BAFF mRNA Expression Research Articles

Expression of B-cell activating factor (BAFF) in proliferative lupus nephritis, revisited

ABSTRACT Introduction Systemic Lupus Erythematosus, an autoimmune disease, can target various organs of the human body. Lupus nephritis (LN) is a major complication affecting almost half of all SLE patients, with classes “III and IV” being the most aggressive. The severity and prognosis of LN can be influenced by different biomarkers, some of which are used as therapeutic targets. One such target is the B-cell activating factor (BAFF), a key figure in the pathophysiology of SLE. New add-on treatments have emerged in the treatment of LN targeting BAFF as well as other pathways. Assortment of patients to suitable treatment combinations needs more precision using guiding markers. Methods This prospective study aims to explore BAFF-expression in patients with active-proliferative LN and its possible association with the response after induction therapy. Peripheral blood mononuclear cells (PBMC) and renal tissue samples (if applicable) were collected from participants before the initiation of induction treatment. RNA was extracted, and the expression levels of BAFF-mRNA were measured using quantitative real-time polymerase chain reaction. Clinical and laboratory data, including disease activity indices and renal functions, were recorded at baseline and 6-months after the commencement of the induction treatment. Results The study included 24 patients,14 responders and 10 non-responders. At baseline, median PBMC BAFF-mRNA expression was nearly identical in responders and non-responders. Renal BAFF-expression was found to be higher in non-responders, although non-significant (p = 0.21). Contrary to PBMC BAFF expression, renal BAFF-mRNA was negatively correlated with baseline glomerular filtration rate and with the primary endpoint of response, which was reduction of proteinuria to≥50% of baseline (p = 0.07). Conclusions Renal BAFF expression could be a better representative of severity and therapeutic response than blood expression. We acknowledge that the use of BAFF expression as a predictive for early refractoriness to therapy in LN is not yet conclusive.

Serum BAFF (B-cell activating factor) and APRIL (a proliferation-inducing ligand) levels in the first trimester may predict the future development of gestational diabetes mellitus

BackgroundGestational diabetes mellitus (GDM) is a prevalent condition with an unclear pathogenesis. B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) are potential key players in GDM. Participants, materials, and methodsIn a longitudinal observational study, we monitored women from the first trimester through 24–28 weeks of gestation, focusing on the development of GDM. Serum levels of BAFF and APRIL, as well as their mRNA expression, were evaluated in both the first and third trimesters. Furthermore, we assessed cytokines, adipokines, and placental hormones in the serum. ResultsIn the first trimester, participants who later developed GDM exhibited elevated serum BAFF and reduced serum APRIL levels, although the mRNA expression of these molecules was similar to controls. Serum BAFF exhibited significant positive correlations with metabolic markers and placental hormones. Conversely, serum APRIL was negatively correlated with insulin resistance and inflammatory markers but positively correlated with adiponectin. In the early third trimester, GDM participants continued to display higher serum BAFF levels and lower serum APRIL levels than controls. There was no significant difference in mRNA expression of BAFF between GDM and control groups. Conversely, APRIL mRNA expression was significantly lower in the GDM group. The predictive potential of first-trimester BAFF and APRIL levels for future GDM development was explored, with both molecules demonstrating strong predictive capability. Discussion and conclusionThis study suggests that elevated serum BAFF and reduced serum APRIL levels during pregnancy may be associated with the development of GDM. These biomarkers can serve as potential early predictors for GDM.

Human gingival fibroblasts are a source of B cell-activating factor during periodontal inflammation.

