Showing papers on "B-cell activating factor published in 2018"
TL;DR: The mechanisms that support the increased activation of B cells in pSS are discussed, including genetic and epigenetic factors and environmental triggers that promote B cell activation via the innate immune system.
Abstract: Primary Sjogren syndrome (pSS) is a prototypical autoimmune disease The involvement of B cells in the pathogenesis of pSS has long been suspected on the basis of clinical observations that include the presence of serum autoantibodies, hypergammaglobulinaemia, increased levels of free light chains and increased risk of B cell lymphoma Moreover, the composition of the B cell subset is altered in pSS In this Review, we discuss the mechanisms that support the increased activation of B cells in pSS, including genetic and epigenetic factors and environmental triggers that promote B cell activation via the innate immune system B cell activating factor (BAFF, also known as TNF ligand superfamily member 13B) is at the crossroads of this process An important role also exists for the target tissue (exocrine glands, namely the salivary and lachrymal glands), which promotes local B cell activation This continuous stimulation of B cells is the main driver of lymphomatous escape Identification of the multiple steps that support B cell activation has led to the development of promising targeted therapies that will hopefully lead to the development of an efficient therapeutic strategy for pSS
187 citations
TL;DR: BAFFR deficiency in humans is characterized by very few circulating B cells, very low IgM and IgG serum concentrations but normal or high IgA levels, which is different from mutations affecting pathway components coupled to B cell antigen receptor (BCR) signaling.
Abstract: The BAFF-receptor (BAFFR) is encoded by the TNFRSF13C gene and is one of the main pro-survival receptors in B cells. Its function is impressively documented in humans by a homozygous deletion within exon 2, which leads to an almost complete block of B cell development at the stage of immature/transitional B cells. The resulting immunodeficiency is characterized by B-lymphopenia, agammaglobulinemia, and impaired humoral immune responses. However, different from mutations affecting pathway components coupled to B cell antigen receptor (BCR) signaling, BAFFR-deficient B cells can still develop into IgA-secreting plasma cells. Therefore, BAFFR deficiency in humans is characterized by very few circulating B cells, very low IgM and IgG serum concentrations but normal or high IgA levels.
174 citations
TL;DR: Novel insights are provided into clinical beneficence of reducing excessive NET formation in SLE by therapeutic targeting ANA production with RTX + BLM, putting forward a new treatment concept that specifically ameliorates underlying SLE pathophysiology.
104 citations
TL;DR: Although the SRI-6 end point was not met, blisibimod was associated with successful steroid reduction, decreased proteinuria and biomarker responses, and was well-tolerated.
Abstract: Background Targeted inhibitors of B-cell activating factor (BAFF) have been evaluated in phase III trials in over 4000 patients with systemic lupus erythematosus (SLE). Post hoc analyses of these studies identify greater treatment effect in patients entering with higher disease activity, greater corticosteroid doses, anti double-stranded DNA (dsDNA) and low complement C3 or C4. Objectives To evaluate the efficacy and safety of blisibimod, a BAFF inhibitor, in a population of patients with SLE enriched for high disease activity. Methods 442 patients with SLE with antinuclear antibodies or anti-dsDNA and Safety of Estrogen in Lupus Erythematosus National Assessment – Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score ≥10 on standard-of-care medications were randomised to receive weekly subcutaneous blisibimod (200 mg) or placebo. Corticosteroid taper was encouraged from week 8. The primary end point was the week 52 SLE Responder Index-6 (SRI-6). Results The SRI-6 primary end point was not met. There was a statistically significant steroid-sparing effect, and significantly more blisibimod-treated subjects achieved corticosteroid taper. Increased blisibimod treatment effect on SRI-6 was observed in subjects who achieved a concomitant decrease in corticosteroid dose from baseline. In subjects with baseline urinary protein:creatinine ratio (UPCR) ≥56.5 mg/mmol, significantly higher proportions of blisibimod subjects achieved >50% reduction in UPCR and/or UPCR Blisibimod was well-tolerated. The most common adverse events were upper respiratory tract infection, urinary tract infection, injection site erythema/reaction and diarrhoea. Conclusions Although the SRI-6 end point was not met, blisibimod was associated with successful steroid reduction, decreased proteinuria and biomarker responses. Trial registration number NCT01395745.
