An immunoglobulin (Ig) consists of 2 identical light chains (L) and 2 identical heavy chains (H) (for example IgG-type); at the three-dimensional level, an Ig chain consists of one N-terminal variable domain, V, and one (for an L chain) or several (for an H chain) C-terminal constant domain(s), C.
The cells of the B line synthesize immunoglobulins. They are either produced at a membrane (on the surface of the B-lymphocytes) or are secreted (by the plasmocytes).
See also : IMGT Education - Fig 1
As soon as the main characteristics of the immunoglobulins were discovered, a number of questions arose:
Note:Only the genes for the immunoglobulins and T-receptors undergo DNA rearrangement.
See also : IMGT Education - Fig 2
Each IGKV gene is followed downstream (in the 3 position) by an RS consisting of a CACAGTG heptamer, and then by a 12-bp spacer, and then an ACAAAAACC nonamer.
Each IGKJ gene is preceded upstream (in the 5 position) by an RS consisting, between 5 and 3, of a GGTTTTTGT nonamer, a 23-bp spacer and a CACTGTG heptamer.
See also : IMGT Education - Fig 3
IGL (lambda) genes at the 22q11 position on chromosome 22; the V-J rearrangement mechanism is the same as that described for the IGK genes: the rearrangements take place between one of the 29 to 33 functional IGLV genes and a J gene; it should be noted that there are 4 to 5 functional IGLC genes, each of which is preceded by a IGLJ gene.
Allele exclusion can be explained in part by the timing of rearrangements, and partly by the surface expression of a functional immunoglobulin, which inhibits the rearrangements and therefore the expression of a second chain. Only one 14 chromosome and one 2 (or 22) chromosome are therefore productive (answer to question D).
IGH (heavy) genes at 14q32 on chromosome 14.
There are 11 IGHC genes, 9 of which are functional (IGHM, IGHD, IGHG1, IGHG2, IGHG3, IGHG4, IGHA1, IGHA2 and IGHE) and correspond respectively to 9 heavy chain isotypes m, d, g1, g2, g3, g4, a1, a2 and e.
DNA rearrangements between one of the 38 to 46 functional variable IGHV genes, one of the 23 functional diversity IGHD genes, and one of the 6 functional junction IGHJ genes: there are also some RSs, which are located downstream (in position 3) of the V genes, either side of the D genes and upstream (at 5) of the J genes. During V-D-J rearrangement, a junction is first formed between 1 D and 1 J, and then one between 1 V and the D-J complex.
See also : IMGT Education - Fig 4
Note: there are also 2 or 3 open reading frames for the D genes; each of which can code for 2 or 3 different peptide sequences. The V-D-J junctions are also characterized by nucleotide deletions (by an exonuclease) and by the random addition of nucleotides (by means of TdT, terminal deoxynucleotidyl transferase);the V regions which result are not, therefore, coded in the genome of the individual and considerably increase the diversity of the V-D-J junctions of the variable domains of the heavy chains of the immunoglobulins.
See also : IMGT Education - Fig 5 and IMGT Education - Fig 6
Alternative splicing of the pre-messenger RNA of the heavy chain can yield either a membrane heavy chain (membrane Ig of B lymphocytes), or a secreted heavy chain (plasmocyte secreted Ig), which retain the same V-D-J rearrangement (idiotype) and the same constant region (isotype) (answer to question B).
See also : IMGT Education - Fig 7
Note: the same mechanism (alternative splicing of a pre-messenger) expresses the IgMs and IgDs in the same B cell (situation in mature B cells leaving the bone marrow and reach the lymph nodes via the circulation).
Finally, somatic mutations are extremely numerous (somatic hypermutations) and produce very targeted characterization of the rearranged V-J and V-D-J genes of the Ig, but their mechanism of onset is not yet known. AID (activation-induced cytidine deaminase) may be implicated both in the occurrence of the mutations and the switch mechanism. The mutations appear during the differentiation of the B lymphocyte in the lymph glands and contribute to increasing the diversity of the Igs by a further factor of 103, which makes it possible to achieve a potential diversity of 1012 different Igs (answer to question A).
These different mechanisms of diversity make it possible to obtain 1012 different immunoglobulins, capable of responding to the several million known antigens (answer to question A).
The number of different Igs is in fact limited by the number of B cells in a given species.
For further details, see: IMGT
Lefranc MP, Huret JL
Atlas of Genetics and Cytogenetics in Oncology and Haematology 2002-03-01
Online version: http://atlasgeneticsoncology.org/teaching/30083/immunoglobulin-genes