RESUMEN
The contribution of the lambda-light chain to the development of peripheral B cell repertoire and generation of specific antibodies to haptens and polysaccharide antigens was studied in genetically manipulated kappa-deficient and lambda 2-transgenic mice. The results clearly demonstrate a non-stoichiometric VH gene family expression in the absence of k-light chain and suggest a non-stochastic pairing between VH and V lambda genes, expressed in the peripheral B cell repertoire. A shift in VH gene utilization in the case of VI lambda + antibodies was evident in response to beta 2-6 fructosan and TNP hapten. These observations demonstrate the availability of compensatory mechanisms in the absence of VK genes and are consistent with the hypothesis that VH gene family expression is controlled by genetic factors from inside the VH locus. Furthermore, genetic factors from outside the VH locus, namely restricted available light chain diversity, may lead to a shift in VH gene utilization in the peripheral B cell repertoire.
Asunto(s)
Fructanos/inmunología , Reordenamiento Génico de Cadena Ligera de Linfocito B , Genes de Inmunoglobulinas/genética , Haptenos/inmunología , Cadenas Pesadas de Inmunoglobulina/genética , Cadenas lambda de Inmunoglobulina/genética , Familia de Multigenes/inmunología , Animales , Hibridomas/metabolismo , Cadenas Pesadas de Inmunoglobulina/biosíntesis , Cadenas Pesadas de Inmunoglobulina/química , Región Variable de Inmunoglobulina/biosíntesis , Región Variable de Inmunoglobulina/química , Región Variable de Inmunoglobulina/genética , Cadenas kappa de Inmunoglobulina/genética , Cadenas lambda de Inmunoglobulina/biosíntesis , Cadenas lambda de Inmunoglobulina/química , Ratones , Ratones Endogámicos BALB C , Ratones Mutantes , Ratones Transgénicos , Péptidos/inmunología , Polímeros , Trinitrobencenos/inmunologíaRESUMEN
The experiments outlined here provide evidence that most VH gene families are expressed in association with either of three V lambda genes available in kappa-deficient mice, though their expression is nonrandom. An exclusive use of V lambda L-chain genes, where predominantly expressed V lambda 1 and V lambda 2 differ by only seven amino acid substitutions in the germline, results in a higher degree of self-reactive antibodies to conserved natural antigens like albumin, thyroglobulin, and stress proteins. The higher levels of self-reactive antibodies, characteristic of preimmune B-cell repertoire, are likely to be a product of nonrandom VH gene family expression and their restricted pairing with three V lambda L-chain genes. These data suggest that a low lambda L-chain expression in normal mice is due, in part, to endogenous selection against lambda L chain in order to restrict self reactivity within the homeostatic threshold.
Asunto(s)
Diversidad de Anticuerpos , Reordenamiento Génico de Cadena Ligera de Linfocito B , Región Variable de Inmunoglobulina/genética , Cadenas lambda de Inmunoglobulina/genética , Animales , Autoanticuerpos/genética , Autoanticuerpos/inmunología , Autoantígenos/inmunología , Regiones Constantes de Inmunoglobulina/genética , Cadenas kappa de Inmunoglobulina/genética , Cadenas mu de Inmunoglobulina/genética , Ratones , Ratones Noqueados , Familia de MultigenesRESUMEN
Since the murine Vh11 gene family shows 75% homology with group III VH gene families and is preferentially expressed in B-1 lymphocytes, we have analyzed if corresponding Vh11 genes existed across phylogenetically distant mammalian lineages. In a Southern blot, homologues of the murine Vh11 gene were detected in the genomic DNA from rats, pigs, sheep, cattle, horses, dogs and man. These observations suggest conservation of corresponding sequences of the Vh11 gene family during evolution, similar to group III VH genes, either because of strong selection pressures essential for species fitness and survival or molecular drive leading to these consequences.