Synthetic CpG oligodeoxynucleotides augment BAFF‐ and APRIL‐mediated immunoglobulin secretion

Abstract

The B lymphocyte-activating factor belonging to TNF superfamily (BAFF) acts on B lymphocytes through BAFF receptor (BAFF-R), the transmembrane activator, calcium modulator, and cyclophilin ligand interactor (TACI), and the B cell maturation antigen (BCMA). Another cytokine, a proliferation-inducing ligand (APRIL), only binds to TACI and BCMA. In this study, we sought to determine the effect of Toll-like receptor agonists (TLR-A) on the expression of BAFF/APRIL receptors by murine splenic B lymphocytes. CpG oligodeoxynucleotides (ODN) and LPS strongly up-regulated TACI expression, while BAFF-R was only up-regulated by CpG ODN. CpG ODN pretreatment up-regulated TACI expression on follicular and marginal zone B lymphocytes and increased their responses to BAFF-and APRIL-mediated Ig secretion. TACI seemed to be playing a pivotal role in BAFF-or APRIL-induced Ig secretion because B lymphocytes from TACIknockout mouse or the blocking of TACI with a neutralizing antibody resulted in total inhibition of IgA and IgG secretion in CpG ODN-pretreated and BAFF-or APRIL-stimulated B cells. Thus, CpG ODN-induced increase in TACI expression is likely to play an important role in Ig secretion following activation of B lymphocytes through TLR9.

Deficient TACI Expression on B Lymphocytes of Newborn Mice Leads to Defective Ig Secretion in Response to BAFF or APRIL

“…BAFF-or APRIL-stimulated cells yielded a significant increase in culture supernatant IgM, IgA, IgG1, IgG2a, IgG2b, and IgG3 compared with B lymphocytes that had been incubated with medium. Similar to our previous report (27) CpG ODN pretreatment of adult B lymphocytes also led to an increase in Ig production after BAFF and APRIL stimulation (Fig. 7A).…”

“…We (27) and others (19) have previously shown that adult TACI KO mice do not secrete IgG and IgA when stimulated with BAFF or APRIL. We therefore sought to understand whether decreased TACI expression in newborns would also lead to impaired Ig secretion.…”

“…After 6 days of stimulation, culture supernatant Ig isotype levels were determined in ELISA. Blocking goat anti-TACI Abs (27) were also used when stimulating CpG ODN pretreated newborn B lymphocytes with BAFF or APRIL. Newborn B lymphocyte sets were incubated with increasing concentrations of polyclonal anti-TACI Abs or control goat Igs together with BAFF (1 g/ml) or APRIL (1 g/ml).…”

“…We have recently shown that in vitro prestimulation of adult B lymphocytes with CpG ODN up-regulates TACI and BAFFR expression, and leads to TACI-dependent augmentation of Ig secretion following BAFF or APRIL stimulation (27). We therefore asked whether CpG ODN enhances the expression of TACI on newborn B lymphocytes as well.…”

An evolutionary approach to the medical implications of the tumor necrosis factor receptor superfamily member 13B (TNFRSF13B) gene

“…This finding was also confirmed by the nearly homogeneous genetic background of worldwide populations emphasized by AMOVA results and by very similar F ct values for each sequence variation across the gene, leading to the acceptance of a neutral model of evolution for the analyzed genomic region. Nevertheless, such an absence of sharp TNFRSF13B interpopulation genetic differentiation, in spite of its proved function in humoral responses, is not so unlikely if we take into account the recent remarks about relationships between innate and adaptive components of the immune system 39,40 and the hypothesis of a not negligible involvement of its protein product TACI in innate immune functions. 3 TNFRSF13B, CVID and IgAD from an evolutionary perspective Together with described population-based evolutionary analyses, a direct comparison of Italian samples with CVID and IgAD and control samples was performed applying the same methods.…”