Host-modulating therapy is a possible treatment for individuals that respond poorly to conventional periodontal therapy. B cells, abundant in periodontitis lesions, require the cytokines B cell-activating factor (BAFF) and A proliferation-inducing ligand (APRIL) for survival and maturation. Although mRNA levels of BAFF and APRIL are increased in tissue from periodontitis lesions, it is unknown if periodontal resident cells express BAFF and/or APRIL during periodontal inflammation. In this study, we aim to analyze the expression of BAFF and APRIL in human gingival fibroblasts after stimulation with proinflammatory cytokines. Furthermore, we perform protein analysis in tissues and serum from periodontitis patients and healthy controls. Human gingival fibroblasts were cultured and stimulated with the proinflammatory cytokines' tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β). The mRNA expression of BAFF and APRIL was analyzed by real-time quantitative polymerase chain reaction (qPCR), and the protein was detected in tissue sections using immune staining. Serum levels of BAFF were analyzed with enzyme-linked immunosorbent assay (ELISA). In gingival fibroblasts, TNF-α upregulated BAFF mRNA, but APRIL was unaffected. IL-1β affected neither BAFF nor APRIL expression. BAFF protein was detected in the oral epithelium and in cells of the underlying connective tissue in periodontitis tissue, and BAFF protein was increased in the serum of periodontitis patients. Periodontal resident cells express BAFF during periodontal inflammation and participate in providing a favorable milieu for the survival and action of B cells.

Excessive MALAT1 promotes the immunologic process of neuromyelitis optica spectrum disorder by upregulating BAFF expression.

Increased B cell activating factor (BAFF) expression in patients with neuromyelitis optica spectrum disorder (NMOSD) is associated with B cell overstimulation, but the underlying mechanism remains unclear. This study aimed to reveal the emerging mechanisms that regulate BAFF expression in the inflammatory process of NMOSD. The results showed that the expression of miR-30b-5p was significantly decreased in NMOSD CD14+ monocytes compared with the normal control. Furthermore, we confirmed that metastasis-associated lung adenocarcinoma transcription 1 (MALAT1) is an upstream target of miR-30b-5p, and it could act as a ceRNA and absorb miR-30b-5p with reduced expression of miR-30b-5p. The low expression of miR-30b-5p could not bind to BAFF messenger RNA (mRNA), which resulted in the overexpression of both BAFF mRNA and protein expression. Overexpression of BAFF could bind to the corresponding receptors on B cells, which may initiate activation and proliferation of B cells and increase their production of autoantibodies. Therefore, these findings interpreted that excessive MALAT1 expression in NMOSD mononuclear macrophages led to increased BAFF expression by targeting miR-30b-5p, which caused B cell autoimmune reaction and autoantibodies production, aggravated the disease progression of NMOSD.

Skeletal muscle fibers produce B-cell stimulatory factors in chronic myositis.

We aimed to identify B-cell-mediated immunomechanisms in inclusion body myositis (IBM) and polymyositis (PM) as part of the complex pathophysiology. Human primary myotube cultures were derived from orthopedic surgery. Diagnostic biopsy specimens from patients with IBM (n=9) and PM (n=9) were analyzed for markers of B cell activation (BAFF and APRIL) and for chemokines that control the recruitment of B cells (CXCL-12 and CXCL-13). Results were compared to biopsy specimens without myopathic changes (n=9) and hereditary muscular dystrophy (n=9). The mRNA expression of BAFF, APRIL, and CXCL-13 was significantly higher in IBM and PM compared to controls. Patients with IBM displayed the highest number of double positive muscle fibers for BAFF and CXCL-12 (48%) compared to PM (25%), muscular dystrophy (3%), and non-myopathic controls (0%). In vitro, exposure of human myotubes to pro-inflammatory cytokines led to a significant upregulation of BAFF and CXCL-12, but APRIL and CXCL-13 remained unchanged. The results substantiate the hypothesis of an involvement of B cell-associated mechanisms in the pathophysiology of IBM and PM. Muscle fibers themselves seem to contribute to the recruitment of B cells and sustain inflammation.

