B Cell-activating Factor Research Articles

High BAFF expression associated with active disease in systemic lupus erythematosus and relationship with rs9514828C>T polymorphism in TNFSF13B gene

B cell-activating factor (BAFF) promotes the survival, proliferation and maturation of B lymphocytes, which are key elements in the pathogenesis of systemic lupus erythematosus (SLE). This cytokine is encoded on TNFSF13B gene, and diverse single-nucleotide polymorphisms have been associated with susceptibility in different autoimmune disorders. In this study, the relationship of TNFSF13B gene rs9514827T>C, rs1041567T>A and rs9514828C>T polymorphisms, mRNA expression and soluble BAFF levels was investigated in 175 SLE patients and 208 healthy controls (HC). The TNFSF13B polymorphisms were evaluated by PCR-RFLP technique. The TNFSF13B gene expression was quantified through the RT-PCR assays. The soluble BAFF (sBAFF) levels were measured with ELISA test. There were no differences in genotype and allele frequencies for the three TNFSF13B polymorphisms, between SLE patients and HC. SLE patients showed 3.15-fold more TNFSF13B gene expression than HC. The patients who displayed most mRNA expression were those with active disease and the carriers of rs9514828 T variant allele. The sBAFF serum levels were higher in SLE patients compared to HC (2.083 vs. 0.742ng/mL, p < 0.001). The SLE patients with active disease showed the higher sBAFF serum levels (2.403ng/mL), mainly patients with lupus nephritis and hematological manifestations. In addition, a correlation of sBAFF with disease activity was found (r = 0.32, p < 0.001). In conclusion, the TNFSF13B gene polymorphisms were not found to be associated with SLE susceptibility in Mexican mestizos. Nevertheless, rs9514828C>T polymorphism seems to increase TNFSF13B gene expression. High BAFF expression is related to active disease, renal and hematological involvement; therefore, it could be considered as follow-up biomarker in SLE patients.

A proliferation-inducing ligand-mediated anti-inflammatory response of astrocytes in multiple sclerosis.

The two related tumor necrosis factor members a proliferation-inducing ligand (APRIL) and B-cell activation factor (BAFF) are currently targeted in autoimmune diseases as B-cell regulators. In multiple sclerosis (MS), combined APRIL/BAFF blockade led to unexpected exacerbated inflammation in the central nervous system (CNS) of patients. Here, we investigate the role of the APRIL/BAFF axis in the CNS. APRIL expression was analyzed in MS lesions by immunohistochemistry. The in vivo role of APRIL was assessed in the murine MS model, experimental autoimmune encephalitis (EAE). Functional in vitro studies were performed with human and mouse astrocytes. APRIL was expressed in lesions from EAE. In its absence, the disease was worst. Lesions from MS patients also showed APRIL expression upon infiltration of macrophages. Notably, all the APRIL secreted by these macrophages specifically targeted astrocytes. The upregulation of chondroitin sulfate proteoglycan, sometimes bearing chondroitin sulfate of type E sugar moieties, binding APRIL, in reactive astrocytes explained the latter selectivity. Astrocytes responded to APRIL by producing a sufficient amount of IL-10 to dampen antigen-specific T-cell proliferation and pathogenic cytokine secretion. Finally, an intraspinal delivery of recombinant APRIL before disease onset, shortly reduced EAE symptoms. Repeated intravenous injections of recombinant APRIL before and even at disease onset also had an effect. Our data show that APRIL mediates an anti-inflammatory response from astrocytes in MS lesions. This protective activity is not shared with BAFF. ANN NEUROL 2019;85:406-420.

Efficacy of BAFF in Monitoring Treatment Response in Early Vietnamese Systemic Sclerosis Patients.