98 citations
TL;DR: It is indicated that Beffs play a pathogenic role in the scleroderma model, while Bregs plays a protective role and BAFF inhibition is a potential therapeutic strategy for SSc via alteration of B cell balance.
Abstract: Systemic sclerosis (SSc) is an autoimmune disease characterized by skin and lung fibrosis More than 90% of patients with SSc are positive for autoantibodies In addition, serum B cell activating factor (BAFF) level is correlated with SSc severity and activity Thus, B cells are considered to play a pathogenic role in SSc However, there are two opposing subsets: regulatory B cells (Bregs) and effector B cells (Beffs) Interleukin-10 (IL-10)-producing Bregs negatively regulate the immune response, while IL-6-producing Beffs positively regulate it Therefore, a protocol that selectively depletes Beffs would represent a potent therapy for SSc The aims of this study were to investigate the roles of Bregs and Beffs in SSc and to provide a scientific basis for developing a new treatment strategy targeting B cells A bleomycin-induced scleroderma model was induced in mice with a B cell-specific deficiency in IL-6 or IL-10 We also examined whether BAFF regulates cytokine-producing B cells and its effects on the scleroderma model IL-6-producing Beffs increased in number and infiltrated the inflamed skin in the scleroderma model The skin and lung fibrosis was attenuated in B cell-specific IL-6-deficient mice, whereas B cell-specific IL-10-deficient mice showed more severe fibrosis In addition, BAFF increased Beffs but suppressed Bregs Furthermore, BAFF antagonist attenuated skin and lung fibrosis in the scleroderma model with reduction of Beffs but not of Bregs The current study indicates that Beffs play a pathogenic role in the scleroderma model, while Bregs play a protective role BAFF inhibition is a potential therapeutic strategy for SSc via alteration of B cell balance
85 citations
TL;DR: It is shown that experimental lupus in NZB/W F1 mice can be treated with a highly selective and potent NIK small molecule inhibitor, which results in improved survival, reduced renal pathology, and lower proteinuria scores, suggesting that NIK inhibition is a potential therapeutic approach for SLE.
Abstract: NF-κB-inducing kinase (NIK) mediates non-canonical NF-κB signaling downstream of multiple TNF family members, including BAFF, TWEAK, CD40, and OX40, which are implicated in the pathogenesis of systemic lupus erythematosus (SLE). Here, we show that experimental lupus in NZB/W F1 mice can be treated with a highly selective and potent NIK small molecule inhibitor. Both in vitro as well as in vivo, NIK inhibition recapitulates the pharmacological effects of BAFF blockade, which is clinically efficacious in SLE. Furthermore, NIK inhibition also affects T cell parameters in the spleen and proinflammatory gene expression in the kidney, which may be attributable to inhibition of OX40 and TWEAK signaling, respectively. As a consequence, NIK inhibition results in improved survival, reduced renal pathology, and lower proteinuria scores. Collectively, our data suggest that NIK inhibition is a potential therapeutic approach for SLE.
79 citations
TL;DR: This study demonstrates major miRNAs deregulation in T and B cells from patients with pSS in two independent cohorts, which might target genes known to be involved in the pathogenesis of pSS.
