![]() ![]() 12 At this immature B‐cell stage, the cells are first tested for tolerance to self‐antigens. After functional V‐(D)‐J recombination of IgH and IgL chain genes, the resulting immature naïve B‐cells transcribe the IgH and IgL genes, and are able to produce IgD and IgM immunoglobulin isotype by alternative splicing of the transcript to fuse the μ and δ exon to the IgHJ exon, respectively. Therefore, each mature antigen‐naïve B‐cell typically expresses BCR sequences encoding the heavy‐ and light‐chains. 11 When a cell has successfully rearranged a IgH gene, the B‐cell begins to rearrange the light‐chain genes. Likewise, each IgL chain locus encodes multiple distinct copies of λ chain and κ chain variable (V) gene segments and joining (J) gene segments. Class‐switch recombination (CSR) can also occur during B‐cell activation, which is a chromosomal deletion process leading to the expression of a different antibody isotype. Somatic hypermutation (SHM) can occur during B‐cell activation, in which mutations are introduced into the V‐(D)‐J region of the BCR. The resulting B‐cell receptor (BCR) may be expressed as both surface IgD and IgM on naïve B‐cells through alternative splicing. Similarly, V‐J recombination occurs in the light‐chain. During B‐cell development, V‐D‐J recombination occurs to produce a functional heavy‐chain. B‐cells are generated from haematopoietic stem cells. Schematic diagram of the processes of B‐cell differentiation and selection, annotated with known human genetic modifiers of the process and the point in selection at which they are thought to act. 8 These pre‐B‐cells are selected for functional heavy‐chain by IgV‐D‐J expression and IgH assembly by pairing. 7 Further mechanisms that contribute to the generation of diversity include alternative IgHD reading frames and IgHD–IgHD fusions. This results in sequence diversification at the junctional regions. 5, 6 The imprecise joining of the V, D and J gene segments leads to the introduction of random deletions and insertions of nucleotides through exonucleases and terminal deoxynucleotidyl transferase (TdT), respectively. ![]() This process of site‐specific recombination is highly orchestrated and mediated by recombination activating genes 1 (RAG1) and 2 (RAG2). This encodes the protein sequence for the antigen‐binding region of the IgH protein 2, 4 (Fig. 2 During B‐cell development, functional immunoglobulin genes are generated through the deletion of intervening DNA, 3 creating a IgH gene containing one V, one D and one J gene (VDJ). The germline immunoglobulin heavy‐chain (IgH) gene locus encodes multiple distinct copies of the variable (V), diversity (D) and joining (J) genes, which are separated by over 100 kbp from a much smaller number of DNA segments encoding the constant genes. 1ī‐cells develop from haematopoietic stem cells and differentiate through several maturation stages in the bone marrow. Defects in B‐cell development and function can lead to a breakdown of immunological tolerance and therefore autoimmune diseases, which affect approximately 1 in 12 people worldwide. B‐cells have the potential to recognize a vast array of pathogens, but diversity in the B‐cell repertoire comes at a price, namely that there is a potential for autoreactivity in a subset of B‐cells. BCRs are the membrane‐form of antibodies and are generated through DNA recombination. B‐cell clones selectively expand following antigen recognition by B‐cell receptors (BCRs). It has been hypothesized that these differences may signify differences in B‐cell tolerance however, the mechanisms and implications of these defects are not clear.ī‐cells produce antibodies and are crucial for effective immunity. ![]() B‐cell clones have effectively been characterized and tracked between different tissues and blood in autoimmune disease. Interestingly, some common repertoire defects are shared between diseases, such as elevated IGHV4‐34 gene usage. These autoimmune diseases exhibit significantly skewed B‐cell receptor repertoires compared with healthy controls. Here, we discuss the current research using B‐cell antibody repertoire sequencing in three polygenic autoimmune diseases where there is good evidence for a pathological role for B‐cells, namely systemic lupus erythematosus, multiple sclerosis and rheumatoid arthritis. The advent of technologies, such as whole‐genome sequencing, offers the chance to link abnormalities in the B‐cell antibody repertoire to specific genomic variants and polymorphisms. It can address key questions, including: (i) how the B‐cell repertoire differs in health and disease and (ii) if it does differ, the point(s) in B‐cell development at which this occurs. High‐throughput sequencing of the DNA/RNA encoding antibody heavy‐ and light‐chains is rapidly transforming the field of adaptive immunity. ![]()
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