BACKGROUND:B-cell activating factor (BAFF) is considered to have a role in the pathogenesis of systemic sclerosis (SSc).AIM:We conducted a longitudinal study on early SSc patients to determine the change in BAFF serum level after treatment and its association with organ involvements.METHODS:A total of 46 patients (32 diffuse, 14 limited) were recruited, among which 35 patients (24 diffuse, 11 limited) completed 12-month follow-up.RESULTS:Higher pretreatment BAFF levels were observed in patients with positive anti-topoisomerase antibody (ATA) (2252.1 ± 899.7 pg/ml versus 1475.5 ± 697.6 pg/ml in ATA-negative patients; p = 0.01) and muscular involvement (2741.9 ± 1039.9 pg/ml versus 1897.2 ± 762.9 pg/ml in patients without muscular involvement; p = 0.005). Lower levels were observed in patients with interstitial lung disease (ILD) (1926.7 ± 757.9 pg/ml versus 2721.6 ± 1131.4 pg/ml in non-ILD patients; p = 0.01). After treatment, BAFF level reduced significantly in diffuse SSc patients (1652.2 ± 892.7 pg/ml versus 2147.6 ± 945.5 pg/ml before treatment; p = 0.03).CONCLUSION:Patients with worsening outcome had the highest pretreatment BAFF level and was associated with increased BAFF level after treatment. BAFF can be used to predict and monitor patients’ response to therapy.

Molecular targeted therapies for microscopic polyangiitis and granulomatosis with polyangiitis.

Clinical trials and observational studies have established cyclophosphamide (CY) or rituximab plus glucocorticoid (GC) as standard remission induction therapies in patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA). However, because these regimens are associated with serious adverse drug reactions, the development of drugs with novel mechanisms of actions are needed. Progress in basic and clinical research has identified novel candidate targeting molecules, including B-cell activating factor (BAF), C5a receptor, and interleukin-6. The combination of rituximab and BAF blockade in patients with MPA and GPA is under investigation in an effort to strike a better benefit-risk balance. Phase II clinical trials of avacopan (CCX168), an orally administered C5a receptor antagonist, have suggested a reduction in the dosage of concomitant GC or the replacement of GC in patients with MPA and GPA. The results from a currently ongoing phase III trial are awaited. Anecdotal case reports and an open-label pilot study have indicated the effectiveness of tocilizumab in patients with MPA and GPA. A randomized clinical trial comparing tocilizumab and intravenous CY in combination with GC is currently in progress. Molecular targeted therapy is expected to transform the treatment strategy for MPA and GPA to allow GC-free or at least less GC-dependent forms of therapy.

Molecular Evidence for Precursors of Sjögren's Foci in Histologically Normal Lacrimal Glands.

Understanding the formation of Sjogren’s lymphocytic infiltrates could permit earlier diagnosis and better outcomes. We submitted gene transcript abundances in histologically normal rabbit lacrimal glands to principal component analysis. The analysis identified a cluster of transcripts associated with Sjögren’s foci, including messenger RNAs (mRNAs) for C–X–C motif chemokine ligand 13 (CXCL13) and B-cell activating factor (BAFF), which dominated the major principal component. We interpreted the transcript cluster as the signature of a cluster of integrally functioning cells. Pregnancy and dryness increased the likelihood that the cluster would develop to high levels, but responses were subject to high levels of stochasticity. Analyzing microdissected samples from high- and low-cluster-level glands, we found that certain transcripts, including mRNAs for C–C motif chemokine ligand 21 (CCL21), CXCL13, cluster of differentiation 4 (CD4), CD28, CD25, BAFF, and interleukin 18 (IL-18) were significantly more abundant in immune cell clusters (ICs) from the high-cluster-level gland; mRNAs for CCL2, CD25, and IL-1RA were significantly more abundant in acinus-duct axis samples; mRNAs for CCL4, BAFF, IL-6, and IL-10 were more abundant in some acinus-duct samples; cells with high prolactin immunoreactivity were more frequent in interacinar spaces. In conclusion, integrated functional networks comprising Sjögren’s infiltrates, such as ICs, acinar cells, ductal cells, and interacinar cells, can form in histologically normal glands, and it is feasible to detect their molecular signatures.

