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In: Biology

How does the immune system VDJ region recombination work, and why do animals employ this system...

How does the immune system VDJ region recombination work, and why do animals employ this system vs. separately encoding all their antibodies as separate genes?

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Expert Solution

In humans, the immunoglobulin genes are organized into three families – λ-family, κ- family and H-family. The λ-family and κ- family are light chain families encoding the light chains in the immunoglobulin tetramer. λ-family is located on chromosome number 22 and κ- family on chromosome number 2. The H-family located on chromosome No.14 encodes the heavy chain in the immunoglobulin. Both light and heavy chains in the immunoglobulin tetramer contain variable and constant regions. The amino acid sequence of the variable region vary in different Igs. In each Ig gene family there are many genes coding for the V-region (variable region in the peptide chain) and only a few genes coding for the C-region. The v-genes code for the variable region and the c-genes code for the constant region; although neither of the gene is expressed as an independent unit. To construct a unit that can be expressed as an authentic light or heavy chain a v-gene must be joined physically to a c-gene by intra-chromosomal somatic recombination of appropriate DNA sequences in the lymphocyte in which the antibody is expressed. In this system, three or more genes code for one polypeptide. In most vertebrates the number of v-genes in each family is very high, probably organized into a huge gene cluster. The variety in choice of v-gene is partly responsible for antibody diversity. Recombination of v and c-genes to form a functional locus occurs in immature B-cells. Each B-cell produces only a single type of antibody as it undertakes only one productive rearrangement of light chain family and heavy chain family. This rearrangement occurs before exposure to the antigen. In both the light chain families the variable region is encoded by two genes - v-gene and J-gene. The v-genes encode 95 N-terminal amino acids of the variable region the rest of the variable region (13 amino acids) is encoded by the J-gene. In fact, a tandem array of J-genes is located close to the c-gene. The J-gene joins v-gene with c-gene.

The lambda light chain family of man includes some 300 v-genes; and 4 J-C genes. To make a productive gene for the lambda light chain a v-gene is translocated to a position adjacent to a J-gene. Close to each J-gene is a C-gene. In the kappa family the number of v-genes in man is roughly 80; number of J-genes is around 40 and there is only one C-gene. To make an active gene for kappa light chain any one of the v-gene is joined to any one of the J-gene.

In the H-family the variable region of the heavy chain is encoded by three genes – v-gene; D-gene and J-gene. The H-family contains many V-genes; few D-genes and a few J-genes. To construct an authentic heavy chain gene any one of the v-gene must join with any one of D-gene and any one of J-gene. Downstream of the J-gene cluster is a tandem array of C- genes that encode the constant regions of IgM, IgD, IgG, IgE and IgA.

A given lymphocyte generates either kappa or lambda light chain to associate with the heavy chain. In man, 60% of the light chains are kappa. During the recombination of immunoglobulin genes deletions and rearrangements are common. This may change the amino acids coded at the v-j junction in light chain and V-D and D-J junction in the heavy chain. Some extra nucleotides are also incorporated at the coding joints by the activity of an enzyme called deoxy nucleoside transferase - an active enzyme in lymphocytes. This mechanism ensure that a coding joint may have a sequence that is different from what would be expected by the direct joining of the coding ends of V,D and J-genes.

If antibodies were coded by separate genes the number of antibodies that an animal can make is very small. For example consider an animal with a genome having 200 light chain genes and 200 heavy chain genes. For 200 light chain genes and 200 heavy chain genes a maximum of 4 x 104 antibodies could be produced by the combination of (200 x 200) light and heavy chains.


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