Dipeptidyl Peptidase 4 Inhibitor‒Associated Bullous Pemphigoid Is Characterized by an Altered Expression of Cytokines in the Skin

Dipeptidyl peptidase 4 inhibitors (DPP4is), commonly used drugs for treatment of type 2 diabetes, increase the risk for bullous pemphigoid (BP). Currently, the mechanism leading to the loss of immunological tolerance of the cutaneous adhesion molecule BP180 as well as similarities and differences in disease progression between DPP4i-associated BP (DPP4i-BP) and DPP4i-independent regular BP are largely unknown. We analyzed the expression of 32 cytokines and two proteases by Luminex and ELISA assays in samples taken from lesional and nonlesional skin of patients with regular BP or DPP4i-BP and healthy controls. Cytokines mediating B-cell survival and targeting such as BAFF, CCL4, CXCL12, and IL-6 were expressed at a higher level in the lesional regular BP skin than the levels in the lesional DPP4i-BP skin. The DPP4i-BP samples had increased levels of eosinophilic cytokines CCL1, CCL17, CCL26, and IL-5, which correlated with the serum level of anti-BP180 NC16A IgG autoantibodies. The mRNA expression of BAFF, IL6, CCL1, CCL17, CCL26, and IL5 measured by qPCR correlated with the protein levels. Taken together, the cutaneous cytokine profiles were found to provide distinctive molecular fingerprints between regular BP and DPP4i-BP.

High triiodothyronine levels induce myocardial hypertrophy via BAFF overexpression.

Activated B cells contribute to heart diseases, and inhibition of B‐cell activating factor (BAFF) expression is an effective therapeutic target for heart diseases. Whether activated B cells participate in the development and progression of hyperthyroid heart disease, and what induces B cells activation in hyperthyroidism are unknown. The present study aimed to determine the roles of BAFF overexpression induced by high concentrations of triiodothyronine (T3) in the pathogenesis of hyperthyroid heart disease. Female C57BL/6J mice were subcutaneously injected with T3 for 6 weeks, and BAFF expression was inhibited using shRNA. Protein and mRNA expression of BAFF in mouse heart tissues evaluated via immunohistochemistry, western blotting and polymerase chain reaction (PCR). Proportions of B cells in mouse cardiac tissue lymphocytes were quantified via flow cytometry. Morphology and left ventricle function were assessed using pathological sections and echocardiography, respectively. Here, we demonstrate that compared with the control group, the proportion of myocardial B cells was larger in the T3 group; immunohistochemistry, western blotting and PCR analyses revealed increased protein and mRNA expression levels of TNF‐α and BAFF in heart tissues of the T3 group. Compared with the normal controls group, in the T3 group, the diameter of myocardial cells and some echocardiographic values significantly increased and hypertrophy and structural disorder were noticeable. Our results revealed that elevated levels of circulating T3 can promote the expression of BAFF in myocardial cells and can lead to B‐cell activation, an elevated inflammatory response and ventricular remodelling.

Treatment-Induced BAFF Expression and B Cell Biology in Multiple Sclerosis.

Although fingolimod and interferon-β are two mechanistically different multiple sclerosis (MS) treatments, they both induce B cell activating factor (BAFF) and shift the B cell pool towards a regulatory phenotype. However, whether there is a shared mechanism between both treatments in how they influence the B cell compartment remains elusive. In this study, we collected a cross-sectional study population of 112 MS patients (41 untreated, 42 interferon-β, 29 fingolimod) and determined B cell subsets, cell-surface and RNA expression of BAFF-receptor (BAFF-R) and transmembrane activator and cyclophilin ligand interactor (TACI) as well as plasma and/or RNA levels of BAFF, BAFF splice forms and interleukin-10 (IL-10) and -35 (IL-35). We added an in vitro B cell culture with four stimulus conditions (Medium, CpG, BAFF and CpG+BAFF) for untreated and interferon-β treated patients including measurement of intracellular IL-10 levels. Our flow experiments showed that interferon-β and fingolimod induced BAFF protein and mRNA expression (P ≤ 3.15 x 10-4) without disproportional change in the antagonizing splice form. Protein BAFF correlated with an increase in transitional B cells (P = 5.70 x 10-6), decrease in switched B cells (P = 3.29 x 10-4), and reduction in B cell-surface BAFF-R expression (P = 2.70 x 10-10), both on TACI-positive and -negative cells. TACI and BAFF-R RNA levels remained unaltered. RNA, plasma and in vitro experiments demonstrated that BAFF was not associated with increased IL-10 and IL-35 levels. In conclusion, treatment-induced BAFF correlates with a shift towards transitional B cells which are enriched for cells with an immunoregulatory function. However, BAFF does not directly influence the expression of the immunoregulatory cytokines IL-10 and IL-35. Furthermore, the post-translational mechanism of BAFF-induced BAFF-R cell surface loss was TACI-independent. These observations put the failure of pharmaceutical anti-BAFF strategies in perspective and provide insights for targeted B cell therapies.