Impact of belimumab on patient-reported outcomes in systemic lupus erythematosus: review of clinical studies.

Systemic lupus erythematosus (SLE) is a chronic autoimmune, multisystem rheumatic disease with significant impact on health-related quality of life (HRQoL). Patient-reported outcomes (PROs) provide valuable data on patient perceptions across a variety of domains, such as HRQoL, pain, fatigue, and depression. The measurement and results of PROs with respect to HRQoL in randomized controlled trials (RCTs) on belimumab (B-lymphocyte stimulator inhibitor) in SLE are reviewed here, including BLISS-52 and BLISS-76, as well as publications related to belimumab trials that included HRQoL data. Other trials that evaluated belimumab did not include HRQoL data and were therefore not included in the analysis. The BLISS-52 and BLISS-76 RCTs met their primary endpoints and demonstrated improvements in PROs, measured by the 36-item Short Form Health Survey, EuroQol 5 Dimensions, and Functional Assessment of Chronic Illness Therapy-Fatigue Scale. Belimumab was shown overall to improve PROs in adult autoantibody-positive lupus patients.

Depletion of BAFF cytokine exacerbates infection in Pseudomonas aeruginosa infected mice

BackgroundCystic fibrosis (CF) is a genetic disease characterized by chronic inflammation of the lungs that is ineffective at clearing pathogens. B-cell activating factor (BAFF), a cytokine involved in the development of B-cells, is known to be elevated in CF patients with subclinical infections. We postulate that the elevated BAFF levels in CF patients might be triggered by Pseudomonas aeruginosa infection and it might play a protective role in the regulation of lung responses to infection. MethodsTo address this hypothesis, we used a well characterized model of CFTR.KO mice infected with a clinical strain of P. aeruginosa (PA508). We quantified cell types with flow cytometry, concentration of cytokines by ELISA tests, bacterial load by colony counting and lung physiology by metacholine-induced lung resistance. ResultsOur data demonstrates that BAFF is not elevated in uninfected CF mice, and infection with Pseudomonas leads to significant induction of this regulatory cytokine. We also demonstrate that the maintenance of BAFF levels and its induction during the infection is important for clearance of Pseudomonas infection as its depletion during the course of infection leads to decrease in the resolution of infection both in WT and CFTR-KO mice. Interestingly, the depletion of BAFF not only results in a depletion of B cells numbers but also to a significant decrease in the number of regulatory T cells in the non-infected lungs. ConclusionsOverall, our data demonstrate for the first time that BAFF is an important regulatory molecule helping to maintain the immunological response to infection and clearance of lung infection.

The Un-BLyS-Ful State: Blocking Factor VIII Inhibitor Development with BLyS Depletion

