Translocations involving immune genes in normal cells

Several of the interlocus recombinations that involve immune receptor genes have also been observed in a small fraction of lymphocytes of healthy individuals. These recombinations include those that form hybrid immune receptor complexes by stitching together VDJ regions between different immune receptors genes. Our ability to dietect these rearrangements suggests that they may be positively selected for. The finding that the hybrid receptors frequently recom-bine to be in-frame is in support of this argument. The analyses of these rearrangements (translocations or inversions) also suggest that they are mediated by the VDJ recombinases at a frequency of about 10 4 and predominantly involve chromosomes 7 and 14. It has been demonstrated that the frequency increases following exposure to pesticides. This increase is intermittent and reversible. Exposure to pesticides may also increase the risk of developing lymphoid malignancy. These observations, coupled with the increase of such rearrangements in AT patients, indicate that rearrangements involving immune receptor loci are subject to both exogenous and endogenous influences on DNA stability and that some of these rearrangements, for example the frequency of hybrid receptors, may serve as monitors of error-prone recombinase activity.

The functional consequences of these interlocus rearrangements are not clear. At least one of the translocations described in lymphomas, the t(14;18) which juxtaposes the Bcl-2 locus within the transcriptional influence of the immunoglobulin heavy chain gene, has also been shown to occur in lymphocytes of healthy individuals, and also bears the 'signature' of recombinase activity. The frequency of this translocation increases with age and parallels the age-dependent incidence of follicular lymphomas. Whether this particular rearrangement is affected by exogenous influences such as exposure to pesticides is not known. However, its frequency is not increased in lymphocytes of AT patients. It is entirely possible that an error in recombinase will promote illegitimate recombination between interlocus immune genes more readily than between an immune and a nonimmune locus.

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