BAFF信号的免疫调节作用

B淋巴细胞活化因子(BAFF)是肿瘤坏死因子超家族的新成员,是B淋巴细胞生长、分化和发育所需的细胞因子,其通过与细胞表面的3种受体——B细胞成熟抗原(BCMA)、穿膜蛋白活化物(TACI)和B细胞活化因子受体(BAFF-R)结合产生信号发挥重要调节作用。BAFF的缺陷或过量表达均能引起机体的免疫失衡,从而诱发多种疾病。     

TACI attenuates antibody production costimulated by BAFF-R and CD40

B cell activating factor of the TNF family (BAFF), plays critical roles in B cell survival, activation, differentiation, and antibody (Ab) production. BAFF binds to three receptors: BAFF-R, transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) and B cell maturation antigen. While BAFF-R is the primary receptor for B cell costimulation by BAFF, TACI is reported to serve as a positive or negative regulator for B cell responses depending on conditions. To determine the real role of TACI in B cell responses, we examined the functional relationship between TACI and BAFF-R in Ab production from human peripheral blood B cells using agonistic mAb. BAFF-R and CD40 enhanced IgG secretion and B cell proliferation, which were inhibited by TACI. Although TACI induced mild B cell apoptosis, its extent did not correlate with that of TACI-mediated inhibition of IgG secretion. In addition, TACI inhibited B-lymphocyte-induced maturation protein-1 expression, IgG secretion from previously IgG-negative selected B cells, and activation-induced cytidine deaminase expression enhanced by BAFF-R and CD40. Importantly, BAFF-R and CD40 enhanced B cell responsiveness to TACI-mediated suppression. Thus, BAFF may attenuate T cell-independent and -dependent B cell responses by TACI.     

Synthetic CpG oligodeoxynucleotides augment BAFF- and APRIL-mediated immunoglobulin secretion

The B lymphocyte-activating factor belonging to TNF superfamily (BAFF) acts on B lymphocytes through BAFF receptor (BAFF-R), the transmembrane activator, calcium modulator, and cyclophilin ligand interactor (TACI), and the B cell maturation antigen (BCMA). Another cytokine, a proliferation-inducing ligand (APRIL), only binds to TACI and BCMA. In this study, we sought to determine the effect of Toll-like receptor agonists (TLR-A) on the expression of BAFF/APRIL receptors by murine splenic B lymphocytes. CpG oligodeoxynucleotides (ODN) and LPS strongly up-regulated TACI expression, while BAFF-R was only up-regulated by CpG ODN. CpG ODN pretreatment up-regulated TACI expression on follicular and marginal zone B lymphocytes and increased their responses to BAFF- and APRIL-mediated Ig secretion. TACI seemed to be playing a pivotal role in BAFF- or APRIL-induced Ig secretion because B lymphocytes from TACI-knockout mouse or the blocking of TACI with a neutralizing antibody resulted in total inhibition of IgA and IgG secretion in CpG ODN-pretreated and BAFF- or APRIL-stimulated B cells. Thus, CpG ODN-induced increase in TACI expression is likely to play an important role in Ig secretion following activation of B lymphocytes through TLR9.     

The role of BAFF in autoimmune diseases]

B cell activating factor belonging to the tumor necrosis factor family (BAFF) is a tumor necrosis factor (TNF) superfamily member best known for its role in the survival and maturation of B cells. BAFF is a ligand for three TNF receptor superfamily members: B-cell maturation antigen (BCMA), transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI), and BAFF receptor (BAFF-R). Among them, BAFF-R plays the central role in the BAFF system, whereas TACI plays the inhibitory role. BAFF/BAFF receptors appear to span nearly all stages of B-lineage differentiation, ranging from the development, selection, and homeostasis of naive primary B cells to the maintenance of long-lived bone marrow plasma cells. Furthermore, excessive BAFF rescues self-reactive B cells from anergy, which may play a crucial role in the induction and development of autoimmunity. Mice overexpressing BAFF exhibit increased B cell numbers in spleen and lymph node and autoimmune phenotype similar to patients with systemic lupus erythematosus (SLE) and Sj?gren's syndrome. Furthermore, inhibition of BAFF by TACI-Ig and BAFFR-Ig has been successful in treating murine models of SLE and rheumatoid arthritis. In humans, previous reports have shown elevated serum BAFF levels in SLE, rheumatoid arthritis, Sj?gren's syndrome, and systemic sclerosis patients. Thus, the dysregulation of BAFF/BAFF receptor system may contribute to induction and development of autoimmune diseases and become one of important therapeutic targets.     

