B cell pathway dual inhibition for systemic lupus erythematosus: a prospective single-arm cohort study of telitacicept.

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease associated with B-cell hyperactivity. Telitacicept is a transmembrane activator, calcium modulator, and cyclophilin ligand interactor-Fc fusion protein, which can neutralize both B-cell lymphocyte stimulator and a proliferation-inducing ligand. Patients with active SLE who received telitacicept were prospectively followed at month 1, 3, 6, 9, and 12 after telitacicept initiation. Thirty-seven participants were involved and followed for 6.00 [3.00, 6.00] months. SRI-4 rate at month 6 was 44.7%. The median dosage of prednisone was decreased by 43.8% (from 10 to 5.62 mg/d) at month 6. The anti-dsDNA level was significantly decreased, while complement levels were significantly increased at month 6 from baseline. Continuously significant reductions in serum immunoglobin (Ig)G IgA, and IgM levels were also observed. Patients experienced significant decreases in the numbers of total and naive B cells, whereas memory B cells and T cell populations did not change. The number of NK cells was significantly increased during the follow-up. At month 6, 58.3% (14 out of 24) patients experienced improved fatigue accessed by FACIT-Fatigue score exceeding the minimum clinically important difference of 4. Most adverse events were mild, but one each case of severe hypogammaglobulinemia, psychosis with suicidal behavior, and B-cell lymphoma were occurred. In our first prospective real-world study, telitacicept treatment led to a significant clinical and laboratory improvement of disease activity, as well as fatigue amelioration in patients with SLE. Safety profile was favorable overall, but more studies are greatly needed.

[Advances of using antibody against B cell activating factor for treatment of autoimmune diseases].

In recent decades, the treatment of autoimmune diseases has moved from the use of hormones and conventional immunosuppressive drugs to biological agents. B cell proliferation and maturation play crucial roles in the development of autoimmune diseases. The tumor necrosis factor superfamily ligand B cell activating factor (BAFF) and its receptor mediate B cell survival through regulating signaling pathways. Therefore, BAFF and its receptors are important therapeutic targets for the treatment of autoimmune diseases. This review describes the mechanism of BAFF and its receptor in the human body system and introduces the latest views on how over-activation of BAFF pathway promotes the development of autoimmune diseases including systemic lupus erythematosus, Sjogren's syndrome, and rheumatoid arthritis. In connection to the treatment of the above three diseases, this review discusses the clinical trials and application status of three BAFF-targeting antibody drugs, including Belimumab, Tabalumab and Atacicept. Finally, this review proposes new strategies that targeting the BAFF pathway to provide a new treatment for autoimmune diseases.

A nasal double DNA adjuvant system induces atheroprotective IgM antibodies via dendritic cell-B-1a B cell interactions.

We previously demonstrated that the dendritic cell (DC)-targeting nasal double DNA adjuvant system, which consists of a DNA plasmid expressing Flt3 ligand (pFL) and CpG oligodeoxynucleotide 1826 (CpG ODN), elicits specific immune responses to various antigens in the mucosal and systemic compartments. Here, we investigated, using phosphorylcholine (PC)-conjugated keyhole limpet hemocyanin (PC-KLH) as an antigen, whether the nasal double DNA adjuvant system induces protective immunity to atherosclerosis in apolipoprotein E-deficient (ApoE KO) mice. Further, we assessed the molecular and cellular mechanisms in the induction of anti-PC-specific immune responses. Nasal immunization with PC-KLH plus pFL and CpG ODN enhanced induction of PC-specific IgM in plasma, peritoneal fluids, and nasal washes when compared with mice administered PC-KLH alone. Of importance, these antibodies exhibited highly specific binding to the PC molecule, and dose-dependent binding to anti-T15 idiotype (AB1-2). Twelve weeks after the last immunization, the nasal double DNA adjuvant system with PC-KLH resulted in a reduction of atherogenesis in the aortic arch of ApoE KO mice. Therefore, we next assessed immunocytological mechanism to induce these antibodies. The nasal double DNA adjuvant system with PC-KLH resulted not only in significantly increased frequencies of CD11c+ DCs in the spleen, peritoneal cavity (PEC), and nasopharyngeal-associated lymphoid tissues (NALT), but also significantly increased expression of a proliferation-inducing ligand and B-cell-activating factor by CD11c+ DCs. In addition, the double DNA adjuvant system induced significantly increased numbers of B-1 B cells in the spleen, PEC, and NALT, and increased expression of transmembrane activator and calcium modulator and cyclophilin ligand interactor on CD5+ B220+ (B-1a) B cells. These findings demonstrated that the nasal double DNA adjuvant system with PC-KLH resulted in the induction of T15-like antibodies in the mucosal and systemic lymphoid tissues through interaction between DCs and B-1a B cells, and inhibited the progression of atherogenesis.

