Normal Induction but Attenuated Progression of Germinal Center Responses in BAFF and BAFF-R Signaling–Deficient Mice

Abstract

The factors regulating germinal center (GC) B cell fate are poorly understood. Recent studies have defined a crucial role for the B cell–activating factor belonging to TNF family (BAFF; also called BLyS) in promoting primary B cell survival and development. A role for this cytokine in antigen-driven B cell responses has been suggested but current data in this regard are limited. A BAFF receptor expressed by B cells (BAFF-R/BR3) is defective in A/WySnJ mice which exhibit a phenotype similar to BAFF-deficient (BAFF−/−) animals. Here, we show that although GC responses can be efficiently induced in both A/WySnJ and BAFF−/− mice, these responses are not sustained. In BAFF−/− mice, this response is rapidly attenuated and accompanied by perturbed follicular dendritic cell development and immune complex trapping. In contrast, analysis of the A/WySnJ GC response revealed a B cell autonomous proliferative defect associated with reduced or undetectable Ki67 nuclear proliferation antigen expression by GC B cells at all stages of the response. These data demonstrate a multifaceted role for the BAFF pathway in regulating GC progression.

The role of APRIL and BAFF in lymphocyte activation

“…via lymphotoxin b). In BAFF-R-null mice, however, FDC networks are present but B cells fail to proliferate, possibly because TACI and/or BCMA signals, in the absence of BAFF-R, prevent cell cycle progression [42]. In this respect, it is interesting to note that human germinal center B cells express BCMA [39 ].…”

“…[40] Switching to IgA and IgG occurs [50] Reduced Increased number [45] Impaired + [35] Normal in PP and mLN GCs [40] Impaired + No Ki67 in B cells [42] Marginal zone B cells…”

Expression of the autoimmune Fcgr2b NZW allele fails to be upregulated in germinal center B cells and is associated with increased IgG production

“…25 Immunohistology was performed using the antibodies listed above and the stained sections were analyzed using a fluorescence microscopy (Leitz Diaplan, Wetzlar, Germany) and images were captured as described. 26 Flow cytometry Four-color flow cytometric analysis was performed on cell suspensions prepared from spleens of naive and immunized mice stained with multiple combinations of antibodies listed above. Biotinylated Abs were detected with SA-CyChrome.…”

Affinity of antigen encounter and other early B-cell signals determine B-cell fate

“…We have shown that a CD40 agonist coupled with a TD antigen ablates long-lived humoral immunity in favor of short-lived extrafollicular PCs, with this situation partially mimicked in vivo by enhancing T-cell help [19]. Other factors that impact the B cell include the interactions of BAFF (B-cell activating factor belonging to the TNF family) and APRIL (a proliferation inducing ligand) with their B-cell expressed receptors, Tolllike receptor ligation, cytokines and downstream signaling mediators of the BCR such as Lyn tyrosine kinase, which can attenuate or exacerbate total signal strength to the GC B cell and thus influence terminal B-cell differentiation [24][25][26][27].…”