The block in immunoglobulin class switch recombination caused by activation-induced cytidine deaminase deficiency occurs prior to the generation of DNA double strand breaks in switch mu region

Affinity maturation of the Ab repertoire in germinal centers leads to the selection of high affinity Abs with selected heavy chain constant regions. Ab maturation involves two modifications of the Ig genes, i.e., somatic hypermutation and class switch recombination. The mechanisms of these two proce...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2003-09, Vol.171 (5), p.2504-2509
Main Authors: Catalan, Nadia, Selz, Françoise, Imai, Kohsuke, Revy, Patrick, Fischer, Alain, Durandy, Anne
Format: Article
Language:English
Subjects:
B-Lymphocyte Subsets - enzymology
B-Lymphocyte Subsets - immunology
Base Sequence
Cells, Cultured
Cytidine Deaminase - biosynthesis
Cytidine Deaminase - deficiency
Cytidine Deaminase - genetics
DNA - genetics
DNA - isolation & purification
DNA - metabolism
DNA Damage
Gene Rearrangement, B-Lymphocyte, Heavy Chain - genetics
Humans
Hypergammaglobulinemia - enzymology
Hypergammaglobulinemia - genetics
Hypergammaglobulinemia - immunology
Immunoglobulin Class Switching - genetics
Immunoglobulin Heavy Chains - biosynthesis
Immunoglobulin Heavy Chains - genetics
Immunoglobulin M - biosynthesis
Immunoglobulin M - genetics
Immunoglobulin Switch Region - genetics
Immunoglobulin Variable Region - biosynthesis
Immunoglobulin Variable Region - genetics
Lymphocyte Activation - genetics
Molecular Sequence Data
Somatic Hypermutation, Immunoglobulin
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Summary:Affinity maturation of the Ab repertoire in germinal centers leads to the selection of high affinity Abs with selected heavy chain constant regions. Ab maturation involves two modifications of the Ig genes, i.e., somatic hypermutation and class switch recombination. The mechanisms of these two processes are not fully understood. As shown by the somatic hypermutation and class switch recombination-deficient phenotype of activation-induced cytidine deaminase (AID)-deficient patients (hyperIgM type 2 syndrome) and mice, both processes require the AID molecule. Somatic DNA modifications require DNA breaks, which, at least for class switch recombination, lead to dsDNA breaks. By using a ligation-mediated PCR, it was found that class switch recombination-induced dsDNA breaks in S mu switch regions were less frequent in AID-deficient B cells than in AID-proficient B cells, thus indicating that AID acts upstream of DNA break induction.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.171.5.2504