The development of neutralizing alloantibodies (inhibitors) to infused factor VIII (FVIII) remains the most significant complication of therapy in hemophilia A (HA). Despite some insights into genetic and environmental risk factors associated with inhibitor development, the immunological mechanisms behind this complication remain incompletely understood. Given that infused FVIII is likely encountered in the periphery, transitional B cell response to FVIII may regulate inhibitor development. Transitional B cell survival, maturation and proliferation are tightly regulated by the cytokine BLyS (B-lymphocyte stimulator). Elevated levels of BLyS have been described in both auto- and allo-immune disease processes and may be genetically determined in a subset of patients with lupus and multiple sclerosis. In prior experiments, we noted that BLyS levels are higher in HA patients with inhibitors as opposed to 10 other pro- and anti-inflammatory cytokines. However, BLyS levels normalized amongst those who underwent successful immune tolerance induction. Thus, we hypothesized that BLyS may regulate FVIII inhibitor development or persistence. Here, we present results from animal studies aimed at 1) preventing inhibitor development in naïve HA mice and 2) maintaining long-term tolerance.For prevention experiments, HA C57Bl/6 mice (n=8-10/group) were given a single dose of anti-BLyS neutralizing antibody (Sandy-2, Adipogen) or PBS control one week prior to immunization with recombinant human FVIII (rhFVIII) at 80 IU/kg via tail vein injection every 14 days for four injections (Fig 1). Plasma samples were obtained at baseline and 7 days after last immunization and analyzed for FVIII antibody by Bethesda assay, anti-FVIII IgG by ELISA, and BLyS levels by ELISA. To test long-term tolerance, 22 weeks after initial anti-BLyS antibody injection, mice without inhibitors were challenged with 4 additional rhFVIII intravenous infusions and plasma obtained 7 days following each injection (Fig 1). Data was analyzed using Prism and is reported as median (IQR) with Mann-Whitney test for two-group comparisons and Mantel-Cox log-rank test for Kaplan-Meier survival analysis.Anti-BLyS treated mice achieved nadir BLyS levels at 14 days post-injection compared to control (0.2 [0.09-0.3] vs 8.2 [7.3-8.5] ng/ml, respectively, p < 0.0001), and levels equalized by day 28 between groups. Only 2 of 9 mice in the anti-BLyS treated group developed inhibitors to FVIII (0 [0-12.5] BU) compared to 9 of 10 in the treated group (21.1 [2.5-157.3] BU) with a significant log-rank survival of 0.0007 and favorable hazard ratio of 0.16 (95% CI 0.05-0.56) after initial immunization. Total anti-FVIII IgG was lower in the treated group (4.7 [1.1-11.5] mcg/ml) compared to control mice (27.6 [24-42] mcg/ml) with p of 0.003. Of the anti-BLyS treated inhibitor-free mice that have been challenged with rhFVIII, no inhibitors were detected until after the fourth rhFVIII injection. In these mice, there was a trend towards lower inhibitor titers compared to controls with a range of 1-1.8 BU vs. 85.6-1016 BU and lower FVIII IgG (23 [20.9-25.2] vs 69.9 [65.1-129.9] mcg/ml), respectively.Here, we demonstrate that BLyS depletion prior to FVIII exposure in naïve HA mice can prevent antibody development and may result in long-term sustained FVIII tolerance. As BLyS is central to the survival and maturation of transitional B cells, including marginal zone B cells which have recently been demonstrated to be important in inhibitor formation, this may provide a strategy for both antibody prevention and eradication in HA patients. Notably, the anti-BLyS monoclonal antibody belimumab is already FDA approved for the treatment of patients with lupus. Further studies to confirm the duration of immune tolerance obtained with anti-BLyS therapy in animal models may allow for translation of this strategy to provide long-lasting FVIII tolerance to patients with high risk of inhibitor development. [Display omitted] DisclosuresDoshi:Bayer Hemophilia Awards Program: Research Funding.

Efficacy of Belimumab for active lupus nephritis in a young Hispanic woman intolerant to standard treatment: a case report