The role of APRIL and BAFF in lymphocyte activation

The TNF family ligands BAFF (also called BLyS) and APRIL regulate lymphocyte survival and activation. BAFF binds to three receptors, BAFF-R, TACI and BCMA, whereas APRIL interacts with TACI, BCMA and proteoglycans. The contribution of BAFF and APRIL to B-cell and plasma-cell survival, CD154 (CD40L)-independent antibody isotype switching, germinal center maintenance, T-dependent and T-independent antibody responses, and T cell co-stimulation are relatively well understood. Constitutive BAFF produced by stromal cells determines the size of the peripheral B cell pool, whereas inducible BAFF produced by myeloid and other cells supports local survival of B lymphocytes and can be associated with development of autoimmunity when deregulated.     

To switch or not to switch--the opposing roles of TACI in terminal B cell differentiation

The TNF superfamily ligands BAFF and APRIL and their three receptors BAFFR, BCMA, and TACI comprise a network that is critically involved in the development and function of humoral immunity. Failure of this complex system is associated with autoimmune disease, B lymphocyte tumours, and antibody deficiency. While BAFF:BAFFR interactions control peripheral B cell survival and homeostasis, BCMA function seems limited to the survival of long-lived bone marrow plasma cells. The functional activity of the third receptor TACI is, however, ambiguous: while TACI-/- mice predominantly develop autoimmunity and lymphoproliferation, TACI deficiency in humans primarily manifests itself as an antibody deficiency syndrome. An article in this issue of the European Journal of Immunology demonstrates a negative regulation via TACI in human B cells by using TACI specific antibodies. B cell proliferation, class switch recombination, and Ig production induced by various stimuli were inhibited via TACI. Within the BAFF/APRIL network, the expression of the receptors and ligands is spatially, as well as temporally, highly regulated at various stages of B cell development and function. Defining the exact contribution of TACI stimulation by specific triggers in vitro enables us to better understand the complex, context-dependent responses initiated by TACI in vivo.     

The expression of BAFF-binding receptors is not altered in multiple sclerosis or myasthenia gravis

Multiple sclerosis (MS) is a chronic, progressive disease of the central nervous system (CNS) characterized by consistent myelin injury. Antibody-mediated death of oligodendrocytes is a pathological feature in a subset of MS patients and may be of relevance to disease pathogenesis. In myasthenia gravis (MG), acetylcholine receptors (AChR) situated at the neuromuscular endplate are destroyed by autoreactive antibodies. B-cell activating factor of the tumour necrosis factor (TNF) superfamily (BAFF) is essential for B-cell survival. Using flow cytometry, we evaluated the expression of three BAFF-binding receptors, namely, BAFF-receptor (BAFF-R), B-cell maturation antigen (BCMA), and transmembrane activator and calcium modulating and cyclophilin ligand interactor (TACI) in peripheral-blood lymphocytes. Nearly all CD19(+) B cells and CD19(+)CD27(+) memory B cells expressed BAFF-R. The intensity of BAFF-R expression was not statistically different in MS or MG compared with healthy controls. Very few T cells expressed BAFF-R. BCMA expression was strictly limited to B cells. Although both B and T cells expressed TACI, levels were much higher on B cells compared with levels on T cells. The percentages of B and T cells expressing BCMA and TACI did not differ significantly in MS or MG versus controls. We conclude that the expression of BAFF-binding receptors is not appreciably altered in MS or MG.     

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

Microorganisms with pathogen-associated molecular patterns (PAMP) activate B cells directly by binding to TLR and also indirectly by inducing APC to release cytokines such as BAFF that promote B cell survival. We found that murine B cells activated concomitantly with LPS (TLR-4 ligand) and BAFF are protected from spontaneous apoptosis, but are more susceptible to Fas/CD95-mediated cell death. This increased susceptibility to Fas-induced apoptosis is associated with a dramatic coordinated up-regulation of Fas/CD95 and IRF-4 expression through a mechanism mediated, at least in part, by inhibition of the MEK/ERK pathway. Up-regulation of Fas/CD95 by BAFF is restricted to B cells activated through TLR-4, but not through TLR-9, BCR or CD40. TLR ligands differ in the BAFF family receptors (R) they induce on B cells: BAFF-R is increased by the TLR4 ligand, LPS, but not by the TLR9 ligand, CpG-containing oligodeoxynucleotides, which, in contrast, strongly up-regulates transmembrane activator and CAML interactor (TACI). This suggests the up-regulation of Fas by BAFF is mediated by BAFF-R and not by TACI. Consistently, APRIL, which binds to TACI and B cell maturation antigen but not BAFF-R, did not enhance Fas expression on LPS-activated B cells. Increased susceptibility to Fas-mediated killing of B cells activated with LPS and BAFF may be a fail-safe mechanism to avoid overexpansion of nonspecific or autoreactive B cells.     

