Ig class switch recombination (CSR) defi ciencies are rare primary immunodefi ciencies characterized by normal or increased serum IgM levels and a contrasting, marked decrease or absence of IgG, IgA, and IgE. As a result of this molecular defect, defective CSR may be associated with faulty generation of somatic hypermutations (SHMs) in the Ig variable (V) region. The molecular identifi cation and analysis of several CSR defi ciencies has made it possible to better describe the mechanisms underlying CSR and SHM, which are both key elements in the maturation of antibody responses.CSR results in the production of antibodies of diff erent isotypes (IgG, IgA, and IgE) with the same V(D)J specifi city and, therefore, the same antigen affi nity. SHM primarily introduces stochastic mutations into the V region of the Ig, a genetic modifi cation followed by positive selection of B cells harboring a B cell receptor with high antigen affi nity.Mutations in the gene encoding CD40L ( 1 ) or CD40 ( 2 ) result in a CSR defi ciency generally associated with reduced SHM generation, demonstrating the essential role of the B cell ' s CD40 signaling pathway for both CSR and SHM. Other CSR defi ciencies are a consequence of an intrinsic defect in the CSR machinery. The activation-induced cytidine deaminase Immunoglobulin (Ig) class switch recombination (CSR) defi ciencies are rare primary immunodefi ciencies characterized by the lack of switched isotype (IgG/IgA/IgE) production. In some cases, CSR defi ciencies can be associated with abnormal somatic hypermutation. Analysis of CSR defi ciencies has helped reveal the key functions of CSR-triggering molecules, i.e., CD40L, CD40, and effector molecules such as activation-induced cytidine deaminase and uracil N-glycosylase. We report a new form of B cell -intrinsic CSR deficiency found in three patients with deleterious, homozygous mutations in the gene encoding the PMS2 component of the mismatch repair machinery. CSR was found partially defective in vivo and markedly impaired in vitro. It is characterized by the defective occurrence of double-strand DNA breaks (DSBs) in switch regions and abnormal formation of switch junctions. This observation strongly suggests a role for PMS2 in CSR-induced DSB generation.

Remodeling of immunoglobulin genes by activation-induced deaminase (AID) is required for affinity maturation and class-switch recombination in mature B lymphocytes. In the immunoglobulin heavy chain locus, these processes are predominantly controlled by the 3' cis-regulatory region. We now show that this region is transcribed and undergoes AID-mediated mutation and recombination around phylogenetically conserved switchlike DNA repeats. Such recombination, which we term locus suicide recombination, deletes the whole constant region gene cluster and thus stops expression of the immunoglobulin of the B cell surface, which is critical for B cell survival. The frequency of this event is approaching that of class switching and makes it a potential regulator of B cell homeostasis.