BackgroundLupus nephritis (LN) is a frequent severe complication of Systemic Lupus Erythematosus (SLE), especially in patients of non-Caucasian ethnicity. Induction treatment for LN consists in the combination of steroids plus a second agent (cyclophosphamide or mycophenolate mofetil) or, as a second-line, calcineurin inhibitors or Rituximab. Induction treatment for LN can be complicated by a series of side effects, the most severe being serious infections. Belimumab is a fully humanized monoclonal antibody that targets soluble B lymphocyte stimulator (BLyS), approved for treatment of serologically active SLE in addition to standard of care.Case presentationA young Hispanic woman was diagnosed with SLE at the age of 15. After several immunosuppressive treatments for arthritic symptoms (high-dose steroids, mycophenolate mofetil, Rituximab, cyclophosphamide) leading to serious complications and scarce clinical improvement, she developed severe LN. Induction treatment with a combination of intravenous high-dose methylprednisolone and cyclophosphamide was started but, after few days, the patient developed cryptococcal meningitis. After institution of appropriate antifungal therapy, treatment with Tacrolimus was attempted but poorly tolerated by the patient and withdrawn. Eventually, Belimumab was initiated off-label as a last resource to treat LN. Belimumab was well tolerated by the patient and resulted in a rapid and marked improvement in clinical symptoms and reduction in proteinuria, serum complement levels and anti-dsDNA titer; of note, the patient developed no infectious complications.ConclusionsWe report the case of a severe LN in a young Hispanic woman who did not respond to conventional and second-line induction therapies, due both to intolerance and to the development of serious infectious complications. Eventually, Belimumab was successfully added to steroids and was well tolerated by the patient, resulting in a marked improvement in clinical and biochemical parameters. We suggest that Belimumab should be considered as a potentially efficacious treatment in patients with LN who cannot tolerate conventional therapies.

Urinary B-cell-activating factor of the tumour necrosis factor family (BAFF) in systemic lupus erythematosus.

We examined the clinical relevance of urinary concentrations of B-cell-activating factor of the tumour necrosis factor family (BAFF) and a proliferation-inducing ligand (APRIL) in systemic lupus erythematosus (SLE). We quantified urinary BAFF (uBAFF) by enzyme-linked immunosorbent assay in 85 SLE, 28 primary Sjögren syndrome (pSS), 40 immunoglobulin A nephropathy (IgAN) patients and 36 healthy controls (HCs). Urinary APRIL (uAPRIL) and monocyte chemoattractant protein 1 (uMCP-1) were also quantified. Overall and renal SLE disease activity were assessed using the Systemic Lupus Erythematosus Disease Activity Index 2000. uBAFF was detected in 12% (10/85) of SLE patients, but was undetectable in HCs, IgAN and pSS patients. uBAFF was detectable in 28% (5/18) of SLE patients with active nephritis vs 5/67 (7%) of those without ( p = 0.03), and uBAFF was significantly higher in active renal patients ( p = 0.02) and more likely to be detected in patients with persistently active renal disease. In comparison, uAPRIL and uMCP-1 were detected in 32% (25/77) and 46% (22/48) of SLE patients, respectively. While no difference in proportion of samples with detectable uAPRIL was observed between SLE, HCs and IgAN patients, both uAPRIL and uMCP-1 were significantly detectable in higher proportions of patients with active renal disease. uBAFF was detectable in a small but a significant proportion of SLE patients but not in other groups tested, and was higher in SLE patients with active renal disease.

Interaction between B-cell activation factor and methotrexate impacts immunogenicity of seasonal influenza vaccination in patients with rheumatoid arthritis

Methotrexate (MTX) with its proven efficacy and safety profile remains as the anchor drug for the treatment of rheumatoid arthritis (RA).1 2 However, the impact of MTX alone or in...

Exploring the Possible Prognostic Role of B-Lymphocyte Stimulator (BLyS) in a Large Series of Patients with Neuroendocrine Tumors.

BLyS (B-Lymphocyte stimulator) is over-expressed in several tumoral settings, with direct or indirect effects on neoplastic proliferation and possibly representing a therapeutic target. In this study, we explored the role of BLyS in a large population of patients with neuroendocrine tumors (NETs). The study analyzed the stored sera of 124 consecutive unselected patients with NETs: 36 lung carcinoids (24 typical, 12 atypical), 47 gastroenteric tract and 41 pancreatic (30 non-functioning and 11 functioning: 9 insulinomas, 2 glucagonomas). In 23 cases, BLyS was repeatedly assessed during the follow-up and the disease was monitored (progression, stabilization or remission) according to the RECIST criteria. Patients were compared to 92 age and sex-matched blood donors (BDs). Serum levels of BLyS and Chromogranin A (CgA) were analyzed by ELISA. NET patients showed significantly higher BLyS levels than BDs (1274±809 pg/ml vs. 587±173 pg/ml; p<0.0001). BLyS correlated weakly with CgA (r=0.19 and p=0.035) but did not correlate with Ki67, grading, metastasis, histological type and site. In patients with sustained remission after surgery, BLyS and CgA both showed a gradual reduction over time. Patients with progressing disease showed higher BLyS levels compared to stable patients (1524±694 pg/ml vs. 1168± 373 pg/ml; p= 0.033). BLyS serum levels remained stable in remission and therapy-controlled patients, while increased in the follow-up of progressing cases. Higher BLyS levels identify patients with a more severe disease, characterized by progression despite treatments, possibly representing a factor implicated in the proliferation of the neoplastic cells or in sustaining the neoplastic environment.