Abstract: Objective MicroRNAs (miRNAs) play an important role in the pathogenesis of autoimmune diseases such as primary Sjogren’s syndrome (pSS). This study is the first to investigate miRNA expression patterns in purified T and B lymphocytes from patients with pSS using a high-throughput quantitative PCR (qPCR) approach. Methods Two independent cohorts of both patients with pSS and controls, one for discovery and one for replication, were included in this study. CD4+ T cells and CD19+ B cells were isolated from peripheral blood mononuclear cells by magnetic microbeads and expression of miRNAs was profiled using the Exiqon Human miRNome panel I analysing 372 miRNAs. A selection of differentially expressed miRNAs was replicated in the second cohort using specific qPCR assays. Results A major difference in miRNA expression patterns was observed between the lymphocyte populations from patients with pSS and controls. In CD4 T lymphocytes, hsa-let-7d-3p, hsa-miR-155–5 p, hsa-miR-222–3 p, hsa-miR-30c-5p, hsa-miR-146a-5p, hsa-miR-378a-3p and hsa-miR-28–5 p were significantly differentially expressed in both the discovery and the replication cohort. In B lymphocytes, hsa-miR-378a-3p, hsa-miR-222–3 p, hsa-miR-26a-5p, hsa-miR-30b-5p and hsa-miR-19b-3p were significantly differentially expressed. Potential target mRNAs were enriched in disease relevant pathways. Expression of B-cell activating factor ( BAFF) mRNA was inversely correlated with the expression of hsa-miR-30b-5p in B lymphocytes from patients with pSS and functional experiments showed increased expression of BAFF after inhibiting hsa-miR-30b-5p. Conclusions This study demonstrates major miRNAs deregulation in T and B cells from patients with pSS in two independent cohorts, which might target genes known to be involved in the pathogenesis of pSS.
74 citations
TL;DR: It is concluded that B2‐lymphocyte activation is an early event in NAFLD evolution and contributes to the disease progression through the interaction with T‐cells and elevated circulating anti‐OSE IgG can identify a subset ofNAFLD patients in whom adaptive immunity has a relevant role in the disease evolution toward fibrosis.
68 citations
TL;DR: Different contributions of soluble and cellular components of the PC niche in the spleen demonstrate that the LLPC expression profile is not cell intrinsic but largely depends on signals provided by the splenic microenvironment, implying that interfering with these components at the time of B-cell depletion might improve the response rate in autoimmune cytopenia.
60 citations
TL;DR: B cell depletion therapy with rituximab is an effective alternative to cyclophosphamide for the induction of remission in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV).
Abstract: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is an organ-threatening and life-threatening multi-system autoimmune disease in which B cell-derived ANCAs cause neutrophil activation and endothelial damage, strongly implicating these autoantibodies in the pathogenesis of AAV. B cell depletion with rituximab combined with glucocorticoids is associated with a reduction in ANCA concentrations and with clinical remission in the majority of patients with AAV. However, the safety profile of rituximab is no better than that of conventional therapy with cyclophosphamide, and long-term glucocorticoid treatment is needed to achieve and maintain disease-free remission. A need for new therapies exists to reduce the time to remission, to spare the use of glucocorticoids and to promote long-lasting remission without the risk of relapse. Over the past 20 years, there has been great interest in therapeutically targeting B cell cytokines, such as B cell-activating factor (BAFF), in many autoimmune disease settings. Dual B cell-targeted immunotherapy that combines B cell depletion and BAFF blockade could potentially be more efficacious than targeting either mechanism alone. In this Review, the theoretical background for use of this combination approach in AAV is presented and discussed.
52 citations
TL;DR: It is shown that testosterone may modulate the production of B cell survival factor BAFF by fibroblastic reticular cells via regulation of splenic neurotransmitter levels and raises important questions about BAFF in testosterone-mediated protection against autoimmunity.
Abstract: Testosterone deficiency in men is associated with increased risk for autoimmunity and increased B cell numbers through unknown mechanisms. Here we show that testosterone regulates the cytokine BAFF, an essential survival factor for B cells. Male mice lacking the androgen receptor have increased splenic B cell numbers, serum BAFF levels and splenic Baff mRNA. Testosterone deficiency by castration causes expansion of BAFF-producing fibroblastic reticular cells (FRCs) in spleen, which may be coupled to lower splenic noradrenaline levels in castrated males, as an α-adrenergic agonist decreases splenic FRC number in vitro. Antibody-mediated blockade of the BAFF receptor or treatment with the neurotoxin 6-hydroxydopamine revert the increased splenic B cell numbers induced by castration. Among healthy men, serum BAFF levels are higher in men with low testosterone. Our study uncovers a previously unrecognized regulation of BAFF by testosterone and raises important questions about BAFF in testosterone-mediated protection against autoimmunity.