Advances of using antibody against B cell activating factor for treatment of autoimmune diseases / 生物工程学报

In recent decades, the treatment of autoimmune diseases has moved from the use of hormones and conventional immunosuppressive drugs to biological agents. B cell proliferation and maturation play crucial roles in the development of autoimmune diseases. The tumor necrosis factor superfamily ligand B cell activating factor (BAFF) and its receptor mediate B cell survival through regulating signaling pathways. Therefore, BAFF and its receptors are important therapeutic targets for the treatment of autoimmune diseases. This review describes the mechanism of BAFF and its receptor in the human body system and introduces the latest views on how over-activation of BAFF pathway promotes the development of autoimmune diseases including systemic lupus erythematosus, Sjogren's syndrome, and rheumatoid arthritis. In connection to the treatment of the above three diseases, this review discusses the clinical trials and application status of three BAFF-targeting antibody drugs, including Belimumab, Tabalumab and Atacicept. Finally, this review proposes new strategies that targeting the BAFF pathway to provide a new treatment for autoimmune diseases.

Analysis of serum B cell-activating factor from the tumor necrosis factor family (BAFF) and its soluble receptors in systemic lupus erythematosus.

OBJECTIVES: To determine the presence and clinical associations of the soluble receptors of B cell-activating factor from the tumor necrosis factor family (BAFF) in serum of patients with systemic lupus erythematosus (SLE). METHODS: Serum BAFF and soluble BAFF receptor (sBAFF-R) were quantified using ELISA, and soluble B cell maturation antigen (sBCMA) and transmembrane activator and cyclophilin ligand interactor (sTACI) by Luminex, in 87 SLE patients and 17 healthy controls (HC). Disease activity and organ damage were assessed using SLE Disease Activity Index 2000 (SLEDAI-2K) and Systemic Lupus International Collaborating Clinics (SLICC) SLE Damage Index (SDI), respectively. RESULTS: BAFF and all receptors were detectable in all serum samples. Serum sBCMA and sTACI, but not sBAFF-R, were significantly higher in SLE than in HC. Serum BAFF was also increased in SLE, but this association was attenuated after adjusting for age and ethnicity. Increased serum BAFF was associated with flare and organ damage. Increased serum sBCMA was associated with the presence of anti-dsDNA, but not with overall or organ-specific disease activity, flare or organ damage. Neither sTACI nor sBAFF-R was associated with any SLE clinical parameters in multivariable analysis. While serum BAFF correlated negatively with sBAFF-R in HC, no statistically significant correlations were observed between BAFF and its receptors in SLE patients. CONCLUSION: Serum BAFF was associated with flare and organ damage independent of the presence of its soluble receptors. While sBCMA was associated with anti-dsDNA positivity, other soluble BAFF receptors were not associated with SLE clinical indicators.

B-cell activating factor receptor expression is associated with germinal center B-cell maintenance.

B-cell activating factor (BAFF) is a major cytokine that regulates B-cell survival, maturation and differentiation through its binding with its receptors: BAFF receptor (BAFF-R), transmembrane activator and cyclophilin ligand interactor (TACI) and B-cell maturation antigen (BCMA). These receptors have been demonstrated to be involved in tertiary lymphoid structure formation; however, their role in germinal centers (GCs) has remained elusive. The aim of the present study was to determine the expression profiles of BAFF and its receptors in secondary lymphoid tissues. Tonsils resected due to chronic tonsillitis were used as lymphoid tissues. To confirm the presence of GCs identified based on their typical structure, CD21 antibody staining was employed. The expression of BAFF, BAFF-R, TACI and BCMA was assessed by immunohistochemistry. BAFF was highly expressed in all regions of the follicle, but the highest BAFF expression was detected in the mantle zone (MZ). A high expression of BAFF-R was observed on lymphocytes in the MZ in comparison with the other regions (~80%; P<0.05), which was co-localizated with BAFF (r=0.646; P<0.001), in the MZ. TACI and BCMA exhibited similar expression among the different zones of the GCs, and co-localization with BAFF was observed inside the follicle, mainly in the dark zone. The present results indicate that BAFF is implicated in the maintenance of GCs. BAFF-R overexpression in the MZ, co-localizated with BAFF, suggests that these proteins constitute the principal pathway for the maintenance of the naïve B-cell population. Furthermore, TACI and BCMA have a role in the GC, where processes of B-cell selection, proliferation and differentiation into immunoglobulin-secreting plasma cells occur.