Cooperative translational control of polymorphic BAFF by NF90 and miR-15a.

Polymorphisms in untranslated regions (UTRs) of disease-associated mRNAs can alter protein production. We recently identified a genetic variant in the 3′UTR of the TNFSF13B gene, encoding the cytokine BAFF (B-cell-activating factor), that generates an alternative polyadenylation site yielding a shorter, more actively translated variant, BAFF-var mRNA. Accordingly, individuals bearing the TNFSF13B variant had higher circulating BAFF and elevated risk of developing autoimmune diseases. Here, we investigated the molecular mechanisms controlling the enhanced translation of BAFF-var mRNA. We identified nuclear factor 90 (NF90, also known as ILF3) as an RNA-binding protein that bound preferentially the wild-type (BAFF-WT mRNA) but not BAFF-var mRNA in human monocytic leukemia THP-1 cells. NF90 selectively suppressed BAFF translation by recruiting miR-15a to the 3′UTR of BAFF-WT mRNA. Our results uncover a paradigm whereby an autoimmunity-causing BAFF polymorphism prevents NF90-mediated recruitment of microRNAs to suppress BAFF translation, raising the levels of disease-associated BAFF.

Increased B-cell activating factor, interleukin-6, and interleukin-8 in induced sputum from primary Sjögren’s syndrome patients

Objective: Small airway disease and chronic obstructive pulmonary disease are common in primary Sjögren’s syndrome (pSS). However, the underlying inflammatory mechanisms behind pSS-associated airway disease have not been studied in detail. We therefore wanted to study cytokine and leucocyte levels in induced sputum in never-smoking patients with pSS.Method: Induced sputum cytokines and leucocytes were assessed in 20 never-smoking patients with pSS and 19 age- and gender-matched population-based controls. In addition, pulmonary function, disease activity, respiratory symptoms, and inflammatory and serological features of pSS were assessed.Results: B-cell activating factor (BAFF), interleukin-6 (IL-6) and IL-8 were significantly increased in induced sputum in pSS patients compared to population-based controls, while IL-1β, interferon-α, and tumour necrosis factor-α levels and leucocytes were not. The proportion of lymphocytes and BAFF levels in induced sputum correlated significantly in pSS patients. However, cytokine levels in induced sputum were not associated with pulmonary function tests, disease activity, respiratory symptoms, or serological features of pSS.Conclusion: The increase in BAFF, IL-6, and IL-8 in induced sputum suggests a specific ongoing inflammatory disease process in the airways in pSS patients. Its association with pSS-associated airway disease needs to be further examined in future larger studies.