TL;DR: To examine whether a JAK inhibitor regulates functional responses of human salivary gland epithelial cells (SGECs) and disease parameters in an animal model of Sjögren's syndrome (SS), data are presented on how these responses are regulated by JAK inhibitors and their actions in animals.
Abstract: Objective To examine whether a JAK inhibitor regulates functional responses of human salivary gland epithelial cells (SGECs) and disease parameters in an animal model of Sjogren's syndrome (SS). Methods Common differentially expressed genes (DEGs) were analyzed among peripheral blood mononuclear cells from patients with primary SS and other data sets, using blood and SG tissue. Validation of expression in SGs was analyzed by focus score. Inhibition of messenger RNA expression of DEGs and BAFF by filgotinib was analyzed using reverse transcription-polymerase chain reaction in primary SGECs. SG organoid cultures were used to determine the association between DEGs and BAFF via knockdown using small interfering RNAs or to determine regulation of BAFF by JAK inhibitor. Filgotinib (1.5 mg/kg) was intraperitoneally injected into 8-week-old NOD/ShiLtJ mice 3 times per week to analyze manifestations of disease. Finally, STAT signaling was assessed in human and mouse SGECs. Results Expression of the DEGs IFNG and BAFF increased in SGs from patients with primary SS, as assessed by focus score. There was a significant correlation between IFIT2 and BAFF expression. JAK inhibitor suppressed interferon (IFN)-induced transcription of DEGs and BAFF in human primary SGECs. Knockdown of DEGs or inhibition of JAK caused reduced secretion of BAFF in human SG organoid cultures. In addition, filgotinib-treated mice exhibited increased salivary flow rates and marked reductions in lymphocytic infiltration of SGs. JAK inhibitor regulated IFNα- and IFNγ-induced pSTAT-1Y701 , pSTAT-3Y705 , and protein inhibitor of activated STAT-3 (PIAS-3) in human SGECs as well as IFNγ-induced pSTAT-1Y701 , pSTAT-3S727 , and PIAS-1 in mouse SGECs. Conclusion JAK inhibition controls aberrant activation of SGECs and may be a novel therapeutic approach for primary SS.
TL;DR: It is demonstrated here that anti-BAFF antibody treatment increased atherosclerosis in mice, despite efficient depletion of mature B-2 cells, suggesting a unique mechanism of action.
Abstract: Background: Atherosclerotic cardiovascular disease (heart attacks and strokes) is the major cause of death globally and is caused by the buildup of a plaque in the arterial wall. Genomic data showe...
TL;DR: High BAFF serum levels in the upper 4th quartile as well as BAFF genetic variants seem to increase susceptibility for both l upus and lupus related subclinical atherosclerosis implying B-cell hyperactivity as a potential contributor in the pronounced lupu related atherosclerotic risk.
TL;DR: Investigating whether renal tubular epithelial cells (TEC) are an important source of BAFF and thus may contribute to the pathogenesis and progression of SLE indicates that renal-derived BAFF may play an important role in the pathophysiology of the systemic autoimmune disease SLE.
