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Chapter: Medical Immunology: Genetics of Immunoglobulins

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Allelic Exclusion

One of the most fascinating observations in immunology is that immunoglobulin heavy-chain genes from only one of the two homologous chromosomes 14 (one paternal and one maternal) are expressed in a given B lymphocyte.

ALLELIC EXCLUSION

One of the most fascinating observations in immunology is that immunoglobulin heavy-chain genes from only one of the two homologous chromosomes 14 (one paternal and one maternal) are expressed in a given B lymphocyte. Recombination of VDJC genes described earlier usually takes place on one of the homologs. Only if this rearrangement is unpro-ductive (i.e., it does not result in the secretion of an antibody molecule) does the other ho-molog undergo rearrangement. Consequently, of the two H-chain alleles in a B cell, one is productively rearranged and the other is either in the germline pattern or is aberrantly rear-ranged (in other words, excluded). Involvement of the chromosomes is random; in one B cell the paternal allele may be active, and in another it may be a maternal allele. (Allelic ex-clusion is reminiscent of the X-chromosome inactivation in mammals, although it is ge-netically more complex.)

Two models have been proposed to explain allelic exclusion: stochastic and regu-lated. The main impetus for proposing the stochastic model was the finding that a high pro-portion of VDJ or VJ rearrangements are nonproductive, i.e., they do not result in tran-scription of mRNA. Therefore, according to this model, allelic exclusion is achieved because of the very low likelihood of a productive rearrangement on both chromosomes. According to the regulated model, a productive H- or L-chain gene arrangement signals the cessation of further gene rearrangements (feedback inhibition).

Results from experiments with transgenic mice (mice in which foreign genes have been introduced in the germline) favor the regulated model. It appears that a correctly re-arranged H-chain gene not only inhibits further H-chain gene rearrangements but also gives a positive signal for the k -chain gene rearrangement. The rearrangement of the λ gene takes place only if both alleles of the k gene are aberrantly rearranged. (Although in some cases, it appears that the λ gene rearrangement is autonomous, that is, it does not depend on the prior deletion and/or nonproductive rearrangement of both k alleles.) This mutually exclu-sive nature of a productive L-gene rearrangement results in isotypic exclusion, i.e., a given plasma cell contains either k or λ chains, but not both.

Allelic exclusion is evident at the level of the GM system. A given plasma cell from an individual heterozygous for G1M* 17/G1M* 3 will secrete IgG carrying either G1M 17 or G1M 3, but not both. Since this is a random exclusion process, serum samples from such as individual will have both G1M 17 and G1M 3 secreted by different immunoglobulin-producing cells.

The process of allelic exclusion results in the synthesis of molecules with identical V regions in each single plasma cell because all expressed mRNA will have been derived from a single rearranged chromosome 14 and from a single rearranged chromosome 2 or 22. Therefore, the antibodies produced by each B lymphocyte will be of a single speci-ficity.


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