The changes and significance of the soluble B cell-activating factor in the peripheral blood of patients with chronic human immunodeficiency virus infection

Objective To elaborate the changes of the soluble B cell-activating factor of the tumor necrosis factor family (BAFF) in the peripheral blood of chronic human immunodeficiency virus (HIV)-infected patients, and to study the correlation between the soluble BAFF in HIV-infected patients and the progressions of acquired immune deficiency syndrome (AIDS). Methods Fifty untreated HIV outpatients and 30 healthy controls were recruited. According to the counts of CD4+ T lymphocytes, HIV-infected patients were divided into three groups, 350 cells/μL group. B cell counts and the BAFF levels were compared among the three groups and the healthy controls. The correlation analysis was conducted for the levels of BAFF, the counts of CD4+ T lymphocytes and B cells, and viral load in HIV-infected patients. The value of BAFF in staging of HIV disease was identified by receiver operating characteristic (ROC) curve. Results The B cell counts were (90.3±43.1) cells/μL in 350 cells/μL group and (307.1±97.0) cells/μL in healthy controls, which was significantly different among the four groups (F=47.92, P<0.05). The concentrations of BAFF in the four groups were (1 737.5±719.7), (962.8±341.1), (859.8±270.4), and (456.9±163.7) ng/L, with significant difference among the groups (F=36.72, P<0.05). The level of BAFF was negatively correlated with both B cell counts and CD4+ T lymphocyte counts (r=-0.722 and -0.568, respectively; both P<0.05), and positively correlated with viral load (r=0.607, P<0.05). The area under the ROC curve was 0.881. If the level of BAFF was 1 281.5 ng/L, the sensitivity and specificity to predict the period of AIDS were 74.1% and 87.0%, respectively. Conclusion The levels of soluble BAFF in HIV-infected patients are significantly increased and related with the reduction of B cell counts and disease progression. Key words: HIV-1; B-lymphocytes; BAFF

IgD-activated mast cells induce IgE synthesis in B cells in nasal polyps

Although upregulated expression of local IgD has been reported in patients with chronic rhinosinusitis (CRS), its function is unclear. We sought to explore the expression and function of soluble IgD in patients with CRS, particularly CRS with nasal polyps. IgD levels in sinonasal mucosa were analyzed by using RT-PCR and ELISA. Numbers and phenotypes of IgD+ cells were studied by means of immunohistochemistry, immunofluorescence, and flow cytometry. HMC-1cells, a human mast cell line, and mast cells purified from eosinophilic polyps were cultured alone or with naive B cells purified from peripheral blood. The antigen specificity of nasal IgD was investigated by using ELISA. The mRNA expression of immunoglobulin heavy constant delta gene, numbers of IgD+ cells, and protein levels of secretory IgD in sinonasal mucosa were increased in patients with CRS with or without nasal polyps compared with control subjects. Numbers of IgD+ plasmablasts were increased in both eosinophilic and noneosinophilic polyps, whereas numbers of IgD+ mast cells were only increased in eosinophilic polyps. Cross-linking IgD induced serum preincubated HMC-1cells and polyp mast cells to produce B-cell activating factor, IL-21, IL-4, and IL-13 and to promote IgM, IgG, IgA, and IgE production from B cells. In eosinophilic polyps expression of those B cell-stimulating factors in mast cells and close contact between mast cells and B cells were found. Moreover, positive correlations of total IgD levels with total IgE levels and eosinophilia and upregulation of specific IgD against house dust mites were discovered in eosinophilic polyps. IgD-activated mast cells can facilitate IgE production and eosinophilic inflammation in patients with CRS with nasal polyps.

Cytokine profiling in active and quiescent SLE reveals distinct patient subpopulations