Abstract: B-cell activating factor of the tumour necrosis factor family (BAFF) is a cytokine, mainly produced by hematopoietic cells (e.g. monocytes/macrophages, dendritic cells), indispensable for B-cell maturation. The BLISS studies have demonstrated that blocking BAFF by the human monoclonal antibody belimumab is a valuable therapeutic approach in patients with clinically and serologically active systemic lupus erythematosus (SLE). However, the defined sources of BAFF, which contributes to SLE, are still unclear. Recent findings show that BAFF expression is not restricted to myeloid cells. Since lupus nephritis is the main cause of morbidity and mortality for SLE patients, the aim of this study was to investigate whether renal tubular epithelial cells (TEC) are an important source of BAFF and thus may contribute to the pathogenesis and progression of SLE. We found BAFF expression both in cultured murine and human TEC. These results could be verified with in situ data from the kidney. Moreover, BAFF expression in the kidneys of lupus-prone MRL- Faslpr mice correlated with disease activity, and BAFF expression on TEC in biopsies of patients with diffuse proliferative lupus nephritis showed a correlation with the histopathological activity index. In vitro functional assays revealed an autocrine loop of BAFF with its binding receptors on TEC, resulting in a strong induction of colony stimulating factor-1. Finally, we identified divergent effects of BAFF on TEC depending on the surrounding milieu ('inflammatory versus non-inflammatory'). Taken together, our findings indicate that renal-derived BAFF may play an important role in the pathophysiology of the systemic autoimmune disease SLE.
TL;DR: Lead chemical series of NIK inhibitors identified through a scaffold-hopping strategy exhibited selective inhibition of LTβR-dependent p52 translocation and transcription of NF-κB2 related genes and are shown to have a favorable pharmacokinetic profile across species.
Abstract: NF-κB-inducing kinase (NIK) is a protein kinase central to the noncanonical NF-κB pathway downstream from multiple TNF receptor family members, including BAFF, which has been associated with B cell survival and maturation, dendritic cell activation, secondary lymphoid organ development, and bone metabolism. We report herein the discovery of lead chemical series of NIK inhibitors that were identified through a scaffold-hopping strategy using structure-based design. Electronic and steric properties of lead compounds were modified to address glutathione conjugation and amide hydrolysis. These highly potent compounds exhibited selective inhibition of LTβR-dependent p52 translocation and transcription of NF-κB2 related genes. Compound 4f is shown to have a favorable pharmacokinetic profile across species and to inhibit BAFF-induced B cell survival in vitro and reduce splenic marginal zone B cells in vivo.
Journal Article•
TL;DR: The modulation of plasma BLyS kinetics in patients undergoing sequential treatment with rituximab and belimumab may represent a possible rationale behind the effectiveness of this combined therapy.
Abstract: Objectives B cells play an important role in the initiation and progression of systemic lupus erythematosus (SLE). Accordingly, B cell-targeted therapy has been suggested as a new rational approach for treating lupus. Belimumab, a human monoclonal antibody directed against B lymphocyte stimulator (BLyS), was reported as the first biological treatment effective in reducing mild-to-moderate SLE disease activity by using different scoring systems and endpoints. Conversely clinical trials with rituximab, a chimeric monoclonal antibody directed against the CD20 expressed by B cells, have failed to achieve primary endpoints in spite of a number of reports showing its beneficial effects. Anecdotal reports have described the sequential use of rituximab and belimumab as a more effective treatment than using the individual drugs alone, without compromising safety. Methods We report a case series of three patients with active SLE refractory to conventional therapies, who underwent treatment with rituximab followed by belimumab as maintenance therapy. Results We observed a beneficial effect after sequential treatment with rituximab and belimumab. All patients achieved long-standing remission and could reduce or discontinue corticosteroids. Concomitantly, after rituximab administration we observed a rise in BLyS levels, which were dramatically reduced after belimumab introduction. Conclusions The modulation of plasma BLyS kinetics in patients undergoing sequential treatment with rituximab and belimumab may represent a possible rationale behind the effectiveness of this combined therapy.
TL;DR: It is found that B cell-activating factor regulates the transitional B cell checkpoint, with conservation of transitional 1 (T1) cells and approximately 90% loss of T3 and naive B cells after chronic belimumab treatment.
