Effect of Xinfeng capsule in the treatment of active rheumatoid arthritis: a randomized controlled trial.

OBJECTIVE: To explore the use of Xinfeng capsule (XFC) in the treatment of active rheumatoid arthritis (RA) and its effect on immunoglobulin titer, B cell-activating factor (BAFF) and its receptor (BAFF-R). METHODS: A multi-center randomized, double-blind, parallel-controlled study was conducted. 45 RA patients were assigned to two groups: one was treated with XFC plus the placebo for leflunomide (LEF) and the second group was treated with LEF plus XFC placebo, for 12 weeks. The clinical and laboratory parameters were collected at baseline and at 12 weeks. RESULTS: After 12 weeks of treatment, patients in the two groups all showed an therapeutic effect when ACR20, ACR50 and ACR70 were compared, but the differences between two groups were not significant (P < 0.05). The serum levels of IgG1, BAFF and BAFF-R in the XFC group were lower than those in the LEF group (P < 0.05). The level IgG subtypes correlated with clinical parameters; IgG2 levels positively correlated with C-reactive protein (CRP) (P < 0.01); IgG3 levels positively correlated with white blood cell count and CRP (P < 0.01); IgG4 levels positively correlated with Complement 4 ( C4) (P < 0.01); the level of BAFF negatively correlated with Lymphocyte (LYMPH#) (P < 0.01); however, BAFF-R positively correlated with Platelet (PLT) and a1-acid glycoprotein (AGP) (P < 0.01). CONCLUSION: XFC can regulate the level of BAFF/BAFF-R in active rheumatoid arthritis and improve the levels of immunoglobulins in RA patients.

BAFF/BAFF-R involved in antibodies production of rats with collagen-induced arthritis via PI3K-Akt-mTOR signaling and the regulation of paeoniflorin.

ETHNOPHARMACOLOGICAL RELEVANCE: Paeoniflorin (Pae) is extracted from the root of paeonia lactiflora which have attracted attention for anti-rheumatic and immune modulating properties. AIM OF THE STUDY: To investigate the role of PI3K/Akt/mTOR signaling mediated by BAFF/BAFF-R in antibodies production and the regulation of Pae on the signaling pathway in rats with collagen-induced arthritis (CIA). MATERIALS AND METHODS: CIA rats were randomly separated into different groups and treated with Pae (25, 100mg/kg) from day 18 to day 38 after immunization. The effects of Pae on B lymphocytes of CIA rats were evaluated by the levels of BAFF, anti-CII antibody, IgA, IgG and IgM, and the expressions of BAFF-R, PI3K, p-Akt and mTOR. RESULTS: In CIA rats, the levels of anti-CII antibody, IgA, IgG and IgM in serum enhanced, BAFF, BAFF-R, PI3K, p-Akt and mTOR were highly expressed. Pae (100mg/kg) obviously decreased arthritis score, relieved ankle and paw swelling, improved spleen histopathology in CIA rats, decreased the levels of IgA, IgM, IgG and anti-CII antibody, and significantly decreased the expressions of BAFF, BAFF-R, PI3K, p-Akt and mTOR. CONCLUSION: PI3K/Akt/mTOR signaling mediated by BAFF/BAFF-R participates in antibodies production by B lymphocytes of CIA rats. Pae had therapeutic effects on rats with CIA. These effects might be relative to regulating PI3K/Akt/mTOR signal mediated by BAFF/BAFF-R, and down regulate the antibodies production further.

TACI-Ig induces immune balance of Th cells in MLN via BLyS/APRIL-receptors signaling in rats with adjuvant-induced arthritis.