BackgroundPatients with SLE display marked clinical and immunlogical heterogeneity. The purpose of the study was to investigate patterns of serum cytokines in patients with active and stable systemic lupus erythematosus (SLE) and to determine how they relate to clinical phenotype.MethodsSerum levels of 10 cytokines were measured retrospectively in a cohort of patients with SLE and in healthy controls using a high-sensitivity multiplex bead array. Disease activity was determined using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) and British Isles Lupus Assessment Group (BILAG-2004) indices. Logistic regression models were used to determine the association between cytokine levels and active SLE. Principal component analysis (PCA) and cluster analysis was then used to identify subgroups of patients on the basis of cytokine levels.ResultsSerum chemokine (C-X-C motif) ligand 10 (CXCL10) and CXCL13 were significantly higher in patients with SLE compared to healthy controls. Two cytokines (pentraxin-related protein (PTX3) and CXCL10) were significantly higher in patients with active disease after adjustment for potential confounding factors. Measurement of four cytokines (CXCL10, IL-10, IL-21 and PTX3) significantly improved the performance of a model to identify patients with clinically active disease. Cluster analysis revealed that the patients formed 3 distinct groups, characterised by higher levels of interferon alpha (IFNα) and B lymphocyte stimulator (BLyS) (group 1), increased CXCL10 and CXCL13 (group 2) or low levels of cytokines (group 3). Group 2 had significantly lower serum complement and higher anti-double-stranded DNA antibodies and increased prevalence of inflammatory arthritis.ConclusionsMultiplex analysis has identified a serum cytokine signature for active SLE. Within the SLE population distinct cytokine subgroups were identified, with differing clinical and immunological phenotypes that appeared stable over time. Assessment of cytokine profiles may reveal unique insights into disease heterogeneity.

Proteasome inhibition with bortezomib induces a therapeutically relevant depletion of plasma cells in SLE but does not target their precursors.

Long-lived plasma cells (PCs) not only provide protective humoral immunity, they are also an essential component of the autoreactive immunologic memory that may drive chronic immune responses in systemic autoimmunity, such as systemic lupus erythematosus (SLE). The therapeutic relevance of their targeting has been demonstrated in preclinical models and severe, treatment-refractory cases of autoimmune diseases using the proteasome inhibitor bortezomib. Herein, we describe in detail the dynamic serologic changes and effects on immune effector cells in eight SLE patients receiving a median two cycles of 1.3 mg/m2 intravenous bortezomib. Upon proteasome inhibition, immunoglobulin levels gradually declined by ∼30%, associated with a significant reduction of autoantibodies, and serum complement whereas B-cell activation factor levels increased. While proteasome inhibition was associated with a significant depletion of short- and long-lived PCs in peripheral blood and bone marrow by ∼50%, including those with a distinctly mature CD19- phenotype, their precursor B cells and T cells largely remained unaffected, resulting in a rapid repopulation of short-lived PCs after bortezomib withdrawal, accompanied by increasing autoantibody levels. Collectively, these findings identify proteasome inhibitors as a promising treatment option for refractory SLE, but also indicate that PC depletion needs to be combined with targeted B-cell therapies for sustained responses in systemic autoimmunity.

Toll-like receptor 9 ligands increase type I interferon induced B-cell activating factor expression in chronic rhinosinusitis with nasal polyposis

B-cell activating factor (BAFF) has been proposed to play a crucial role in the pathogenesis of chronic rhinosinusitis with nasal polyp (CRSwNP). The aim of this study was to evaluate the role of toll-like receptor (TLR) 9-mediated BAFF activation on the pathogenesis of CRSwNP. NP and uncinate tissue (UT) were obtained from patients with CRSwNP or CRS without NP, and control subjects. The expression of TLR9, high mobility group box-1 protein (HMGB1), type I interferon (IFN), BAFF, and anti-double stranded DNA (dsDNA) antibody were examined in the tissues and the cultured dispersed NP cells (DNPCs). The expression of TLR9, HMGB1, type I IFN, BAFF, and anti-dsDNA antibody were elevated in NP tissue compared to the UTs. Exposure to TLR9 agonist increased the type I IFN expression in vitro, which further increased BAFF production. In conclusion, we provided a novel therapeutic potential of TLR9 agonist in CRSwNP.

Increased B-cell activating factor (BAFF)/B-lymphocyte stimulator (BLyS) in primary antiphospholipid syndrome is associated with higher adjusted global antiphospholipid syndrome scores

### Key messages #### What is already known about this subject? #### What does this study add? #### How might this impact on clinical practice? Antiphospholipid syndrome (APS) is a...