Abstract: Belimumab has therapeutic benefit in active systemic lupus erythematosus (SLE), especially in patients with high-titer anti-dsDNA antibodies. We asked whether the profound B cell loss in belimumab-treated SLE patients is accompanied by shifts in the immunoglobulin repertoire. We enrolled 15 patients who had been continuously treated with belimumab for more than 7 years, 17 matched controls, and 5 patients who were studied before and after drug initiation. VH genes of sort-purified mature B cells and plasmablasts were subjected to next-generation sequencing. We found that B cell-activating factor (BAFF) regulates the transitional B cell checkpoint, with conservation of transitional 1 (T1) cells and approximately 90% loss of T3 and naive B cells after chronic belimumab treatment. Class-switched memory B cells, B1 B cells, and plasmablasts were also substantially depleted. Next-generation sequencing revealed no redistribution of VH, DH, or JH family usage and no effect of belimumab on representation of the autoreactive VH4-34 gene or CDR3 composition in unmutated IgM sequences, suggesting a minimal effect on selection of the naive B cell repertoire. Interestingly, a significantly greater loss of VH4-34 was observed among mutated IgM and plasmablast sequences in chronic belimumab-treated subjects than in controls, suggesting that belimumab promotes negative selection of activated autoreactive B cells.
TL;DR: Within the SLE population distinct cytokine subgroups were identified, with differing clinical and immunological phenotypes that appeared stable over time, and assessment of cytokine profiles may reveal unique insights into disease heterogeneity.
Abstract: Patients 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. Serum 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. Serum 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. Multiplex 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.
TL;DR: This review of cytokines, including interferon (IFN)-γ and IL-17, and several other molecules that represent candidate targets for treating inflammation in SS-related dry eye are discussed.
Abstract: Various cytokines, including interferon (IFN)-γ and IL-17, are augmented, and autoreactive T cells and B cells are activated in the immune pathogenesis of Sjogren’s syndrome (SS). In particular, IFNs are involved in both the early stages of innate immunity by high level of type I IFN in glandular tissue and sera and the later stages of disease progression by type I and type II IFN producing T cells and B cells through B cell activating factor in SS. Genetically modified mouse models for some of these molecules have been reported and will be discussed in this review. New findings from human SS and animal models of SS have elucidated some of the mechanisms underlying SS-related dry eye. We will discuss IFN-γ and several other molecules that represent candidate targets for treating inflammation in SS-related dry eye.
TL;DR: It is shown that a 'flap' region of BAFF converts BAFFR binding events into survival signals and, with structural data, that this ‘flap’ differentially modulates binding of drugs such as belimumab or atacicept.
Abstract: The B cell survival factor (TNFSF13B/BAFF) is often elevated in autoimmune diseases and is targeted in the clinic for the treatment of systemic lupus erythematosus. BAFF contains a loop region designated the flap, which is dispensable for receptor binding. Here we show that the flap of BAFF has two functions. In addition to facilitating the formation of a highly active BAFF 60-mer as shown previously, it also converts binding of BAFF to TNFRSF13C (BAFFR) into a signaling event via oligomerization of individual BAFF-BAFFR complexes. Binding and activation of BAFFR can therefore be targeted independently to inhibit or activate the function of BAFF. Moreover, structural analyses suggest that the flap of BAFF 60-mer temporarily prevents binding of an anti-BAFF antibody (belimumab) but not of a decoy receptor (atacicept). The observed differences in profiles of BAFF inhibition may confer distinct biological and clinical efficacies to these therapeutically relevant inhibitors.
TL;DR: The present review will focus on the current knowledge regarding the role of a molecule related to BAFF, a proliferation-inducing ligand (APRIL), in autoimmune diseases, which acts on antibody-producing plasma cells.
TL;DR: Investigation of BCMA as a target for therapeutic intervention in multiple myeloma (MM) were initiated in 2007, using cSG1 as a naked antibody as well as an Ab–drug conjugate (ADC) targeting BCMA, ultimately leading to ongoing clinical studies for previously treated MM patients.
