2 Role of RAG1 and RAG2 in B-cell development | 17 Adaptive immune system The adaptive immune system evolved into a system that allows specific and targeted responses, capable of recognizing particular pathogens after repeated encounters, ensuring a long-lasting defense. The hallmark feature of the adaptive immune system is its unique specificity for distinct molecules, primarily facilitated by lymphocytes and antigen-presenting cells (APCs). Among lymphocytes, B cells specialize in recognizing extracellular antigens and producing antibodies, essential for humoral immunity. The antibodies initiate processes leading to antigen neutralization. On the other hand, T cells play a vital role in cellular immunity by recognizing antigens from intracellular microbes and eliminating infected cells. Unlike B cells, T cells do not produce antibodies. Antibodies have a polypeptide structure consisting of four protein chains: two identical heavy (H) chains and two identical light (L) chains, connected by disulfide bonds and non-covalent interactions. These chains come together to form a Y-shaped structure known as the basic antibody monomer. Each chain consists of a constant region and a variable region. The variable regions of the heavy and light chains contain antigen-binding sites and it is responsible for pathogen recognition. To achieve an efficient adaptive immune response, the immune system is equipped with the capability to generate an enormously large array of antibodies of different specificities, recognizing the different pathogens. In a cell, single proteins are typically coded by single genes. The number of antibodies that are required to fight off hundreds of thousands of different pathogens is so high, that one’s genome would have to accommodate hundreds of thousands of genes to make the various antigen receptors available for immune response. However, today it is clear that the genome of vertebrates contains just around 20,000 genes and thus not enough to give rise to the large repertoire of antibodies1. In B and T cells, an intricate system has evolved allowing the flexible generation of a virtually unlimited number of different antibodies, also referred to as immunoglobulins (Ig) or B-cell receptor (BCR) in B cells, and T-cell receptors (TCR) in T cells, or collectively, antigen receptors. In this system, the recombination of gene segments is responsible for the generation of genetic variation. This is achieved by the ordered recombination of so-called variable (V), diversity (D), and joining (J) gene segments, which together code for the antigen-binding portion of the antigen receptor. These genes are non-functional in their germline configuration but become functional following the process of somatic gene recombination, also called V(D)J recombination, where one of the V-genes, one of the D-genes (only for the Ig heavy chain) and one of the J-genes are ligated together and the intervening parts are excised from the genome. V(D)J recombination is initiated by recombination-activating gene 1 (RAG1) and recombination-activating gene 2 (RAG2) proteins, which introduce a double-stranded DNA breaks into the V(D)J genes – first, the heavy chain is recombined, followed by the recombination of the light chain. This newly assembled sequence encodes
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