BAFF and BAFF-R Levels Are Associated With Risk of Long-Term Kidney Graft Dysfunction and Development of Donor-Specific Antibodies
A. Thibault-EspitiaYohann FoucherRichard DangerThi MigoneAnnaïck PallierSophie CastagnetClaire GuéguenAnne DevysAnne Cesbron GautierMagali GiralJ.P. SoulillouSophie Brouard
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There are lines of evidence that B cells may play a role in transplantation. B cell activating factor, BAFF, is a homotrimer that has been shown to play a role in B cell survival, maturation and activation. To date, little is known of the role of BAFF and its receptors in transplantation. We analyzed the level of BAFF mRNA and its soluble protein, as well as transcripts coding for its receptors, BAFF-R, TACI and BCMA, in the blood of 143 patients with stable kidney transplant function 5 years or more posttransplantation. Three endpoints were analyzed: the time to renal dysfunction, the time to appearance of anti-HLA antibodies and the time to development of donor-specific antibodies. We established threshold values for BAFF and BAFF-R and showed that (1) stable patients with high BAFF-R levels had a higher risk of developing graft dysfunction, (2) patients with lower levels of BAFF transcripts or a higher level of soluble BAFF had a significantly higher risk of developing donor-specific antibodies. These data suggest that BAFF constitutes a risk factor for renal graft dysfunction and development of donor-specific antibodies. They also suggest that agents targeting BAFF-R interactions may offer new therapeutic opportunities in transplantation.The effects of B cell-activating factor belonging to the TNF family (BAFF) on B cell maturation and survival in the mouse are relatively well understood. In contrast, little is known about the role of BAFF in B cell development in other mammals, such as rabbits, that use GALT to develop and maintain the B cell compartment. We examined the expression and requirement of BAFF and a proliferation-inducing ligand (APRIL) during peripheral B cell development in young rabbits. By neutralizing BAFF and APRIL in neonates with a soluble decoy receptor, transmembrane activator calcium modulator and cyclophilin ligand interactor-Fc, we found a marked reduction in the number of peripheral B cells, but found no change in the bone marrow (BM) compartment. In the appendix, the size and number of proliferating B cell follicles were greatly reduced, demonstrating that although BAFF/APRIL is dispensable for B cell development in BM, it is required for B cell development in GALT. We found that all rabbit B cells expressed BAFF receptor 3, but did not bind rBAFF, suggesting that the BAFF-binding receptors (BBRs) are bound by endogenous soluble BAFF. Further, we found that B cells themselves express BAFF, suggesting that the soluble BAFF bound to BBRs may be endogenously produced and stimulate B cells in an autocrine fashion. Additionally, we propose that this chronic occupancy of BBRs on B cells may provide a tonic and/or survival signal for the maintenance of peripheral B cells in adults after B lymphopoiesis is arrested in BM.
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There is emerging evidence that B-lineage neoplasms have aberrant expression of B-cell activating factor (BAFF) that enables the B cells to escape apoptosis. The aim of the study therefore was to investigate circulating levels of BAFF in paediatric malignancies related to B-cell growth, i.e. B-cell acute lymphoblastic leukaemia (B-ALL) and B-lineage lymphomas. We observed significant differences in circulating levels of BAFF between the B-ALL patients and B-cell lymphoma patients (Bcp-ALL: 7764 ± 6329 pg / ml, B-cell lymphoma: 2675 ± 1544 pg / ml; P = 0.0268), the circulating levels of BAFF being substantially higher in B- ALl cases. doi:10.4021/jh104e
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Abstract The cytokines BLyS (B lymphocyte stimulator) and APRIL (a proliferation-inducing ligand) interact with three receptors – BR3, TACI, and BCMA – to regulate peripheral B cell homeostasis. Experimental evidence indicates that the BLyS-BR3 interaction governs the size and composition of primary B cell subsets by controlling the proportion of transitional (TR) cells that complete differentiation and determining the lifespan of follicular (FO) and marginal zone (MZ) B cells. The role of the BLyS family in the regulation and maintenance of memory B cell subsets remains less understood. Accordingly, we have directly tested the role of BLyS in the maintenance of memory B cells in vivo using a neutralizing anti-BLyS antibody. Mice injected with anti-BLyS show profoundly reduced numbers of TR, FO, and MZ B cells within two weeks following treatment, as well as significantly reduced serum BLyS levels. However, for mice previously immunized with NP-CGG and injected with anti-BLyS, this treatment, while similarly reducing primary B cell pools, has no effect on NP-specific memory B cell numbers. Further, upon rechallenge, the expansion of NP specific memory B cells and serum anti-NP antibody levels are similar to controls that did not receive anti-BLyS. Together, these findings indicate that memory B cells are largely independent of BLyS availability, and therefore occupy a separate homeostatic niche from primary B cells. Supported by USPHS AI054488 to MPC and T32-AI-055428 to JEC
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Abstract B lymphocyte stimulator (BLyS) controls the proportion of transitional B cells completing differentiation and the longevity of most primary B cells. These key roles in B cell selection, survival and homeostasis make BLyS and its receptors attractive candidates for targeted B cell therapeutics. Here we have used a neutralizing hamster anti-mouse BLyS antibody to assess how BLyS depletion influences developing and primary B cell subsets, as well as how this treatment impacts primary TD and TI immune responses. Mice treated with 10F4 show rapid and substantial reductions in the transitional, follicular, and marginal zone pools which persist for ~40 days. In contrast, the only bone marrow subset affected is the mature recirculating B cell fraction. Interestingly, splenic B1 cells, but not peritoneal B1 cells, are reduced as well. Following the recovery of serum BLyS levels, peripheral reconstitution occurs gradually, such that normal B cell numbers return by day 70–80. Mice challenged with T-dependent or T-independent antigen at day 30 post-treatment with anti-BLyS mount attenuated humoral responses compared with untreated mice. Together, our results show that BLyS neutralization ablates most primary B cells but spares B lineage progenitors; and indicate that these populations, as well as BLyS per se, may be required for unabridged primary immune responses.