Rifaximin as a Potential Treatment for IgA Nephropathy in a Humanized Mice Model.

: BackgroundIgA Nephropathy (IgAN) is the most common glomerulonephritis worldwide, characterized by the mesangial deposition of abnormally glycosylated IgA1 (Gd-IgA). The production of Gd-IgA occurs in mucose-associated lymphoid tissue (MALT). The microbiota plays a role in MALT modulation. Rifaximin (NORMIX®), a non-absorbable oral antibiotic, induces positive modulation of the gut microbiota, favoring the growth of bacteria beneficial to the host. Here, we evaluate the effect of rifaximin on a humanized mice model of IgAN (α1KI-CD89Tg). Methods: The α1KI-CD89Tg mice were treated by the vehicle (olive oil) or rifaximin (NORMIX®). Serum levels of hIgA, hIgA1–sCD89, and mIgG–hIgA1 immune complexes were determined. Glomerular hIgA1 deposit and CD11b+ cells recruitment were revealed using confocal microscopy. Furthermore, the mRNA of the B-Cell Activating Factor (BAFF), polymeric immunoglobulin receptor (pIgR), and Tumor Necrosing Factor-α (TNF-α) in gut samples were detected by qPCR. Results: Rifaximin treatment decreased the urinary protein-to-creatinine ratio, serum levels of hIgA1–sCD89 and mIgG–hIgA1 complexes, hIgA1 glomerular deposition, and CD11b+ cell infiltration. Moreover, rifaximin treatment decreased significantly BAFF, pIgR, and TNF-α mRNA expression. Conclusions: Rifaximin decreased the IgAN symptoms observed in α1KI-CD89Tg mice, suggesting a possible role for it in the treatment of the disease.

B Cell Activating Factor (BAFF) Is Required for the Development of Intra-Renal Tertiary Lymphoid Organs in Experimental Kidney Transplantation in Rats.

Intra-renal tertiary lymphoid organs (TLOs) are associated with worsened outcome in kidney transplantation (Ktx). We used an anti-BAFF (B cell activating factor) intervention to investigate whether BAFF is required for TLO formation in a full MHC-mismatch Ktx model in rats. Rats received either therapeutic immunosuppression (no rejection, NR) or subtherapeutic immunosuppression (chronic rejection, CR) and were sacrificed on d56. One group additionally received an anti-BAFF antibody (CR + AB). Intra-renal T (CD3+) and B (CD20+) cells, their proliferation (Ki67+), and IgG+ plasma cells were analyzed by immunofluorescence microscopy. Formation of T and B cell zones and TLOs was assessed. Intra-renal expression of TLO-promoting factors, molecules of T:B crosstalk, and B cell differentiation was analyzed by qPCR. Intra-renal B and T cell zones and TLOs were detected in CR and were associated with elevated intra-renal mRNA expression of TLO-promoting factors, including CXCL13, CCL19, lymphotoxin-β, and BAFF. Intra-renal plasma cells were also elevated in CR. Anti-BAFF treatment significantly decreased intra-renal B cell zones and TLO, as well as intra-renal B cell-derived TLO-promoting factors and B cell differentiation markers. We conclude that BAFF-dependent intra-renal B cells promote TLO formation and advance local adaptive alloimmune responses in chronic rejection.

Bacterial Lipoproteins Induce BAFF Production via TLR2/MyD88/JNK Signaling Pathways in Dendritic Cells.

