Learn how lymphocyte antigen receptor diversity is developed through gene segment rearrangement of Heavy (Beta) and Light (Alpha) chain genes, including key concepts such as allelic exclusion and constant domain addition.

There is a small amount of DNA that encodes the production of the BCR and TCR…too little for it to be possible for a separate gene to exist to produce each unique receptor. Therefore, the millions of unique antigen binding molecules are created by a process of gene segment rearrangement which occurs in the primary lymphoid organs (bone marrow and thymus) in cells developing within the lymphoid lineage.

The gene segments are referred to as V (variable), D (diversity) and J (joining) and when they are randomly recombined by the action of the RAG (recombination activating) genes, they are spliced together to create the RNA coding for the N-terminal amino acids in the variable domains of the BCR or TCR.
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An enzyme known as terminal deoxyribonucleotidyl transferase (Tdt) is active during this process and generates a further level of diversity by randomly inserting non-coded nucleotides (N-nucleotide addition) each time a V is joined to a D, or a D is joined to a J.

Rearrangement of Heavy (or Beta) Chain Genes:

Rearrangement of Light (or alpha) Chain Genes:

Allelic Exclusion

​If the result of these complex, random rearrangements is an abnormal-shaped or truncated protein, the cell will be induced to undergo apoptosis. Since each diploid cell has two copies of each chromosome (one maternal and one paternal), there are two chances for each rearrangement to be successful. Whichever chromosome is randomly rearranged first, if successful in producing a functional chain, the complementary chromosome of that set will be inactivated in a process referred to as allelic exclusion. If unsuccessful, the failed rearranged chromosome will be inactivated, and the other one of that pair will be used to attempt a successful rearrangement. (Thus, only one allele of a given chromosome will ever be expressed at one time). Since the heavy chain genes are all on one chromosome, and the light chain genes are on two separate chromosomes, the cells have two chances to rearrange the heavy chain genes and 4 chances to rearrange the light chain genes.

Constant Domain Addition

​Once VDJ rearrangement has created the coding for the N-terminal 110 amino acids (approximately), the downstream DNA contains the coding for all of the constant domain isotypes in sequence. First is the coding for addition of mu constant domains, so the first isotype of immunoglobulin produced is IgM. By alternative RNA splicing, IgD is made immediately thereafter, and mature naïve B lymphocytes are allowed to leave the bone marrow wearing those two isotypes of receptors, each with identical idiotypes.

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#MMC (Make Me Care!)

1. Can you predict the clinical presentation of a patient with a genetic inability to produce RAG gene products?


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2. A neonatal screening test for severe combined immunodeficiency (SCID) uses detection of T cell receptor excision circles (TRECs) to identify T lymphocyte development. Can you explain what process this assay is measuring and predict whether high or low numbers would associate with normal or abnormal phenotype?

Apply these concepts in a clinical case at Immunology Case Studies.