The transmembrane activator and calcium modulator and cyclophilin ligand interactor-immunoglobulin (TACI-Ig), a recombinant fusion protein that modulates B and T cells activation by binding and neutralizing B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL), has been shown to have a therapeutic effects on autoimmune disorders. The objective of this study was to investigate immunoregulatory efficacy of TACI-Ig on helper T (Th) cells in mesenteric lymph node (MLN) of adjuvant-induced arthritis (AA) in rats. The levels of BLyS, APRIL, interferon (IFN)-γ, interleukin (IL)-4, transforming growth factor beta (TGF)-ß1, and IL-17 were measured by enzyme-linked immunosorbent assay. The localization and expression of TACI, B-cell maturation antigen (BCMA) and B cell activating factor-receptor (BAFF-R) were investigated by immunohistochemistry and western blotting analysis in MLN. Administration of TACI-Ig significantly reduced histological changes, along with decreased Th1 and Th17-cell cytokines and increased CD4(+)CD25(+)FOXP3(+) regulatory T cell (Treg) and Th2-cell cytokines in MLN of AA rats. The levels of BLyS and APRIL were decreased in MLN homogenate of AA rats after treatment with TACI-Ig. TACI-Ig inhibited TACI and BCMA expression, and increased BAFF-R expression in MLN with AA rats. Taken together, BLyS/APRIL-receptors signaling are important not only for B cell function but for T cell-mediated immune responses. TACI-Ig might exert its anti-inflammatory and immunoregulatory effects through inducing immune balance of Th1/Th2 and Treg/Th17 in peripheral MLN. The mechanisms of TACI-Ig on BLyS/APRIL-receptors-dependent signaling in MLN lymphocytes may play key roles in the pathogenesis of autoimmune disorders.

Innate immune defects correlate with failure of antibody responses to H1N1/09 vaccine in HIV-infected patients.

BACKGROUND: Mechanisms underlying the failure of influenza vaccine-induced antibody responses in HIV-infected persons are poorly understood. OBJECTIVE: To investigate innate immune factors regulating B-cell function in HIV-infected persons and to correlate them with serologic responses to H1N1/09 vaccine. METHODS: We evaluated immunologic characteristics of 17 HIV-infected patients and 8 healthy controls (HCs) at 0, 7, and 28 days (designated T0, T1, and T2) following a single 15-µg dose of nonadjuvanted H1N1/09 influenza vaccine by using flow cytometry, ELISpot, and ELISA. All HCs and 9 patients (53%) seroconverted with >1:40 hemagglutination inhibition antibody titer at T2. RESULTS: In vaccine responders and HCs, serum levels of BAFF (B cell-activating factor) and APRIL (a proliferation-inducing ligand) increased from T0 to T2 in conjunction with increases in frequencies of memory B cells. Concurrently, receptors for these factors showed changes, with increases in expression of TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor) and decreases in BAFF receptor in memory B cells. IL-2 secreting cells and IgG antibody-secreting cells increased at T2 in vaccine responders and HCs in ex vivo H1N1 antigen-stimulated cultures. These immunologic responses were not evident at T1 and were deficient in vaccine nonresponder patients at T2. At T0, vaccine nonresponders had lower frequencies of BAFF receptor and TACI-expressing memory B cells than did responders. CONCLUSION: Impaired memory B-cell responses, deficiencies in serum BAFF and APRIL, and alterations in their receptors on B cells were associated with failure of H1N1/09 influenza vaccine responses among virologically controlled HIV-infected patients.

An increase in B cell apoptosis by interfering BAFF-BAFF-R interaction with small synthetic molecules.

B cell-activating factor (BAFF) transmitted signals through binding to specific BAFF receptors (BAFF-R) to regulate B cell survival and development. We used MTT assay to examine the cytotoxicity of chemicals, flow cytometry analysis to measure BAFF-BAFF-R interactions, and western blotting to detect BAFF protein. Here, we established screening method to find specific compounds to interfere with BAFF-BAFF-R interactions in WIL2-NS B lymphoblast cells. According to screening (imidazol-4-ylcarbonyl)guanidine or (oxazol-4-ylcarbonyl)guanidine derivatives, we selected KR32592, KR32673, KR33232, KR33341 and KR33426 as candidates to interfere with BAFF-BAFF-R interaction. No cytotoxicity was detected by KR32592, KR33232, and KR33426 at the concentration of 5 µM, and by KR32673, and KR33341 at the concentration of 0.5 µM. Cell population with BAFF-BAFF-R interactions was reduced by the pre-incubation of chemicals with human BAFF-murine CD8 (BAFF-muCD8). Cell population with BAFF-BAFF-R interactions was also decreased by pre-exposure of WIL2-NS cells to chemicals prior to the incubation with BAFF-muCD8. Chemicals also inhibited LPS-stimulated BAFF production from splenocytes. All these effects of chemicals may contribute to the inhibition of BAFF-mediated anti-apoptosis. These data demonstrate that chemicals interfering with BAFF-BAFF-R interaction may be screened with our experimental condition. It suggests that BAFF-BAFF-R interaction could be a chemical target to develop therapeutics for BAFF-mediated autoimmune diseases.

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.