B-cell activating factor (BAFF) plays a crucial role in survival, differentiation, and antibody secretion of B cells. Microbial products with B-cell mitogenic properties can indirectly promote expansion and activation of B cells by stimulating accessory cells, such as dendritic cells (DCs), to induce BAFF. Although bacterial lipoproteins are potent B-cell mitogen like lipopolysaccharides (LPSs), it is uncertain whether they can stimulate DCs to induce BAFF expression. Here, we evaluated the effect of bacterial lipoproteins on BAFF expression in mouse bone marrow–derived DCs. Lipoprotein-deficient Staphylococcus aureus mutant induced relatively low expression level of membrane-bound BAFF (mBAFF) and the mRNA compared with its wild-type strain, implying that bacterial lipoproteins can positively regulate BAFF induction. The synthetic lipopeptides Pam2CSK4 and Pam3CSK4, which mimic bacterial lipoproteins, dose-dependently induced BAFF expression, and their BAFF-inducing capacities were comparable to those of LPS in DCs. Induction of BAFF by the lipopeptide was higher than the induction by other microbe-associated molecular patterns, including peptidoglycan, flagellin, zymosan, lipoteichoic acid, and poly(I:C). Pam3CSK4 induced both mBAFF and soluble BAFF expression in a dose- and time-dependent manner. BAFF expression by Pam3CSK4 was completely absent in DCs from TLR2- or MyD88-deficient mice. Among various MAP kinase inhibitors, only JNK inhibitors blocked Pam3CSK4-induced BAFF mRNA expression, while inhibitors blocking ERK or p38 kinase had no such effect. Furthermore, Pam3CSK4 increased the DNA-binding activities of NF-κB and Sp1, but not that of C/EBP. Pam3CSK4-induced BAFF promoter activity via TLR2/1 was blocked by NF-κB or Sp1 inhibitor. Collectively, these results suggest that bacterial lipoproteins induce expression of BAFF through TLR2/MyD88/JNK signaling pathways leading to NF-κB and Sp1 activation in DCs, and BAFF derived from bacterial lipoprotein-stimulated DCs induces B-cell proliferation.

Characteristics of BAFF and APRIL factor expression in multiple myeloma and clinical significance.

The characteristics of the proliferation of B-cell activating factor (BAFF) and the proliferation-inducing ligand (APRIL) mRNA expression in mononuclear cell in multiple myeloma patients were detected, and the correlation was analyzed between the BAFF and APRIL concentrations in plasma and tumor burden parameters of multiple myeloma. Bone marrow samples from 60 patients with multiple myeloma and 20 healthy persons taken as controls, were collected. Bone marrow mononuclear cells (BMMCs) were harvested, and plasma was extracted. BAFF and APRIL mRNA expression was quantified using real-time fluorescent quantitative PCR in the BMMCs. ELISA was used to detect the characteristics of gene and protein expression of BAFF and APRIL in KM3 cell line. The BAFF and APRIL mRNA expression in initial treatment group, remission group and non-remission group were markedly higher than that in control group (P<0.05). The expression in initial treatment group and non-remission group was markedly higher than that of the control group (P<0.05). APRIL mRNA expression in mononuclear cells in stage III patients was markedly higher than that in stage II patients (P<0.05). There was positive correlation between APRIL and BAFF concentration in multiple myeloma (P=0.0027). In conclusion, for the gene and protein expression of BAFF and APRIL in patients with multiple myeloma, the initial treatment group and non-remission are higher than control and remission group. The higher the stage was, the more the factors were expressed. Characteristics of expression of BAFF and APRIL may be used as a new index to evaluate the prognosis of multiple myeloma.

Increased BAFF expression in nasal polyps is associated with local IgE production, Th2 response and concomitant asthma.

