Litwin
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.
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.
How do nuclear factor kappa B (NF-κB)1 and NF-κB2 defects lead to the incidence of clinical and immunological manifestations of inborn errors of immunity?
Published in Expert Review of Clinical Immunology, 2023
Nazanin Fathi, Hanieh Mojtahedi, Marzieh Nasiri, Hassan Abolhassani, Mahsa Yousefpour Marzbali, Marzie Esmaeili, Fereshte Salami, Furozan Biglari, Nima Rezaei
Activation-induced deaminase (AID) promotes antibody diversity by somatic hypermutation or class switch recombination. NF-κB is significantly involved in these processes because of the implication of both NF-κB1 and NF-κB2 pathways in inducing AID transcription [46]. NF-κB also induces the expression of IRF4, which, along with AID, results in plasma cell (PC) differentiation. B cell maturation antigen (BCMA), a receptor for BAFF, is connected to maintaining long-lived plasma cells. BCMA induces NF-κB activation, showing the critical role of the NF-κB pathway in the survival of long-lived plasma cells [45]. The GC B cells’ recirculation can lead to the production of memory B lymphocytes and plasma cells with high affinity and frequently isotype-switched types that are affected by NF-κBs.
Telitacicept as a BLyS/APRIL dual inhibitor for autoimmune disease
Published in Immunopharmacology and Immunotoxicology, 2021
Fan Shi, Ran Xue, Xuexiao Zhou, Pei Shen, Shengzhi Wang, Yun Yang
The B lymphocyte stimulator BLyS (also known as B-cell-activating factor, BAFF) and APRIL (a proliferation-inducing ligand), members of tumor necrosis factor (TNF) family, which belongs to trimeric molecules [1]. BLyS existing in three recognized forms, secreted and soluble forms of trimeric and 60mer oligomeric states and membrane-bound form. APRIL, another member of the TNF family, shares almost 50% homology to BLyS and can form biologically active heterotrimers with BLyS [2]. BLyS and APRIL are the members of type-II membrane protein that released by the action of the protease furin to soluble cytokine forms; moreover, BAFF and APRIL have two common receptors, both of which bind to the transmembrane activator and Ca2+ modulator (CAML) interactor (TACI) and B-cell maturation antigen (BCMA), while BAFF additionally binds to a third receptor, BAFF-R; and all the three receptors are expressed by B cells [3]. The BAFF-R contributes to the survival and maturation of transitional and naïve B cells. TACI is crucial for T-cell-independent B-cell responses to certain antigens, regulation of the B-cell compartment, and immunoglobulin (Ig) class switching (also called class-switch recombination). The TACI receptor is located on CD27 + memory B cells and plasma cells; thus, spares earlier B-cell development stages [4]. BCMA mediates the homeostatic survival of plasma cells (Figure 1) [5].
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.