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The Inducible Defense System: Antibody Molecules and Antigen-Antibody Reactions
Published in Julius P. Kreier, Infection, Resistance, and Immunity, 2022
The second process that occurs within germinal centers is known as somatic hypermutation. The precise mechanism responsible for this is unclear, but one or more mutations may occur in the nucleotide sequences that code for the V region of the antibody molecule. As a result, daughter B cells are produced that express slightly different BCR. Since the mutations are random, some of the resulting B cells may have higher affinity receptors for the antigen, and some will have lower affinity receptors. As the immune response progresses and the amount of antigen decreases in the body, those B cells with higher affinity receptors out-compete those with lower affinity receptors. As a result, the overall affinity of the antibody produced during an immune response increases. Thus, during an immune response, IgM antibodies are replaced by either IgG, IgA, or IgE antibodies, and the affinity of these antibodies increases.
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
AID deaminates cytidine in targeted segments of DNA in rapidly dividing centroblasts in the dark zones of germinal centers (see Figure 10.5). The deamination of cytidine generates uridine that is a normal component of RNA, but not DNA. A subsequent balance in activity between cell division, removal of uridine by uracil glycosylase, and lesional repair by error-prone polymerases generates a highly diverse spectrum of mutational outcomes. Somatic hypermutation introduces mostly point mutations but also some insertions and deletions in the immunoglobulin heavy (IgH)- and light-chain (IgL) variable (V) region genes. Mutations tend to cluster in AID-targeted hotspots in the complementarity determining regions (CDRs) that form the antigen-binding loops upon protein folding, rather than in the more structural framework regions. Both murine and human Peyer's patches demonstrate a very high frequency of somatic mutations in IgV genes, indicating the antigen-driven specificity of most antibodies produced at mucosal sites. The very high mutation frequencies of Peyer's patch germinal center cells in mice were helpful in elucidating the mechanisms of somatic hypermutation. However, some intestinal plasma cells, including those with high specificity for transglutaminase 2 in humans with celiac disease, do not show high mutation frequencies.
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.
Components of specific immunity in host defense
Published in International Reviews of Immunology, 2021
The mammalian host can produce numerous kinds of antibodies against numerous biotic and abiotic entities. The generation of diverse antibodies by limited genome was a challenging quest solved by constant efforts of several immunologist, particularly by Susumu Tonegawa whose work received the prestigious Nobel prize for providing molecular basis of antibody diversity in 1987. Initially, B cells produce low affinity antibodies against the antigen and have a limited role in pathogen clearance. To produce high affinity antibodies, B cells undergo the phenomena known as somatic hypermutation (SHM) and class switching recombination (CSR) to efficiently clear the invading pathogen. The fourth review article of this issue by Jaiswal et al. focuses on SHM and CSR in antibody diversity, particularly a crucial enzyme known as Activation-induced cytidine deaminase (AID) and molecular events taking place during antibody diversity [4]. This article will be interesting to the fundamental immunologist working or investigating B cells.
Current strategies for detecting functional convergence across B-cell receptor repertoires
Published in mAbs, 2021
Matthew I. J. Raybould, Anthony R. Rees, Charlotte M. Deane
Once a naïve B-cell’s BCR has been activated through an antigen-binding event (and subsequent T-helper cell assistance), it begins to differentiate into a plasma cell, which is able to rapidly proliferate and secrete antibodies – serum-soluble BCRs. Molecular modifications associated with this transition include displaying different B-cell surface markers and a process known as ‘class switching’ – where the Fc region of the BCR swaps from an IgM or IgD isotype to an IgG, IgA, or IgE isotype. Concurrently, the B-cell migrates to the ‘germinal centre’ of the lymph nodes and on arrival yet more sequence diversity can be introduced through the process of somatic hypermutation (deliberate nucleotide mutations made throughout the receptor V domain sequence of both chains, though predominantly in the CDRs). Positive selection acts to promote mutant BCRs with higher affinity toward the antigen (‘affinity maturation’). Before or after class switching, antigen-activated B-cells can differentiate into long-lived memory cells (often characterized by expression of cell-surface protein CD2712), which persist as a high-sensitivity, low concentration population able to be reactivated and potentially undergo further maturation upon secondary infection.13 Many transitional B-cell states exist, distinguished by their expression of unique combinations of cell markers and cytokines; these were recently reviewed in detail by Sanz et al.12
Decoding intrathecal immunoglobulins and B cells in the CNS: their synthesis, function, and regulation
Published in International Reviews of Immunology, 2020
MS was traditionally considered a T cell-mediated disease, but mounting evidence over the years has implicated B cells as major players in MS immunopathogenesis [53]. The intrathecal production of antibodies leading to oligoclonal band formation in CSF is a characteristic feature of MS [28]. During their development in the bone marrow, B cells begin as immature cells which enter the blood circulation and are converted to transitional B cells [54]. These transitional cells then differentiate into naïve B cells, which upon encountering specific antigens proliferate into short-lived plasma cells (Figure 3). In the germinal centers of secondary lymphoid organs, they go through the process of class switch recombination and somatic hypermutation to become B cells that produce high-affinity antibodies [54]. A small percentage of them develop into long-lived memory B cells or plasma cells. Memory B cells and plasma cells preferentially cross the BBB of MS patients and present antigens to astrocytes, microglia, and T cells by forming ectopic lymphoid follicles, GC-like structures or meningeal tertiary lymphoid organs (TLOs) at the sites of inflammation [51]. Studies on clonal expansion and somatic hypermutation demonstrated a strong correlation between the autoreactive peripheral B cells and the intrathecal B cells present in CSF [55]. A bidirectional movement of B cells occurs between the brain and the DCL nodes across the BBB [56]. This cross-talk suggests that B cells, along with T cells, can carry antigens to DCL nodes and act as stimulators for other resting lymphocytic populations.