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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