Cutting Edge: Germinal Centers Formed in the Absence of B Cell-Activating Factor Belonging to the TNF Family Exhibit Impaired Maturation and Function

Abstract

Germinal centers (GCs) form in B cell follicles and require specific signals for development and maintenance. B cell-activating factor belonging to the TNF family (BAFF) is a fundamental B cell survival factor and therefore may influence GC reactions and subsequent Ab responses. To test this possibility, the effect of BAFF neutralization in immunized mice was assessed. Using B cell maturation Ag-Fc, we demonstrate that BAFF blockade does not inhibit GC formation or somatic hypermutation. However, GCs in B cell maturation Ag-Fc-treated mice dissipated more rapidly than those of control mice and did not form a mature follicular dendritic cell reticulum. Examination of immunized BAFF-null mice validated the BAFF-independent nature of GC formation. Furthermore, Ab responses, including high-affinity responses, were attenuated. This is the first evidence that BAFF is required for maintenance, but not initiation, of the GC reaction, and it further hints that somatic hypermutation within the GC and selection of Ag-specific high-affinity Ab could be uncoupled.

Cutting Edge: BAFF Regulates CD21/35 and CD23 Expression Independent of Its B Cell Survival Function

“…Furthermore, WT mice treated with a BAFF inhibitor produce high-affinity Ab, although the quantity is diminished (16,17). Recently we showed that BAFF KO and BCMA-Fc-treated WT mice form GCs with intact somatic hypermutation (7). Together, these data suggest the existence of mature B cells in BAFF KO mice.…”

“…However, it was shown that while the humoral responses to T-dependent Ags were severely impaired in BAFF KO mice, Ag-specific, classswitched Ab was still produced (2,3). Recently, we showed that BAFF KO mice form germinal centers (GC) with intact somatic hypermutation after Ag challenge (7). These findings suggest that BAFF KO mice possess more differentiated, mature B cells than originally believed.…”

B Lymphocyte Autoimmunity in Rheumatoid Synovitis Is Independent of Ectopic Lymphoid Neogenesis

“…The B cell growth and survival factors BAFF (B cell activation factor of the TNF family) and APRIL (A proliferation-inducing ligand) also contribute to the establishment of FDC networks and GC-reactions in SLO as well as in RA synovitis (39,40). One of their receptors, TACI (soluble transmembrane activator and calcium modulator and cyclophilin ligand-interactor), negatively regulates this process (41,42).…”

Human innate B cells: a link between host defense and autoimmunity?

“…Furthermore, preliminary gene expression experiments using DNA microarrays indicate that as compared to other naïve B cells that regularly participate in productive GC reactions, 9G4 naïve cells express decreased levels of NF-κB and JNK kinase, a profile characteristic of anergic autoreactive transgenic B cells [91,92]. Several mechanisms could be postulated to explain the failure of pre-GC 9G4 B cells to successfully participate in a mature GC reaction including defective responses to stimulation through the BAFF receptor [93,94]. In addition, when stimulated in the presence of surrogate T cell help, healthy naïve 9G4 B cells readily differentiate into antibody-producing plasma cells (PC), thereby suggesting that their inability to do so in vivo may be due, at least in part, to the absence of T cell help, a mechanism known to contribute to the maintenance of tolerance in transgenic anti-DNA B cells [15,95].…”