Lack of Gut Secretory Immunoglobulin A in Memory B-Cell Dysfunction-Associated Disorders: A Possible Gut-Spleen Axis.

Background: B-1a B cells and gut secretory IgA (SIgA) are absent in asplenic mice. Human immunoglobulin M (IgM) memory B cells, which are functionally equivalent to mouse B-1a B cells, are reduced after splenectomy. Objective: To demonstrate whether IgM memory B cells are necessary for generating IgA-secreting plasma cells in the human gut. Methods: We studied intestinal SIgA in two disorders sharing the IgM memory B cell defect, namely asplenia, and common variable immune deficiency (CVID). Results: Splenectomy was associated with reduced circulating IgM memory B cells and disappearance of intestinal IgA-secreting plasma cells. CVID patients with reduced circulating IgM memory B cells had a reduced frequency of gut IgA+ plasma cells and a disrupted film of SIgA on epithelial cells. Toll-like receptor 9 (TLR9) and transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) induced IgM memory B cell differentiation into IgA+ plasma cells in vitro. In the human gut, TACI-expressing IgM memory B cells were localized under the epithelial cell layer where the TACI ligand a proliferation inducing ligand (APRIL) was extremely abundant. Conclusions: Circulating IgM memory B cell depletion was associated with a defect of intestinal IgA-secreting plasma cells in asplenia and CVID. The observation that IgM memory B cells have a distinctive role in mucosal protection suggests the existence of a functional gut-spleen axis.

The role of the BAFF/APRIL system in the T cell-independent specific response to blood stage Plasmodium falciparum hemozoin.

BACKGROUND: The B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) are tumor necrosis factor family members that regulate B cell maturation, proliferation, survival and function. We have previously shown that blood-stage Plasmodium falciparum hemozoin (HZ) can act as a T-independent antigen (TI Ag) that induces the production of specific IgG to soluble crude P. falciparum Ag through the BAFF pathway. However, we have not yet clarified whether HZ need APRIL signaling in the TI response. Here, we aimed to clarify whether both BAFF and APRIL signaling pathways play roles in HZ induction of specific antibody production without T-cell help. METHODS: Normal monocytes alone or co-cultured with naïve B cells were stimulated by HZ (10 µM) in vitro. Naïve B cell cultures, with HZ alone or with exogenous recombinant BAFF (rBAFF) and recombinant APRIL (rAPRIL) plus recombinant IL-4 (rIL-4) for 6 and 10 days were used as controls to investigate activation of B cells. At various times, the levels of sBAFF, sAPRIL, and HZ-specific IgG in the culture supernatants were assessed by enzyme-linked immunosorbent assay. The BAFF and APRIL expression levels on the HZ-stimulated monocytes and their specific receptors on activated B cells, including the BAFF receptor (BAFF-R), the transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) and the B cell maturation antigen (BCMA), were determined by flow cytometry. mRNA expression levels for the receptors were validated using Real-Time quantitative PCR. RESULTS: HZ-activated monocytes released sBAFF and sAPRIL during the 72 h stimulation period. Increased mRNA encoding of their cognate receptors, BAFF-R, TACI, and BCMA, and increased HZ-specific IgG levels were also observed in HZ induction within the monocyte and B cell co-culture. The experiments under control conditions revealed that HZ alone could induce B cell culture to produce a small amount of the specific IgG compared with those in medium alone or rBAFF + rAPRIL + rIL-4. CONCLUSION: Taken together, we suggest that in the TI response HZ stimulates monocyte and B cell co-culture to produce specific IgG through BAFF, APRIL and other independent complimentary signaling pathways.

Fingolimod induces BAFF and expands circulating transitional B cells without activating memory B cells and plasma cells in multiple sclerosis.

Patients with multiple sclerosis (MS) who are treated with fingolimod have an increased proportion of transitional B cells in the circulation, but the underlying mechanism is not known. We hypothesized that B cell-activating factor of the tumor necrosis factor family (BAFF) is involved in the process. Compared with healthy controls and untreated MS patients, fingolimod-treated MS patients had significantly higher serum concentrations of BAFF, which positively correlated with the proportions and the absolute numbers of transitional B cells in blood. Despite the elevated concentrations of BAFF in fingolimod-treated MS patients, serum levels of soluble transmembrane activator and calcium-modulating cyclophilin ligand interactor, and B cell maturation antigen were not elevated. Our results show that fingolimod induces BAFF in the circulation and expands transitional B cells, but does not activate memory B cells or plasma cells in MS, which is favorable for the treatment of this disease.

