Primary antibody repertoire12/8/2023 ![]() This singular feature confers on each Ab a distinct window of Ag specificities, where the entropic space explored constitutes a thermodynamic signature of that particular Ab. We demonstrate that the pluripotency of germline Abs can subsequently be optimized by binding interactions that correlate with thermodynamic changes indicative of structural adaptations at the interface. This revealed a much greater heterogeneity of binders than could be obtained with mutated daughter Abs that presumably had been selected in vivo by nominal Ag during active immune responses. As such, CSR distributes antigen-binding sites across various antibody classes and provides diversity in effector responses and biological functions.In this study, germline Abs were used to select clones from a random dodecapeptide phage-display library. CSR only alters the constant region without influencing the antigen-binding site. CSR is different from V(D)J recombination in that CSR occurs after antigen stimulation, is activated by helper T cells and involves different enzymes that recognize different flanking sequences on the DNA. As such, CSR occurs through intrachromosomal deletions of the switch (S) region within the HC constant region. ![]() The constant region of the HC determines the antibody class. As the immune response progesses, several class switching events occur to generate IgG, IgE, or IgA antibodies generating a secondary antibody response through memory B cells. Once these B cells interact and bind the antigen through the BCR, this results in a switch from membrane bound IgM to soluble IgM. When B cells leave the bone marrow, they begin synthesizing IgM and IgD molecules embedded within the plasma membrane. IgM is the first immunoglobulin to be synthesized by B cells, which are inserted into the plasma membrane as a B cell receptor (BCR). Strong-affinity binders are selected for and proliferate and mature into antibody-secreting cells, whereas lower affinity clones are eliminated by apoptosis.ĭuring B cell development, cells switch between generating one class of antibody to another, a process known as class switch recombination (CSR). Hypermutated B cells undergo a selective process in germinal centers where B cells compete for various signals in an affinity-dependent manner, thereby outcompeting lower-affinity B cell clones. Mutations that enhance antigen-binding tend to be clustered in the CDR regions. Mutations in the framework regions of the variable domain tend to be selected against as they don’t enhance antigen-binding and alter the basic antibody structure. Some immunoglobulin mutants bind antigens better than others, while some mutants produce non-productive rearrangements. SHM facilitates the progressive increase in antibody affinity against the antigen known as affinity maturation (Figure 4). Double stranded DNA breaks are introduced into variable regions, eliciting DNA damage response pathways that facilitate error-prone repair and resulting in mutant antibodies. Point mutations by somatic hypermutation increase variation into the variable region and occur a million-fold more frequently than other genetic mutations. Somatic hypermutation (SHM)provides an additional level of antibody diversity after V(D)J recombination. The formed V(D)J exon is transcribed and translated into a functional HC or LC (Figure 3). This process known as junctional diversification introduces an additional level of antibody diversity in the variable region, specifically in the third complementarity-determining region (CDR3). Nucleotides are often lost or inserted at the joining sites during recombination resulting in a frameshift mutation. DNA ends are repaired by DNA repair enzymes, resulting in deletions or inversions of gene segments. Selected V, D, and J segments are rearranged and joined to form the V(D)J exon. This enzyme complex binds and cleaves the DNA at conserved sequences that flank each V, D, and J segment. Chromosomal DNA double stranded breaks are introduced by RAG recombinase. HCs contain 65 V segments that can join with any of the 6 J and 27 D segments to form roughly 11,000 possible variable HC regions.Ī process called site-specific recombination mediates V(D)J recombination. The genes for human λ LCs contain 30 V segments and 4 J segments resulting in 120 possible variable λ regions. For human κ LCs, 40 V segments can combine with any of the 5 J segments resulting in 200 possible combinations encoded by this pool. ![]() ![]() Recombination and joining of V, D, and J segments create a functional variable immunoglobulin region (Figure 3). Organization of gene segments in human heavy and light chain loci.
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