BAFF, APRIL and their receptors: structure, function and signaling

BAFF, APRIL and their receptors play important immunological roles, especially in the B cell arm of the immune system. A number of splice isoforms have been described for both ligands and receptors in this subfamily, some of which are conserved between mouse and human, while others are species-specific. Structural and mutational analyses have revealed key determinants of receptor-ligand specificity. BAFF-R has a strong selectivity for BAFF; BCMA has a higher affinity for APRIL than for BAFF, while TACI binds both ligands equally well. The molecular signaling events downstream of BAFF-R, BCMA and TACI are still incompletely characterized. Survival appears to be mediated by upregulation of Bcl-2 family members through NF-kappaB activation, degradation of the pro-apototic Bim protein, and control of subcellular localization of PCKdelta. Very little is known about other signaling events associated with receptor engagement by BAFF and APRIL that lead for example to B cell activation or to CD40L-independent Ig switch.     

B淋巴细胞刺激因子的研究进展

肿瘤坏死因子超家族成员B淋巴细胞刺激因子(BAFF)通过和隶属与肿瘤坏死因子受体超家族成员的BCMA、TACI和BAFF-R的结合,在调节外周成熟B淋巴细胞的发育过程中起着重要的作用。由于在多种自身免疫性疾病中的异常表达,BAFF和其受体也被认为是治疗自身免疫性疾病的重要治疗靶点。     

The anti-apoptotic factor Bcl-2 can functionally substitute for the B cell survival but not for the marginal zone B cell differentiation activity of BAFF

The TNF family ligand B cell-activating factor (BAFF, BLyS, TALL-1) is an essential factor for B cell development. BAFF binds to three receptors, BAFF-R, transmembrane activator and CAML interactor (TACI), and B cell maturation antigen (BCMA), but only BAFF-R is required for successful survival and maturation of splenic B cells. To test whether the effect of BAFF is due to the up-regulation of anti-apoptotic factors, TACI-Ig-transgenic mice, in which BAFF function is inhibited, were crossed with transgenic mice expressing FLICE-inhibitory protein (FLIP) or Bcl-2 in the B cell compartment. FLIP expression did not rescue B cells, while enforced Bcl-2 expression restored peripheral B cells and the ability to mount T-dependent antibody responses. However, many B cells retained immaturity markers and failed to express normal amounts of CD21. Marginal zone B cells were not restored and the T-independent IgG3, but not IgM, response was impaired in the TACI-IgxBcl-2 mice. These results suggest that BAFF is required not only to inhibit apoptosis of maturating B cells, but also to promote differentiation events, in particular those leading to the generation of marginal zone B cells.     

BAFF costimulation of Toll-like receptor-activated B-1 cells

B cell-activating factor belonging to the TNF family (BAFF) and its receptor BAFF-R play critical roles in the maturation and survival of conventional peripheral B cells. However, they appeared to be dispensable for the generation and maintenance of CD5(+) B-1 cells as BAFF(-/-) and BAFF-R(-/-) mice have normal B-1 cell populations. Hence, it is presently unclear if B-1 cells are responsive to BAFF and if BAFF regulates some aspects of B-1 cell function. We show here that BAFF-R and transmembrane activator and CAML interactor (TACI) are the major receptors expressed by B-1 cells. Specifically, we show that BAFF treatment of B-1 cells leads to increased NF-kappaB p100 processing and CD21/CD35 expression. Interestingly, toll-like receptor (TLR) engagement of B-1 cells augmented the surface expression of BAFF receptors and rendered them responsive to BAFF costimulation, as evidenced by their increased proliferation, expression of cell surface activation markers and secretion of the pro-inflammatory cytokine IL-6 and the anti-inflammatory cytokine IL-10. This costimulatory effect is achieved primarily through BAFF-R as BAFF failed to costimulate B-1 cells obtained from A/WySnJ mice which have defective BAFF-R signaling. Thus, as TLR are innate immune receptors and B-1 cells are "innate-like" lymphocytes, our data provide evidence that BAFF plays a role in innate immunity.     

B cell activating factor (BAFF) and BAFF receptors: fakes and facts

Analysis of B cell activating factor (BAFF) receptors before and after B cell depletion therapy (BCDT) might offer a clue to the understanding of whether some B cell subsets may represent useful biomarkers of biological and clinical responses. Among the BAFF receptors in a cohort of rheumatoid arthritis (RA) patients, the AA have shown, by fluorescence activated cell sorter (FACS) analysis of median fluorescence intensity (MFI), that transmembrane activator and calcium‐modulating cyclophilin ligand interactor (TACI) and B cell maturation antigen (BCMA) do not change, whereas the most important, BAFF receptor 3 (BR3), appears to be decreased before as well as after BCDT in all B cell subsets but not in plasmablasts, the most important subset, depleted by BCDT.     

