B Lymphocytes: Development, Tolerance, and Their Role in Autoimmunity—Focus on Systemic Lupus Erythematosus
Figure 1
Schematic representation of the components of the H and L chains of immunoglobulins. The light and heavy chain loci are each made up of a series of V (variable) gene elements, followed by several D (diversity) segments (for the heavy chain gene only), some J (joining) segments, and C (constant region) exons. Heavy chains (H) are assembled from 4 segments (VH, D, JH, and CH); light chains (L) are assembled from 3 segments (VL, JL, and CL). The development of the BCR begins when the recombinase enzyme complex catalyzes the fusion of one DH region gene to a JH region gene with the deletion of the intermediate DNA sequences. Next, the recombinase joins one VH region gene to the rearranged DHJH gene. The enzyme terminal deoxynucleotidyl transferase (TdT) is expressed, adding random nucleotides to the sites of VHDHJH joining and enhancing the diversity of amino acid sequences. The rearranged VHDHJH element forms the most 5′ exon of the H chain gene and is followed downstream by exons encoding the constant (C) region (initially μ chain), that pairs with an L chain and produces IgM. When the VHDHJH element is followed downstream by exons encoding the C region for the δ chain, it produces IgD. These events occur as a result of alternative RNA splicing. Finally, if the rearrangement of VH, DH, and JH elements yields an H chain transcript and encodes a functional H chain protein, this heavy chain is synthesized and pairs in with 2 proteins (called λ5 and VpreB), which act as a surrogate light chain, and results in the expression of a pre-BCR. Once a functional heavy chain is produced, the cell downregulates the TdT gene and initiates an L chain rearrangement. It begins first with a κ element and, if this rearrangement is unsuccessful, continues with a λ element. A Vκ element rearranges to a Jκ element and produces a light chain, which, if it is functional, pairs with the H chain to make an immunoglobulin protein.