Increased expression of TACI on NOD B cells results in germinal centre reaction anomalies, enhanced plasma cell differentiation and immunoglobulin production.

B cells have an important pathogenic role in the development of type 1 diabetes in the non-obese diabetic (NOD) mouse. We have previously reported that NOD mice display an increased percentage of TACIhigh -expressing B cells compared with C57BL/6 mice and this trait is linked to chromosomes 1 and 8. In this paper the genetic association of the transmembrane activator, calcium modulator and cyclophilin ligand interactor (TACI) trait was confirmed using double congenic NOD.B6C1/Idd22 mice. TACI ligation by a proliferation-inducing ligand (APRIL) has been shown to influence plasma cell differentiation, immunoglobulin production and isotype switch. Hence, the functional consequence of the up-regulation of TACI on NOD B cells was analysed both in vitro and in vivo. NOD B cells stimulated with APRIL showed an enhanced plasma cell differentiation and class switch to IgG and IgA compared with B cells from C57BL/6 mice. Moreover, flow cytometry analyses revealed that germinal centre B cells in NOD failed to down-regulate TACI. Availability of the TACI ligand B-cell activating factor (BAFF) has been shown to be a limiting factor in the germinal centre reaction. In line with this, upon immunization with 4-hydroxy-3-nitrophenylacetyl hapten-conjugated hen egg lysozyme, NOD mice produced higher titres of low-affinity antibodies compared with C57BL/6 mice. This observation was supported by the detection of increased levels of BAFF in NOD germinal centres after immunization compared with C57BL/6 by immunofluorescence. Our results support the hypothesis that increased TACI expression on NOD B cells contributes to the pathogenesis of type 1 diabetes in the NOD mouse.

Polymorphisms in genes of the BAFF/APRIL system may constitute risk factors of B-CLL--a preliminary study on a Polish population.

The association of single-nucleotide polymorphisms (SNPs) of B-cell activating factor (BAFF)/a proliferation-inducing ligand (APRIL) system with B-cell chronic lymphocytic leukemia (B-CLL) have been suggested, therefore, we investigated 20 SNPs of BAFF, APRIL, BAFF-R, transmembrane activator and calcium modulator and cyclophilin-ligand interactor (TACI), B-cell maturation antigen (BCMA) genes and the risk and outcome of B-CLL in 187 patients and 296 healthy subjects as well as ligand-receptor gene × gene interactions. Although the obtained P-values for all 20 SNPs did not reach statistical significance for this study (α = 0.003), the high value of the global chi-squared statistic (χ(2) df = 38 = 52.65; P = 0.0586), and obtained values of odds ratio indicate that rs9514828 (BAFF), rs3803800 (APRIL) and rs4985726 (TACI) may be associated with the risk of B-CLL. We observed that the B-CLL patients with the genotype rs9514828CT/rs11570136AA were diagnosed with the disease 12 years later than the whole group of patients in this study.

B cells drive Th2 responses by instructing human dendritic cell maturation.

Dendritic cells (DCs) are known to regulate the functions of various immune cells. Reciprocal signaling by these immune cells also "educate" the DCs and determine the quality of the ensuing immune responses. Recently, we demonstrated that human DCs undergo maturation upon interaction with activated B cells to acquire unique abilities to promote polarization of Th2 cells.

A proliferation-inducing ligand sustains the proliferation of human naïve (CD27⁻) B cells and mediates their differentiation into long-lived plasma cells in vitro via transmembrane activator and calcium modulator and cyclophilin ligand interactor and B-cell mature antigen.

Long-lived plasma cells (PCs) contribute to humoral immunity through an undefined mechanism. Memory B cells, but not human naïve B cells, can be induced to differentiate into long-lived PCs in vitro. Because evidence links a proliferation-inducing ligand (APRIL), a tumor necrosis factor family member, to the ability of bone marrow to mediate long-term PC survival, we reasoned that APRIL influences the proliferation and differentiation of naïve B cells. We describe here the development of a simple cell culture system that allowed us to show that APRIL sustained the proliferation of naïve human B cells and induced them to differentiate into long-lived PCs. Blocking the transmembrane activator and calcium modulator and cyclophilin ligand interactor or B-cell mature antigen shows they were required for the differentiation of naïve B cells into long-lived PCs in vitro. Our in vitro culture system will reveal new insights into the biology of long-lived PCs.

Re-thinking the functions of IgA(+) plasma cells.