BAFF binding to T cell-expressed BAFF-R costimulates T cell proliferation and alloresponses

Binding of the TNF family member, B cell activating factor (BAFF), to its receptor (BAFF-R, TNFRSF13C) is required for generation and maintenance of mature B cells, but there are no data as to any role for the BAFF/BAFF-R pathway in T cell functions. We report that the binding of BAFF to BAFF-R expressed by a subset of primarily CD4(+) T cells costimulates T cell activation and allo-proliferation in vitro and in vivo, and that mice with a mutation in the BAFF-R, or with a targeted deletion of BAFF, show prolonged cardiac allograft survival as compared to wild-type or transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI)(-/-) controls. Taken together, these data indicate the BAFF/BAFF-R pathway contributes to both T and B cell responses and may be an attractive target for control of acute and chronic allograft rejection.     

Effect of rituximab on B cell phenotype and serum B cell-activating factor levels in patients with thrombotic thrombocytopenic purpura

Autoantibodies inhibiting the activity of the metalloproteinase, ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), underlie the pathogenesis of thrombotic thrombocytopenic purpura (TTP). Rituximab (RTX) combined with plasma-exchange (PEX) is an effective treatment in TTP. Patients can remain in remission for extended periods following PEX/RTX, and this is associated with continuing reduction in antibodies to ADAMTS13. Factors controlling B cell differentiation to autoantibody production, including stimulation through the B cell receptor and interactions with the B cell-activating factor (BAFF), may thus impact length of remission. In this cross-sectional study, we measured naive and memory B cell phenotypes [using CD19/immunoglobulin (Ig)D/CD27] following PEX/RTX treatment in TTP patients at B cell return (n = 6) and in 12 patients in remission 10–68 months post-RTX. We also investigated relationships among serum BAFF, soluble CD23 (sCD23^– a surrogate measure of acquiring B memory (CD27⁺) phenotype) and BAFF receptor (BAFF-R) expression. At B cell return after PEX/RTX, naive B cells predominated and BAFF-R expression was reduced compared to healthy controls (P < 0·001). In the remission group, despite numbers of CD19⁺ B cells within normal limits in most patients, the percentage and absolute numbers of pre-switch and memory B cells remained low, with sCD23 levels at the lower end of the normal range. BAFF levels were correlated inversely with BAFF-R expression and time after therapy. In conclusion, the long-term effects of RTX therapy in patients with TTP included slow regeneration of memory B cell subsets and persistently reduced BAFF-R expression across all B cell subpopulations. This may reflect the delay in selection and differentiation of potentially autoreactive (ADAMTS13-specific) B cells, resulting in relatively long periods of low disease activity after therapy.     

Abnormal expression of BAFF and its receptors in peripheral blood and skin lesions from systemic lupus erythematosus patients

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease that is characterized by abnormal T and B cells. B-cell activating factor (BAFF) has been suggested to play a crucial role in lupus by promoting the proliferation, differentiation, and survival of B cells. Increased serum levels of BAFF have been found in patients with lupus. However, the expression of BAFF and its receptors on immune cells and in skin has not been systematically reported before. Here, we report that SLE patients showed increased levels of BAFF on circulating CD3⁺ T cells and B-cell maturation antigen (BCMA) on CD14⁺ monocytes and dramatically increased expression of BAFF in lupus skin lesions compared with those of healthy controls. TACI was undetectable on circulating immune cells. An increased serum level of BAFF was also confirmed in lupus patients in this study. Our findings may provide a better understanding of the pathogenesis and predictors of BAFF antibody treatment response, as well as potential targets for skin therapies.     

Age-related changes in BAFF and APRIL profiles and upregulation of BAFF and APRIL expression in patients with primary antibody deficiency

In some patients with common variable immunodeficiency (CVID) and immunoglobulin (Ig) A deficiency (IgAD), tumor necrosis factor (TNF) family receptor transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) gene mutations have been reported. B cells from individuals with TACI mutations do not produce IgG and IgA in response to the TACI ligand a proliferation-inducing ligand (APRIL) which probably suggests impaired isotype switching. To clarify the pathogenesis of CVID and IgAD of Japanese patients, we investigated the mutations of TNF family members TACI, APRIL, B-cell activating factor (BAFF), B-cell maturation antigen (BCMA) and BAFF receptor (BAFF-R) genes and the expression levels of BAFF and APRIL in patients with CVID, IgAD and X-linked agammaglobulinaemia (XLA). We also investigated the relationship between age and the blood plasma levels of BAFF and APRIL. The causative gene mutations of TNF family members in our patients were not detected. In healthy subjects, the BAFF and APRIL plasma levels correlated inversely with age. The BAFF and APRIL plasma levels of patients with CVID, IgAD and XLA were significantly higher than those of healthy children. Elevated BAFF and APRIL expression levels might partially reflect the common immunological feature of primary antibody deficiency.