B-cell activating factor of the TNF family is critical for the survival and maturation of B cells and play a role in the pathophysiology of chronic rhinosinusitis with nasal polyps (CRSwNP). In this study, nasal tissues were enrolled from 25 CRSwNP patients (asthmatic, 16; non-asthmatic, 9), 12 CRSsNP patients and ten control subjects, respectively. The immunoreactivity of BAFF, CD20 and CD138 were examined using immunohistochemistry staining. The mRNA expression of BAFF, CD20, εGLT, AID, GATA3 and CRTH2 were examined using real-time RT-PCR. The protein levels of BAFF, IL-5 and IgE were measured using ELISA assays and the Unicap system, respectively. We found the numbers of BAFF+ cells, CD20+ cells (B cells) and CD138+ cells (plasma cells) were significantly increased in polyp tissues compared with control groups. The concentrations of BAFF, IgE and IL-5 in tissue homogenates were also significantly increased in polyp tissues compared with control groups, and the BAFF protein level in the polyp homogenates was significantly associated with the IgE and IL-5 levels and with concomitant asthma in CRSwNP patients. Our findings indicate that BAFF expression is significantly increased in CRSwNP patients and may orchestrate inflammatory load in polyp tissues by regulating T and B cell-mediated response.

CP-25 attenuates the inflammatory response of fibroblast-like synoviocytes co-cultured with BAFF-activated CD4+ T cells

Ethnopharmacological relevanceTotal glucosides of paeony (TGP) is the first anti-inflammatory immune regulatory drug approved for the treatment of rheumatoid arthritis in China. A novel compound, paeoniflorin-6′-O-benzene sulfonate (code CP-25), comes from the structural modification of paeoniflorin (Pae), which is the effective active ingredient of TGP. The aim of the present study is to investigate the effect of CP-25 on adjuvant arthritis (AA) fibroblast-like synoviocytes (FLS) co-cultured with BAFF-activated CD4+ T cells and the expression of BAFF-R in CD4+ T cells. MethodsThe mRNA expression of BAFF and its receptors was assessed by qPCR. The expression of BAFF receptors in CD4+ T cells was analyzed by flow cytometry. The effect of CP-25 on AA rats was evaluated by their joint histopathology. The cell culture growth of thymocytes and FLS was detected by cell counting kit (CCK-8). The concentrations of IL-1β, TNF-α, and IL-6 were measured by Enzyme-linked immunosorbent assay (ELISA). ResultsThe mRNA expression levels of BAFF and BAFF-R were enhanced in the mesenteric lymph nodes of AA rats, TACI expression was reduced, and BCMA had no change. The expression of BAFF-R in CD4+ T cells was also enhanced. CP-25 alleviated the joint histopathology and decreased the expression of BAFF-R in CD4+ T cells from AA rats in vivo. In vitro, CP-25 inhibited the abnormal cell culture growth of BAFF-stimulated thymocytes and FLS. In the co-culture system, IL-1β, IL-6 and TNF-α production was enhanced by FLS co-cultured with BAFF-activated CD4+ T cells. Moreover, BAFF-stimulated CD4+ T cells promoted the cell culture growth of FLS. The addition of CP-25 decreased the expression of BAFF-R in CD4+ T cells and inhibited the cell culture growth and cytokine secretion ability of FLS co-cultured with BAFF-activated CD4+ T cells. ConclusionThe present study indicates that CP-25 may repress the cell culture growth and cytokine secretion ability of FLS, and its inhibitory effects might be associated with its ability to inhibit the expression of BAFF-R in CD4+ T cells in a co-culture. These observations might provide a scientific basis for the development of new drugs for the treatment of autoimmune diseases by CP-25.

Expression of BAFF and BR3 in patients with systemic lupus erythematosus.

The objective of this study was to examine the relationship between the expression of B cell activating factor (BAFF) and BAFF receptor in patients with disease activity of systemic lupus erythematosus (SLE). Real-time RT-PCR was used to examine BAFF mRNA expression in peripheral blood monocytes of active and stable SLE patients and healthy controls. The percentage of BAFF receptor 3 (BR3) on B lymphocytes was measured by flow cytometry. Soluble BAFF levels in serum were assayed by ELISA. Microalbumin levels were assayed by an automatic immune analysis machine. BAFF mRNA and soluble BAFF levels were highest in the active SLE group, followed by the stable SLE group, and controls (P<0.01). The percentage of BR3 on B lymphocytes was downregulated in the active SLE group compared with the stable SLE group and controls (P<0.01). BAFF mRNA levels and soluble BAFF levels were higher in patients who were positive for proteinuria than in those who were negative (P<0.01). The percentage of BR3 on B lymphocytes was lower in patients who were positive for proteinuria than in those who were negative (P<0.01). The BAFF/BR3 axis may be over-activated in SLE patients. BAFF and BR3 levels may be useful parameters for evaluating treatment.