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The cytokine BLyS (B lymphocyte stimulator) interacts with three receptors – BR3, TACI, and BCMA – to regulate the composition and size of peripheral B cell pools. BLyS-BR3 interactions govern the size and composition of primary B cell subsets by controlling the proportion of transitional (TR) B cells that complete differentiation and determining the lifespan of mature follicular (FO) and marginal zone (MZ) B cells. The role of BLyS family members in the regulation and maintenance of other subsets, particularly antigen-experienced and memory B cells, remains unclear. Accordingly, we have directly interrogated the role of BLyS in a primary T-independent and T-dependent antigen response and the maintenance of memory B cells in vivo, using a neutralizing anti-BLyS antibody. Mice injected with 200 μg of anti-BLyS show profoundly reduced numbers of TR, FO, and MZ B cells within two weeks following treatment, as well as significantly reduced serum BLyS levels. Mice challenged with T-dependent or T-independent antigen at 30d post-treatment with anti-BLyS mount attenuated responses, compared to untreated mice. However, mice that had been immunized with NP-CGG 8wk prior to anti-BLyS treatment show no reduction in NP-specific memory B cells. Further, upon antigen rechallenge, the expansion of NP-specific memory B cells and serum anti-NP antibody levels are similar to controls. Together, these findings indicate that memory B cells are largely independent of BLyS, and therefore occupy a separate homeostatic niche from primary B cells.
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Serum levels of B cell-activating factor (BAFF) rise following rituximab (RTX) therapy in patients with rheumatoid arthritis (RA). Initiation of naive B cell return to the periphery and autoreactive B cell expansion leading to relapse after RTX may therefore be linked to interactions between BAFF and BAFF-binding receptors (BBR). Relationships between serum BAFF and BBR expression [(BAFFR, calcium signal modulating cyclophilic ligand interactor (TACI) and B cell maturation antigen (BCMA)] were determined on B cell subsets, defined using immunoglobulin (Ig)D/CD38. Twenty pre-RTX and 18 RA patients relapsing after B cell depletion were included. Results were analysed with respect to timing of relapse up to 7 months after peripheral B cell return (≥ 5 B cells/μl) and to serum BAFF levels. After B cell return, B cell populations from relapsing patients had significantly lower BAFFR+ expression compared to HC and pre-RTX patients. The percentage of BAFFR+ B cells increased with time after B cell return and was correlated inversely with serum BAFF levels. BAFFR expression remained reduced. The percentage of TACI+ memory B cells were lower in RA patients after RTX compared with healthy controls (HC). BCMA expression (% and expression) did not differ between patients and HC. Relapse following B cell return appeared largely independent of the percentage of BAFFR+ or percentage of BCMA+ B cells or serum BAFF levels. The lower percentage of TACI+ memory B cells may reduce inhibitory signalling for B cell differentiation. In patients relapsing at longer periods after B cell return, recovery of the B cell pool was more complete, suggesting that selection or expansion of autoreactive B cells may be needed to precipitate relapse.
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The presence of autoantibodies in New Zealand Black (NZB) mice suggests a B cell tolerance defect however the nature of this defect is unknown. To determine whether defects in B cell anergy contribute to the autoimmune phenotype in NZB mice, soluble hen egg lysozyme (sHEL) and anti-HEL Ig transgenes were bred onto the NZB background to generate double transgenic (dTg) mice. NZB dTg mice had elevated levels of anti-HEL antibodies, despite apparently normal B cell functional anergy in-vitro. NZB dTg B cells also demonstrated increased survival and abnormal entry into the follicular compartment following transfer into sHEL mice. Since this process is dependent on BAFF, BAFF serum and mRNA levels were assessed and were found to be significantly elevated in NZB dTg mice. Treatment of NZB sHEL recipient mice with TACI-Ig reduced NZB dTg B cell survival following adoptive transfer, confirming the role of BAFF in this process. Although NZB mice had modestly elevated BAFF, the enhanced NZB B cell survival response appeared to result from an altered response to BAFF. In contrast, T cell blockade had a minimal effect on B cell survival, but inhibited anti-HEL antibody production. The findings suggest that the modest BAFF elevations in NZB mice are sufficient to perturb B cell tolerance, particularly when acting in concert with B cell functional abnormalities and T cell help.
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B lymphocyte stimulator (BLyS; also known as B cell activating factor (BAFF)) plays a key role in peripheral B cell tolerance. Mounting evidence indicates that B cell tolerance can be either broken or modulated by deliberately manipulating BLyS levels, and belimumab, a BLyS-neutralizing antibody, was recently approved for the treatment of systemic lupus erythematosus (SLE). Thus, intense investigation has focused on understanding how therapeutics targeting BLyS may work, and accumulating evidence suggests multiple points of action. BLyS signaling, in conjunction with B cell receptor (BCR) signaling, determines the size and quality of the mature primary B cell compartment. Moreover, BLyS family members play roles in antigen-experienced B cell selection and differentiation. Together, these findings have implications for the continued development of novel therapeutics that target BLyS.
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