We each have a vast repertoire of B cells—hundreds of thousands, each with specific receptors for only one antigen. So how is that possible when our human genome has only about 20–25,000 protein-coding genes, and yet we have hundreds of thousands of different receptor specificities? The answer is that during B cell development in the bone marrow, a process known as gene recombination occurs to form that variable region.
The image to the right shows a very simplified version of this process. The first line represents the original genome of the variable coding region (known as the "germline") - there are three types of genes: v, d, and j. There are 46 v genes, 24 d genes, and 6 j genes. One of each is chosen randomly by an enzyme known as Recombinase Activating Gene (RAG), and then they are combined to form a unique structure. So, as you can see, this can lead to many possibilities. Additionally, another enzyme known as Terminal Deoxynucleotidyl Transferase (TdT) sometimes brings in another nucleotide, leading to yet other possible unique products. Combined with the light chains (the variable portions of the light chains undergo similar recombination), it leads to approximately 1.6 million possibilities - thus, the diversity!
The black portion represents the constant genes. These are not recombined but remain as initially coded.
Not all B cells that begin development successfully develop into mature B cells. Only B cells that have functional receptors will survive. Since gene recombination is a random process, the recombined genes might code for a sequence that will not fold properly to form the correct structure. Such a cell will undergo apoptosis in the bone marrow. Also, occasionally, a receptor that recognizes "self-antigens is formed during maturation." This will cause receptor-antigen recognition within the bone marrow, but rather than beginning activation as it would in a lymph node, it triggers cell death through apoptosis. This process is called "negative selection" and is one of the mechanisms that help protect the person from developing autoimmunity. When fully developed, the B cell, known as a "naive B cell," will exit the bone marrow and go to the lymph nodes. It will remain there or circulate until its antigen activates it.
During maturation, other receptors can be synthesized. One example is the Ig alpha-Ig beta co-receptor, which is located near the immunoglobulin receptor. When activated in the lymph nodes, the Ig alpha-Ig beta co-receptor helps send an intracellular signal to initiate cell division.
