B Cell Receptor (BCR) Diversity & Function

• B cell receptors (BCRs) are membrane-bound immunoglobulin molecules that enhance the recognition repertoire of B cells.
• BCRs are composed of two identical immunoglobulin light chains (kappa or lambda) and two identical heavy chains.
• Gene clusters encoding BCR light chains are located on chromosomes 2 (kappa) and 22 (lambda).
• Heavy chain genes are located on chromosome 14.
• Light chains contain a variable domain and a constant domain.
• To generate a light chain, one of 100 variable gene segments combines with one of five joining segments to form a VJ segment.
• A similar process occurs with the heavy chain to rearrange and combine the V, D, and J genes.
• Gene clusters encoding BCR light chains are located on chromosomes 2 and 22, providing nearly 200 combinations.
• Heavy chain clusters are located on chromosome 14 and can result in 24,000 combinations.
• BCR diversity results in nearly 5 million antigen-binding combinations.
• The process of somatic recombination, also known as VDJ recombination, creates a unique antibody that binds to a specific antigen.

Somatic Recombination

• Somatic recombination involves the heavy chain first, typically resulting in an Immunoglobulin M (IgM) antibody.
• The cell becomes a precursor B cell after somatic recombination of the heavy chain.
• The precursor B cell then undergoes another somatic recombination of the light chain to become an immature B cell.
• During heavy chain rearrangement, the germline DNA contains sub-genes for the heavy chains, including V, D, and J segments.
• The heavy chain gene consists of a leader segment, a variable region, a diversity segment, a joining segment, and a constant region (constant mu).
• J and D recombination occurs first, where the J segment binds to the D segment, bringing the constant region in close proximity.
• Next, V, D, and J recombination occurs, where the D and J segments bind to the variable region, bringing the constant mu in close proximity with everything else.
• Following VDJ recombination, an RNA transcript is produced and introns are removed.
• The resulting mRNA is then translated into protein for the heavy chain of the antibody

BCR and TCR Genetic Rearrangement Similarities

• Both utilize somatic recombination to generate diversity.
• Both involve recombination of V, D, and J gene segments in heavy chains (BCR) or β/δ chains (TCR), and V and J segments in light chains (BCR) or α/γ chains (TCR).
• Recombination is mediated by RAG-1 and RAG-2 (Recombination Activating Genes).
• DNA repair follows through the non-homologous end joining (NHEJ) pathway.

BCR and TCR Key Differences in Genetic Rearrangement

• BCR rearrangement involves heavy chain (VDJ) and light chain (VJ) recombination.
• TCR rearrangement involves β chain (VDJ) and α chain (VJ) recombination.
• BCRs undergo somatic hypermutation (SHM) in the germinal center during B cell activation, introducing point mutations in the V region to improve antigen binding affinity.
• Affinity maturation allows for the selection of high-affinity BCRs.
• TCRs do not undergo somatic hypermutation or affinity maturation.
• BCR constant region determines antibody isotype, and class switch recombination (CSR) allows switching from IgM to other isotypes while retaining antigen specificity.
• CSR is mediated by Activation-Induced Cytidine Deaminase (AID).
• TCR constant region is fixed for each chain (α or β), with no isotype switching.
• BCRs recognize soluble or surface-expressed antigens in their native conformation.
• TCRs recognize antigenic peptides presented by MHC molecules.
• BCRs exhibit strict allelic exclusion for both heavy and light chains.
• TCRs exhibit allelic exclusion for the β chain but are less strict for the α chain.

B Cell Receptor Role

• B cell diversity depends on the genetic makeup of the heavy and light chains, or on the variable regions, of the BCR.
• The function of this diversity is to allow for a wide range of antibody recognition.
• The genetic recombination occurs first to the heavy chain, which is determined by the rearrangement of the V, D, and J gene segments on chromosome 22.
• The light chain then undergoes genetic rearrangement either on chromosome 22 for the lambda chain or chromosome 2 for the kappa chain

Genes Responsible for Diversity

• The IgH gene (Immunoglobulin Heavy Chain Gene).
• The Igκ gene (Immunoglobulin Kappa Light Chain Gene) and Igλ gene (Immunoglobulin Lambda Light Chain Gene).
• The IgH gene is located on chromosome 14 in humans.
• Variable (V), diversity (D), and joining (J) gene segments of the IgH gene undergo rearrangement, leading to the formation of a unique variable region for the heavy chain.
• After VDJ recombination, the constant region of the heavy chain is encoded by different gene segments.
• The Igκ gene is located on chromosome 2, and the Igλ gene is located on chromosome 22 in humans.
• Variable (V) and joining (J) gene segments of the Igκ and Igλ genes undergo rearrangement during B cell development.
• The process is VJ recombination.

Lymphomas linked to BCR Diversity Dysfunction

• Burkitt lymphoma is associated with translocations involving the MYC oncogene on chromosome 8 and the IgH gene on chromosome 14 or light chain on chromosomes 2 or 22.
• These translocations lead to dysregulation of MYC, resulting in uncontrolled cell proliferation.
• A translocation, and it can happen in one of three ways: t(8;14), t(8;2) or t(8;22)
• Burkitt lymphoma is the primary lymphoma associated with the t(8;2, 22, or 14) translocation