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Acquired Immunity
Published in Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal, Principles of Physiology for the Anaesthetist, 2020
Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal
B lymphocytes are normally dormant in the lymphoid tissues. After exposure to an antigen, there is an interval of about 2 weeks before antibodies can be found in the blood. The invading antigen (microorganism) is first localized and phagocytosed by macrophages that present it to adjacent B lymphocytes. The antigen also activates helper T lymphocytes. The B lymphocytes then proliferate and differentiate into lymphoblasts that become plasma cells in the lymph gland. The plasma cells release antibodies into the lymph to be carried to the blood. These antibodies do not reach a high concentration and do not persist. This is the primary immune response (Figure 56.3). In the primary response, B lymphocytes produce IgM and then undergo the following changes: (i) class switching – changing, (ii) affinity maturation – antibody binds more tightly to antigen and (iii) memory cell formation.
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
SBA Answers and Explanations
Published in Vivian A. Elwell, Jonathan M. Fishman, Rajat Chowdhury, SBAs for the MRCS Part A, 2018
Vivian A. Elwell, Jonathan M. Fishman, Rajat Chowdhury
The germinal centres of lymph nodes contain mainly B-lymphocytes and follicular dendritic cells. Follicular dendritic cells are able to trap antigen on their cell surface for long periods. They help to initiate a B-cell response to antigens entering the lymph node and play an important role in affinity maturation (a process which results in an increase in the affinity of the antibodies produced during the course of a humoral immune response). Follicular dendritic cells should not be confused with Langerhans’ dendritic cells which are professional antigen-presenting cells found in the skin.
Deep mutational engineering of broadly-neutralizing nanobodies accommodating SARS-CoV-1 and 2 antigenic drift
Published in mAbs, 2022
Adrien Laroche, Maria Lucia Orsini Delgado, Benjamin Chalopin, Philippe Cuniasse, Steven Dubois, Raphaël Sierocki, Fabrice Gallais, Stéphanie Debroas, Laurent Bellanger, Stéphanie Simon, Bernard Maillère, Hervé Nozach
From this perspective, many teams have proposed a wide range of methods to generate candidates with the expected properties, mostly increased affinity.31–34 Affinity maturation aims at improving biological activity by adjusting the kinetic parameters of the binding to the target, which in turn may confer greater therapeutic efficacy.25,35 However, the magnitude of this effect depends largely on the epitope recognized by the antibody and the initial affinity along with the format of the antibody and its valence.25 Several recent studies have described affinity maturation of VHH or conventional antibodies to enhance their binding to SARS-CoV-2 antigens, by CDR-swapping approaches, 36 saturation mutagenesis in CDRs 37,38 or light-chain shuffling. 38
A perspective toward mass spectrometry-based de novo sequencing of endogenous antibodies
Published in mAbs, 2022
Sebastiaan C. de Graaf, Max Hoek, Sem Tamara, Albert J. R. Heck
Because there is an endless and constantly evolving pool of pathogens, the antibody repertoire needs to be incredibly diverse and versatile to counteract these challenges.24,25 In humans, this enormous diversity in the potential antibody repertoire is achieved through several mechanisms. Starting at the genomic level, the light and heavy chains are encoded in four genes each: Variable (V), Diversity (D), Joining (J), and Constant (C), with the light chain lacking the D-gene. These genes are encoded in multiple alleles, which can recombine to a staggering number of combinations (Figure 1b).26 The recombination process is also error-prone, leading to insertions and deletions at the junctions between the regions, referred to as junctional diversity. By recombination alone, the number of possible variable domain sequences already reaches tens of thousands. However, the eventual antibody diversity is expanded even further by natural polymorphisms, mutations, and class switching. As the major contributor to antibody hypervariability, somatic hypermutations can occur during B-cell affinity maturation and do so at a million-fold increased rate compared to the usual mutation rates.11 These mutations are largely concentrated in the complementarity-determining regions (CDR1-3), separated by framework regions (FR1-4), which form the conserved backbone of the Fab structure (Figure 1c). Located at the tips of the Y-shaped antibody structure, CDRs are primarily responsible for antigen binding, and, therefore, elucidation of their sequences is of the utmost importance for antibody discovery.
B Cell Response to Vaccination
Published in Immunological Investigations, 2021
B cells in the GCs are constantly competing for antigens and T-cell signals for selection and affinity maturation (Shlomchik et al. 2019). One possibility is that the intense competition leads to immunodominance as larger clones with higher antigen affinity easily compete out smaller clones with lower affinity and gain dominance. It is later challenged by studies showing that low-affinity B cell clones can coexist with high-affinity ones in the same GC, suggesting that GC selection is more permissive than originally thought (Kuraoka et al. 2016; Lingwood et al. 2012; Tas et al. 2016). However, these studies did not track the fate of these low-affinity B cells. Considering that there might be multiple checkpoints from GC to memory formation, it is unclear whether these low-affinity GC B cells can efficiently form memory. In fact, GC clonal diversity decreased over time (Tas et al. 2016). Since early and late GC mainly produce MBCs and LLPCs, respectively (Weisel et al. 2016), it raises an important question how immunodominance is shaped by these temporal checkpoints in memory development. Interestingly, although the dominant long-lived antibodies (from BM LLPCs) are usually against the globular head of HA in influenza viruses, many HA stalk-specific memory B cells can be generated and ready to mount antibody response in a secondary infection or vaccination (Angeletti et al. 2017; Ellebedy et al. 2014; Krammer and Palese 2015; Nachbagauer et al. 2016; Wrammert et al. 2011).