The Correlation Between Non-Hodgkin Lymphoma and Expression Levels of B-Cell Activating Factor and Its Receptors.

Lymphoma is a malignant tumor of the immune system originating from lymph nodes and extralymphatic tissues. Its occurrence is believed to be associated with various immune cells due to the proliferation and differentiation of lymphocytes during the immune response. It has been found in many studies that B-cell activating factor (BAFF), as a member of the tumor necrosis factor (TNF) superfamily, could specifically activate B lymphocytes and promote their proliferation. To explore correlations between non-Hodgkin lymphoma (NHL) and the expression of BAFF and its receptors in NHL patients. The protein expression of BAFF and its receptors in serum and BAFF mRNA expression in peripheral blood mononuclear cells (PBMCs) of 47 NHL patients and 20 healthy subjects were detected by ELISA and RFQ-PCR and compared with LDH and β2M levels. BAFF mRNA expression in the PBMCs of NHL patients was significantly higher than in healthy controls. The expression levels of serum BAFF and the three receptors (TACI, BCMA and BAFF-R) in NHL patients were significantly higher than in healthy controls, and were not significantly correlated with β2M and LDH levels. The serum protein concentration of BAFF and the expression level of BAFF mRNA in PBMCs of NHL patients underwent abnormal changes, indicating that BAFF and its receptors may play some role in the pathogenesis of NHL.

The interferon type I signature is present in systemic sclerosis before overt fibrosis and might contribute to its pathogenesis through high BAFF gene expression and high collagen synthesis

BackgroundInterferon (IFN) signature has been reported in definite systemic sclerosis (SSc) but it has not been characterised in early SSc (EaSSc). We aim at characterising IFN type I signature in...

B-cell activating factor regulates IL-1β- and IL-17A-mediated pulmonary fibrosis in mice

Introduction Idiopathic pulmonary fibrosis (IPF) is a progressive devastating, yet untreatable fibrotic disease of unknown origin. We investigated the contribution of the B-cell activating factor (BAFF), a TNF family member recently implicated in the regulation of pathogenic IL-17-producing cells in autoimmune diseases. Methods The contribution of BAFF was assessed in a murine model of lung fibrosis induced by airway administered bleomycin, an intercalating agent which causes DNA strand breaks. Lung fibrosis was evaluated in Baff deficient mice and in wild-type mice after neutralization of BAFF with BAFF-R-Ig. Lung cells from bleomycin-treated mice were collected at day 7, labeled with anti-CD115, anti-CD3, anti-CD19 and anti-Gr1 antibodies and sorted by FACS for evaluation of BAFF mRNA expression by qPCR. BAFF was quantified in bronchoalveolar lavage fluid (BALF) of controls and patients with IPF. Results We show that murine BAFF levels were strongly increased in the bronchoalveolar space and lungs after bleomycin exposure. We identified Gr1 + neutrophils as an important source of BAFF upon BLM induced lung inflammation and fibrosis. Genetic ablation of BAFF or BAFF neutralization by a soluble receptor significantly attenuated pulmonary fibrosis and IL-1β levels. We further demonstrate that bleomycin-induced BAFF expression and lung fibrosis were IL-1β- and IL-17A-dependent. BAFF was required for rIL-17A-induced lung fibrosis and augmented IL-17A production by CD3 + T cells from murine fibrotic lungs ex vivo . Finally, we report elevated levels of BAFF in bronchoalveolar lavages from IPF patients. Conclusion The present data, demonstrating a critical role of BAFF by amplifying the IL-17A effect in experimental lung fibrosis, together with increased BAFF levels in the airways of patients with IPF, suggest that BAFF might be a therapeutic target of IPF.

