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Allelic `choice' governs somatic hypermutation in vivo at the immunoglobulin j-chain locus

Summary: Allelic `choice' governs somatic hypermutation in vivo
at the immunoglobulin j-chain locus
Shira Fraenkel1,10, Raul Mostoslavsky1,2,10, Tatiana I Novobrantseva3,4,10, Roberta Pelanda3,5,
Jayanta Chaudhuri2,6, Gloria Esposito7, Steffen Jung8, Frederick W Alt2, Klaus Rajewsky3,9, Howard Cedar1 &
Yehudit Bergman1
Monoallelic demethylation and rearrangement control allelic exclusion of the immunoglobulin j-chain locus (Igk locus) in
B cells. Here, through the introduction of pre-rearranged Igk genes into their physiological position, the critical rearrangement
step was bypassed, thereby generating mice producing B cells simultaneously expressing two different immunoglobulin-j light
chains. Such `double-expressing' B cells still underwent monoallelic demethylation at the Igk locus, and the demethylated allele
was the `preferred' substrate for somatic hypermutation in each cell. However, methylation itself did not directly inhibit the
activation-induced cytidine-deaminase reaction in vitro. Thus, it seems that the epigenetic mechanisms that initially bring
about monoallelic variable-(diversity)-joining rearrangement continue to be involved in the control of antibody diversity at later
stages of B cell development.
The main mechanism for preimmune antigen receptor diversity is
variable-(diversity)-joining (V(D)J) recombination mediated by the
recombination-activating proteins RAG-1 and RAG-2. To ensure that
each B cell or T cell expresses a single product, however, this process is
subject to allelic exclusion. Experiments have indicated that the
mechanisms that bring about allelic exclusion actually begin early
during development when all of the immune receptor loci become


Source: Alt,, Frederick - Immune Disease Institute, Harvard University


Collections: Biology and Medicine