Maturation of the antibody response is marked by class-switch recombination (CSR) and by somatic hypermutation (SHM). With CSR, the μ heavy chain is replaced by other Ig heavy chains. With SHM, mutations are introduced in the Ig V region, allowing affinity maturation. Following CD40LG–CD40 interaction and activation of the NF-κB signaling pathway, expression of activation-induced cytidine deaminase (AID) and of uracil-DNA glycosylase (UNG) occurs in germinal center B lymphocytes (see Fig. 1). AID acts on the DNA of Ig heavy chain switch regions and converts cytidine to uridine, which is recognized and removed by UNG. The abasic sites are cleaved by a DNA endonuclease. DNA repair then brings together two different switch regions, allowing CSR.
Fig1. GENETIC DEFECTS ASSOCIATED WITH COMMON VARIABLE IMMUNODEFICIENCY (CVID). Schematic of cell surface molecules expressed on B cells and their ligands, highlighting those in which defects have been shown to be associated with CVID. Ag, Antigen; APRIL, a proliferation-inducing ligand; BAFF, B-cell–activating factor; BAFFR, B-cell–activating factor receptor; BCMA, B-cell–maturation antigen; DC, dendritic cell; HSPG, heparin sulfate proteoglycan; ICOS, inducible T-cell costimulator; ICOS-L, inducible T-cell costimulator ligand; Ig, immunoglobulin; IL-4, interleukin 4; IL-10, interleukin 10; PC, plasma cell; TACI, transmembrane activator and calcium modulator and cyclophilin ligand interactor; TI-2, T-cell–independent type 2.
Mutations in AID and UNG are inherited as autosomal recessive traits. Patients suffer from recurrent bacterial infections. Autoimmune manifestations have been observed in several patients. Circulating B cells are present, but there is a severe reduction of all Ig isotypes with the exception of IgM, which is often elevated. Lymphadenopathy is common and is associated with expansion of germinal centers. Somatic hypermutation is severely compromised in patients with AID deficiency, and follows an abnormal pattern in patients with UNG deficiency.
Treatment is based on regular administration of Igs, as well as prompt recognition and therapy of infections.
Defects in CSR have also been reported in patients with mutations in INO80 (encoding for a chromatin remodeling complex) and MSH6 (involved in the DNA mismatch repair pathway). The latter group of patients is at increased risk of cancer.
Other Immunoglobulin Defects
Gain-of-function mutations of the PIK3CD gene (encoding for the p110δ catalytic component of PI3K) cause an immunodeficiency characterized by nodular lymphoid hyperplasia, progressive lung disease with bronchiectasis, chronic or recurrent herpesvirus viremia (CMV, EBV, VZV, HSV), and hepatosplenomegaly. There is an increased risk of lymphomas, which are not necessarily associated with EBV infection. The immunologic phenotype includes CD4 cell lymphopenia, a reduced proportion of naïve T cells, expansion of effector memory and “exhausted” CD8+ T cells, defective T-cell proliferation, variable Ig levels (often with low IgG2), reduced pro portion of memory B cells, and poor antibody responses. In these patients, increased PI3K signaling causes hyperactivation of the AKT–mammalian target of rapamycin (mTOR) pathway, shifting the intracellular metabolism of lymphoid cells towards glycolysis and thereby deranging lymphocyte function and differentiation.
A very similar clinical and laboratory phenotype has been observed in patients with heterozygous mutations of the PIK3R1 gene (encoding for the p85α regulatory subunit of PI3K), which permit expression of a mutated p85α protein lacking the p110δ interacting domain. Treatment with rapamycin, to reduce mTOR activation, may be beneficial in both conditions. An alternative strategy, currently under investigation, is based on the use of PI3K inhibitors.