Non-canonical NF-κB Plays a Pivotal Role in Non-Hodgkin's Lymphoma.

This study tried to dissect BAFF/BAFF-R-mediated non-canonical NF-κB signaling in the drug resistance of B-cell non-Hodgkin's lymphoma. FQ-PCR was employ to determine the mRNA expression of BAFF, BAFF-R, Bcl-xL, and RIPK2 in the circulating blood of B-cell non-Hodgkin's lymphoma patients. Further correlation studies were performed with the gene expression in the circulating blood and tumor tissue. MTT assay as used to determine BAFF's role on lymphoma cell proliferation. Western blot was employed to determine protein expression after BAFF stimulation. The mRNA expression of BAFF, BAFF-R, Bcl-xL, and RIPK2 in the circulating blood of the resistant group was higher than that of the non-resistant group, which was statistically significant. The mRNA expression of the target genes was positively correlated. The mRNA expression was positively correlated with disease progression, which was statistically significant. The Bcl-xL mRNA expression in the resistant group was relatively higher than that in the non-resistant group, which was also statistically significant. However, the mRNA expression of other genes only showed increased tendency compared with non-resistant group. There was no significant change between target genes in different tumor tissues. With increased BAFF concentration and prolonged exposure, the proliferation of the tumor cells increased significantly, which was statistically significant. Western blot showed the expression of BAFF, BAFF-R, Bcl-xL, and RIPK2 all increased with increased BAFF concentration, which was also statistically significant. In B-cell, non-Hodgkin's lymphoma, BAFF may activate non-canonical NF-κB signaling to regulate drug resistance.

Suppression of epithelial signal transducer and activator of transcription 1 activation by extracts of Aspergillus fumigatus.

Aspergillus fumigatus (AF) is often pathogenic in immune-deficient individuals and can cause life-threatening infections such as invasive aspergillosis. The pulmonary epithelial response to AF infection and the signaling pathways associated with it have not been completely studied. BEAS-2B cells or primary human bronchial epithelial cells were exposed to extracts of AF and challenged with IFN-β or the Toll-like receptor 3 agonist double-stranded RNA (dsRNA). Cytokine release (B-cell activating factor of the TNF family [BAFF], IFN-γ-induced protein-10 [IP-10], etc.) was assessed. AF extract was separated into low-molecular-weight (LMW) and high-molecular-weight (HMW) fractions using ultra 4 centrifugal force filters to characterize the activity. Real-time PCR was performed with a TaqMan method, and protein estimation was performed using ELISA techniques. Western blot was performed to assess phosphorylation of signal transducer and activator of transcription 1 (STAT1). IFN-β and dsRNA induced messenger RNA (mRNA) expression of BAFF (350- and 452-fold, respectively [n = 3]) and IP-10 (1,081- and 3,044-fold, respectively [n = 3]) in BEAS-2B cells. When cells were pretreated with AF extract for 1 hour and then stimulated with IFN-β or dsRNA for 6 hours, induction of BAFF and IP-10 mRNA was strongly suppressed relative to levels produced by IFN-β and dsRNA alone. When compared with control, soluble BAFF and IP-10 protein levels were maximally suppressed in dsRNA-stimulated wells treated with 1:320 wt/vol AF extract (P < 0.005). Upon molecular size fractionation, a LMW fraction of AF extract had no measurable suppressive effect on IP-10 mRNA expression. However, a HMW fraction of the AF extract significantly suppressed IP-10 expression in BEAS-2B cells that were stimulated with dsRNA or IFN-β. When BEAS-2B cells were pretreated with AF extract and then stimulated with IFN-β, reduced levels of pSTAT1 were observed, with maximum suppression at 4 and 6 hours. Our results show that AF extracts suppressed expression of inflammatory cytokines in association with inhibition of the IFN-β signaling pathway and suppression of the formation of pSTAT1.