Cutting Edge: The Dependence of Plasma Cells and Independence of Memory B Cells on BAFF and APRIL

Abstract

Memory B (BMEM) cells and long-lived bone marrow plasma cells (BM-PCs) persist within local environmental survival niches that afford cellular longevity. However, the factors supporting BMEM cell survival within the secondary lymphoid organs and allowing BM-PC persistence in the bone marrow remain poorly characterized. We report herein that long-lived BMEM cell survival and function are completely independent of BAFF (B cell-activating factor of the TNF family) or APRIL (a proliferation-inducing ligand). Thus, BMEM cells represent the only mature B2 lineage subset whose survival is independent of these ligands. We have previously shown that the TNFR family member receptor BCMA (B cell maturation Ag) is a critical survival receptor for BM-PC survival in vivo. We identify in this study the ligands critical for BM-PC survival and show that either BAFF or APRIL supports the survival of BM-PCs in vivo. These data define the BAFF/APRIL-dependent and -independent components of long-lived humoral immunity.

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

“…Atacicept blocks APRIL in addition to BLyS (8), and APRIL supports plasma cells in the absence of BLyS (34). Therefore, it would be reasonable to hypothesize that the reduction in plasma cell numbers achieved with atacicept, but not belimumab (33), in patients with RA may have additional clinical effects.…”

“…However, clinical efficacy associated with decreased levels of both RF and ACPAs has been demonstrated at 6 months after initiation of treatment with the B celltargeting therapy, rituximab, in RA (35,36), suggesting that the 26-week treatment period in our study was of sufficient duration to evaluate clinical benefit. Rituximab (37) and atacicept (34,38) target different B cell populations, and rituximab may interfere with antigen presentation, cytokine production, and the direct stimulation of T cells by B cells, in addition to its effects on autoantibody production (5), all of which may be relevant for its clinical efficacy. Thus, comparing the time course of the effects of rituximab and atacicept may not be informative.…”

Homing and Adhesion Patterns Determine the Cellular Composition of the Bone Marrow Plasma Cell Niche

“…It deserves mentioning that Ag-specific PCs slowly but steadily accumulated in vaccinated APRIL 2/2 mice and that the BM of APRIL 2/2 mice contains normal total PC numbers (E. Belnoue, C. Tougne, and C.-A. Siegrist, unpublished observations) (22), whereas adoptively transferred PC rapidly disappeared (Fig. 3G).…”

“…A critical in vivo role of APRIL, but not BAFF, was demonstrated using APRIL 2/2 and BAFF 2/2 mice (11). Conversely, the use of blocking reagents concluded that either APRIL or BAFF could support PC survival (21,22). We reported the role of APRIL-producing BM Gr1 int CD11b + cells in the support of BMPCs, referring to these cells as resident BM monocytes (11).…”

BAFF/BLyS inhibitors: A new prospect for treatment of systemic lupus erythematosus

“…Current views are that BCMA may be important for the survival of some, but not all plasma cells, and that both BAFF and APRIL may contribute to this effect. Blocking either BAFF, or APRIL, independently does not result in differences in numbers of bone marrow plasma cells, but blocking both reduces numbers dramatically (18).…”