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Diversity of Antibodies

The expression of antibodies is produced by somatic gene rearrangements that provide the extraordinarily diverse specificities of B lymphocytes. The Gene rearrangement process irreversibly changes the lymphocyte’s DNA, and all its progeny inherits the same receptor specificity. Different germline gene segments coding for the variable Ig heavy and light chains are joined by somatic V(D)J gene rearrangement to generate Immunoglobulin (Ig) diversity. Moreover, the addition or removal of nucleotides during recombination at the junctions and somatic hypermutation in the complementary-determining regions (CDR) of the VL and VH genes results in a high diversity of the Ig repertoire.

The Rearrangement of Antibodies

Ig heavy (H) and light (L) chains are each encoded by a separate multigene family, and the individual V and C domains are each encoded by independent elements: variable (V), diversity (D), and joining (J) gene segments for the V domain and individual exons for the C domains. For the L chain, the joining of a VL and a JL gene segment creates an exon that encodes the whole VL region. The JL gene segment of the rearranged VL region is separated from a CL-region sequence only by a short intron. To make a complete Ig L-chain messenger RNA, the V-region exon is joined to the C-region sequence by RNA splicing after transcription. For the H-chain, there is one additional complication, DH, which lies between the VH and JH gene segments. First, a DH segment is joined to a JH segment. And then a VH segment rearranges to DJH to form a VH-region exon. Finally, the V-region sequence is joined to the neighboring C-region gene by RNA splicing.

The rearrangement of antibodies. Fig1 The rearrangement of antibodies. (Feederle, 2017)

The H- and L-chain Loci in the Human Genome.

There are three sets of Ig chains: the H-chain, and two equivalent types of L-chains, the κ and λ chains.

  • The λ locus, which is located on chromosome 22q11.2. The λ L-chain has 29-33 functional Vλ gene segments and four or five pairs of functional Jλ gene segments and Cλ genes. The functional Cλ exon is associated with its own Jλ. The k locus is located on chromosome 2p11.2.
  • The κ domain contains 5 Jκ and 75 Vκ gene segments upstream of Cκ. One third of the Vκ gene segments contain frameshift mutations or stop codons that preclude them from forming the functional protein. The remaining sequences, about 38 functional Vκ gene segments, have been found in functional Igs.
  • The H-chain locus, which is located on chromosome 14q32.33. There are approximately 40 functional VH gene segments and a cluster of around 23 DH segments lying between these VH gene segments and 6 JH gene segments.

The germline organization of the Ig H- and L-chain loci in the human genome. Fig2 The germline organization of the Ig H- and L-chain loci in the human genome. (Harry, 2010)

RAGs and NHEJ

The recombination of V, D, and J coding genes of antibodies is performed by enzymes collectively called ‘VDJ recombinase’. The products of two genes known as Recombination Activating Gene (RAG)-1 and RAG-2 form this recombinase. RAGs are almost exclusively expressed in developing lymphocytes. RAG1 and RAG2 introduce a DNA double-strand break between the terminus of the rearranging gene segment and its adjacent recombination signal sequence (RSS). These breaks are then repaired by ubiquitously expressed components of a DNA repair process, which is known as nonhomologous end-joining (NHEJ), that are common to all cells of the body. The NHEJ process creates precise joins between the RSS ends and imprecise joins of the coding ends. Terminal deoxynucleotidyl transferase (TdT), which is expressed only in lymphocytes, can variably add non-germline-encoded nucleotides to the coding ends of the recombination product.

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References

  1. Feederle, R.; Schepers, A. Antibodies specific for nucleic acid modifications. Rna Biology. 2017:1089-1098.
  2. Harry, W.; et al. Structure and function of immunoglobulins - ScienceDirect. Journal of Allergy and Clinical Immunology. 2010, 125 (Supplement 2): S348.

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