Defective B-cell Response to Toll-like Receptor-9 Ligands in Common Variable Immunodeficiency

Abstract

Common variable immunodeficiency (CVID) is a primary immune defect typified by low levels of IgG, IgM, and IgA and poor antibody responses to carbohydrate and protein antigens that leads to increased risk of sinopulmonary infections [1]. The organisms responsible for these infections are typically encapsulated bacteria such as Streptococcus pneumoniae and Haemophilus influenzae [2]. Effective treatment is replacement intravenous IgG [1]. Impaired antibody responses in CVID have been explained for some CVID patients by recent discoveries of genetic mutations and polymorphisms such as TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor), CD19, and ICOS (inducible co-stimulator). However, these account for only 10% of CVID patients. For the remaining CVID patients, a molecular defect has not been identified [3, 4]. Toll-like receptors (TLRs) are pathogen-recognition receptors that are crucial for microbial elimination, whether through recruitment of phagocytes or activation of dendritic cells [5]. B cells also use TLRs as a means of activation and differentiation [3]. Of the 10 TLRs expressed in humans, B cells use TLR1, TLR2, TLR6, TLR7, TLR9, and TLR10. Of these, TLR7 and TLR9 are expressed in the endosomal compartment, whereas the other TLRs are expressed on the cell surface. TLR7 and TLR9 are expressed in low levels by naive B cells, and B-cell receptor (BCR) cross-linking leads to rapid upregulation of their expression [6]. Ligation of TLR7 and TLR9 can provide a signal for differentiation of B cells after antigenic stimulation through the BCR [7]. The ligand for TLR7 includes single-stranded RNA, and the ligand for TLR9 is CpG-ODN (CpG motifs in DNA oligodeoxynucleotides), which is more prevalent in prokaryotes. Defects in TLR7 and TLR9 have been reported for the B cells of CVID patients [3].