DCs induce CD40-independent immunoglobulin class switching through BLyS and APRIL

Abstract

Immunoglobulin (Ig) class-switch DNA recombination (CSR) is thought to be highly dependent upon engagement of CD40 on B cells by CD40 ligand on T cells. We show here that dendritic cells up-regulate BLyS and APRIL upon exposure to interferon-alpha, interferon-gamma or CD40 ligand. In the presence of interleukin 10 (IL-10) or transforming growth factor-beta, BLyS and APRIL induce CSR from C(mu) to C(gamma) and/or C(alpha) genes in B cells, whereas CSR to C(epsilon) requires IL-4. Secretion of class-switched antibodies requires additional stimulation by B cell antigen receptor engagement and IL-15. By eliciting CD40-independent Ig class switching and plasmacytoid differentiation, BLyS and APRIL critically link the innate and adaptive immune responses.

TGF-β1 Stimulates Mouse Macrophages to Express APRIL through Smad and p38MAPK/CREB Pathways

“…It has been shown that IFN-γ, IFN-α and CD40 ligation stimulate macrophages and DCs to express APRIL and BAFF mRNA (Litinskiy et al, 2002). In addition, we have previously shown that TGF-β1 and IFN-γ stimulate mouse macrophages to express BAFF (Kim et al, 2008).…”

“…DCs enhance B cell proliferation and differentiation, (Dubois et al, 1997;. Further, B cell-activating factor (BAFF), which belongs to the TNF family, and a proliferationinducing ligand (APRIL), are expressed by macrophages and DCs, and are critical factors for the growth and survival of both normal and malignant B cells (Fagarasan and Honjo, 2000;Litinskiy et al, 2002). Interestingly, APRIL is known to increase IgA and IgM but not IgG responses to T cell-dependent antigens (Stein et al, 2002).…”

BAFF and LPS cooperate to induce B cells to become susceptible to CD95/Fas‐mediated cell death

“…The production of BAFF by accessory cells may be particularly important to modulate not only B cell survival but also other B cell functions. For instance, engagement of TLR4 by LPS stimulates myeloid DC and macrophages to secrete BAFF, which promotes BCR-and CD40-induced B cell proliferation [10] and favors immunoglobulin class switch recombination [11]. DC can also be triggered to produce BAFF by the TLR2 ligand peptidoglycan [12] and by nucleic acid-containing immune complexes, presumably via TLR9 [13].…”

Atacicept in patients with rheumatoid arthritis and an inadequate response to tumor necrosis factor antagonist therapy: Results of a phase II, randomized, placebo-controlled, dose-finding trial

“…APRIL promotes B cell and plasma cell activation and survival and plays important roles in immunoglobulin class switching and antigen presentation (9)(10)(11). BLyS promotes B cell survival and maturation (12)(13)(14)(15).…”