The intestinal mucosa harbors the largest population of antibody (Ab)-secreting plasma cells (PC) in the human body, producing daily several grams of immunoglobulin A (IgA). IgA has many functions, serving as a first-line barrier that protects the mucosal epithelium from pathogens, toxins and food antigens (Ag), shaping the intestinal microbiota, and regulating host-commensal homeostasis. Signals induced by commensal colonization are central for regulating IgA induction, maintenance, positioning and function and the number of IgA(+) PC is dramatically reduced in neonates and germ-free (GF) animals. Recent evidence demonstrates that the innate immune effector molecules tumor necrosis factor α (TNFα) and inducible nitric oxide synthase (iNOS) are required for IgA(+) PC homeostasis during the steady state and infection. Moreover, new functions ascribed to PC independent of Ab secretion continue to emerge, suggesting that PC, including IgA(+) PC, should be re-examined in the context of inflammation and infection. Here, we outline mechanisms of IgA(+) PC generation and survival, reviewing their functions in health and disease.

Genetic defects and the role of helper T-cells in the pathogenesis of common variable immunodeficiency.

Common variable immunodeficfiiency (CVID) is a primary immunodeficiency syndrome representing a heterogeneous set of disorders resulting mostly in antibody deficiency and recurrent infections. However, inflammatory and autoimmune disorders and some kinds of malignancies are frequently reported as a part of the syndrome. Although it is one of the most widespread primary immunodeficiency, only recently some genetic defects in CVID have been identified. Mutations have been detected in inducible T-cell costimulator (ICOS), transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), B-cell activating factor-receptor (BAFF-R), B-cell receptor complex (CD19, CD21 and CD81) and CD20. On the other hand, recent studies have shown a decrease in T-helper-17 cells frequency and their characteristic cytokines in CVID patients and this emphasis on the vital role of the T-cells in immunopathogenesis of the CVID. Furthermore, in the context of autoimmune diseases accompanying CVID, interleukin 9 has recently attracted a plenty of considerations. However, the list of defects is expanding as exact immunologic pathways and genetic disorders in CVID are not yet defined. In this review, we have a special focus on the immunopathogenesis of CVID, recent advances in understanding the underlying etiology and genetics for patients.

BAFF activates Erk1/2 promoting cell proliferation and survival by Ca2+-CaMKII-dependent inhibition of PP2A in normal and neoplastic B-lymphoid cells.

B-cell activating factor (BAFF) is involved in not only the physiology of normal B cells, but also the pathophysiology of aggressive B cells related to malignant and autoimmune diseases. However, how excessive BAFF promotes aggressive B-cell proliferation and survival is not well understood. Here we show that excessive human soluble BAFF (hsBAFF) enhanced cell proliferation and survival in normal and B-lymphoid (Raji) cells, which was associated with suppression of PP2A, resulting in activation of Erk1/2. This is supported by the findings that pretreatment with U0126 or PD98059, expression of dominant negative MKK1, or overexpression of PP2A prevented hsBAFF-induced activation of Erk1/2 and cell proliferation/viability in the cells. It appears that hsBAFF-mediated PP2A-Erk1/2 pathway and B-cell proliferation/viability was Ca(2+)-dependent, as pretreatment with BAPTA/AM, EGTA or 2-APB significantly attenuated these events. Furthermore, we found that inhibiting CaMKII with KN93 or silencing CaMKII also attenuated hsBAFF-mediated PP2A-Erk1/2 signaling and B-cell proliferation/viability. The results indicate that BAFF activates Erk1/2, in part through Ca(2+)-CaMKII-dependent inhibition of PP2A, increasing cell proliferation/viability in normal and neoplastic B-lymphoid cells. Our data suggest that inhibitors of CaMKII and Erk1/2, activator of PP2A or manipulation of intracellular Ca(2+) may be exploited for prevention of excessive BAFF-induced aggressive B-cell malignancies and autoimmune diseases.

The BAFF/APRIL system: emerging functions beyond B cell biology and autoimmunity.

The BAFF system plays a key role in the development of autoimmunity, especially in systemic lupus erythematosus (SLE). This often leads to the assumption that BAFF is mostly a B cell factor with a specific role in autoimmunity. Focus on BAFF and autoimmunity, driven by pharmaceutical successes with the recent approval of a novel targeted therapy Belimumab, has relegated other potential roles of BAFF to the background. Far from being SLE-specific, the BAFF system has a much broader relevance in infection, cancer and allergy. In this review, we provide the latest views on additional roles of the BAFF system in health and diseases, as well as an update on BAFF and autoimmunity, with particular focus on current clinical trials.