Immunoglobulin class switch recombination deficiencies

Abstract

Immunoglobulin class-switch recombination deficiencies (Ig-CSR-Ds) are rare primary immunodeficiencies characterized by defective switched isotype (IgG/IgA/IgE) production. Depending on the molecular defect in question, the Ig-CSR-D may be combined with an impairment in somatic hypermutation (SHM). Some of the mechanisms underlying Ig-CSR and SHM have been described by studying natural mutants in humans. This approach has revealed that T cell-B cell interaction (resulting in CD40-mediated signaling), intrinsic B-cell mechanisms (activation-induced cytidine deaminase-induced DNA damage), and complex DNA repair machineries (including uracil-N-glycosylase and mismatch repair pathways) are all involved in class-switch recombination and SHM. However, several of the mechanisms required for full antibody maturation have yet to be defined. Elucidation of the molecular defects underlying the diverse set of Ig-CSR-Ds is essential for understanding Ig diversification and has prompted better definition of the clinical spectrum of diseases and the development of increasingly accurate diagnostic and therapeutic approaches.

Separation of Function between Isotype Switching and Affinity Maturation In Vivo during Acute Immune Responses and Circulating Autoantibodies in UNG-Deficient Mice

“…Increased levels of circulating autoantibodies in Ung 2/2 mice AID deficiency is associated with autoimmunity (41-43), and one of the UNG-deficient patients experienced development of Sjögren's disease (20,21), a disease characterized by the presence of autoantibodies. We therefore asked whether Ung 2/2 mice would show autoimmune manifestations.…”

“…Ung 2/2 mice have very reduced IgG3 levels but display fairly normal basal serum levels of IgG1 and only modestly reduced IgA (9,10). In contrast, the three UNGdeficient human patients who have been identified to date have very low levels of circulating switched isotype, susceptibility to recurrent infections (19,20), and in one case, Sjögren's disease (20,21). However, this small cohort may be biased, as only severe pathologies would lead to their identification at immunodeficiency clinics.…”

Epigenetic tethering of AID to the donor switch region during immunoglobulin class switch recombination

“…We conclude that KAP1 is involved in mediating CSR but appears to be dispensable for SHM. mediating RNA editing Nonaka et al, 2009) or by recruiting factors that promote efficient DNA repair (Barreto et al, 2003;Ta et al, 2003;Ito et al, 2004;Shinkura et al, 2004;Kracker et al, 2010). In addition, epigenetic modifications at the IgH locus, including histone H3 trimethylation at lysine 9 (H3K9me3), have been suggested to target the CSR machinery to switch regions (Wang et al, 2006Chowdhury et al, 2008;Kuang et al, 2009).…”

“…AID appears to find its targets by its binding to Spt5 and RNA polymerase II (Pavri et al, 2010) and distinguishes between variable and switch regions by its association with proteins like RPA, PKA, 14-3-3, or by the formation of higher-order DNA structures in switch regions Vuong et al, 2009;Xu et al, 2010;Yamane et al, 2011). AID itself also contributes to this choice, as N-terminal mutations in AID result in normal CSR but defective SHM Wei et al, 2011) and conversely C-terminal truncations in AID result in normal SHM but defective CSR Kracker et al, 2010). The latter phenotype is also observed in mice deficient for DNA damage response (DDR) components (Ramiro et al, 2007) and in a subset of hyper IgM patients with a CSR-specific defect (Kracker et al, 2010).…”

“…AID itself also contributes to this choice, as N-terminal mutations in AID result in normal CSR but defective SHM Wei et al, 2011) and conversely C-terminal truncations in AID result in normal SHM but defective CSR Kracker et al, 2010). The latter phenotype is also observed in mice deficient for DNA damage response (DDR) components (Ramiro et al, 2007) and in a subset of hyper IgM patients with a CSR-specific defect (Kracker et al, 2010). It has been proposed that this domain associates with CSR-specific factors that could be required for targeting AID to switch regions (Ta et al, 2003) or for recombination downstream of DSB formation either by lower than AID Flag-HA or EGFP Flag-HA (Fig.…”