Abstract: B-cell maturation antigen (BCMA) was originally identified as a cell membrane receptor, expressed exclusively on late stage B-cells and plasma cells (PCs). Investigations of BCMA as a target for therapeutic intervention in multiple myeloma (MM) were initiated in 2007, using cSG1 as a naked antibody (Ab) as well as an Ab-drug conjugate (ADC) targeting BCMA, ultimately leading to ongoing clinical studies for previously treated MM patients. Since then, multiple companies have developed anti-BCMA-directed ADCs. Additionally, there are now three bispecific antibodies in development, which bind to both BCMA and CD3e on T-cells. This latter binding results in T-cell recruitment and activation, causing target cell lysis. More recently, T-cells have been genetically engineered to recognize BCMA-expressing cells and, in 2013, the first report of anti-BCMA-chimeric antigen receptor T-cells showed that these killed MM cell lines and human MM xenografts in mice. BCMA is also solubilized in the blood (soluble BCMA [sBCMA]) and MM patients with progressive disease have significantly higher sBCMA levels than those responding to treatment. sBCMA circulating in the blood may limit the efficacy of these anti-BCMA-directed therapies. When sBCMA binds to B-cell activating factor (BAFF), BAFF is unable to perform its major biological function of inducing B-cell proliferation and differentiation into Ab-secreting PC. However, the use of γ-secretase inhibitors, which prevent shedding of BCMA from PCs, may improve the efficacy of these BCMA-directed therapies.
TL;DR: Proteolytic shedding of the receptors BCMA, TACI, and BAFFR reduces their cell-surface expression and ligand-mediated survival of B cell subsets, and is partially dependent on ligand binding and receptor interactions.
TL;DR: A potential role for BLyS as therapeutic target in the treatment of CLE skin lesions is suggested and CLE‐typical pro‐inflammatory mediators (immunostimulatory DNAs) significantly enhanced theBLyS expression of keratinocytes in vitro.
Abstract: Belimumab, an anti-B lymphocyte stimulator (BLyS) monoclonal antibody, is approved for systemic lupus erythematosus; however, it is unclear if it can be used to treat specific skin lesions in this disease. In this analysis, we investigated the expression of BLyS and its receptors in skin lesions of different subtypes of cutaneous lupus erythematosus (CLE) using immunohistochemistry and gene expression analyses. Compared to healthy controls, the expression of BLyS was significantly higher in skin lesions of all included CLE subtypes. Similar results were seen for the BLyS receptors BAFF-R and BCMA. Moreover, CLE-typical pro-inflammatory mediators (immunostimulatory DNAs) significantly enhanced the BLyS expression of keratinocytes in vitro. This study suggests a potential role for BLyS as therapeutic target in the treatment of CLE skin lesions.
TL;DR: The data show that belimumab can inhibit membrane-bound BAFF, and that BAFF in U937 cells is processed by furin, showing that furin is the main BAFF processing protease in these cells.
Abstract: B cell activating factor of the TNF family (BAFF, also known as BLyS), a cytokine that regulates homeostasis of peripheral B cells, is elevated in the circulation of patients with autoimmune diseases such as systemic lupus erythematosus (SLE). BAFF is synthetized as a membrane-bound protein that can be processed to a soluble form after cleavage at a furin consensus sequence, a site that in principle can be recognized by any of the several proteases of the pro-protein convertase family. Belimumab is a human antibody approved for the treatment of SLE, often cited as specific for the soluble form of BAFF. Here we show in different experimental systems, including in a monocytic cell line (U937) that naturally expresses BAFF, that belimumab binds to membrane-bound BAFF with similar EC50 as the positive control atacicept, which is a decoy receptor for both BAFF and the related cytokine APRIL (a proliferation inducing ligand). In U937 cells, binding of both reagents was only detectable in furin-deficient U937 cells, showing that furin is the main BAFF processing protease in these cells. In CHO cells expressing membrane-bound BAFF lacking the stalk region, belimumab inhibited the activity of membrane-bound BAFF less efficiently than atacicept, while in furin-deficient U937 cells, belimumab inhibited membrane-bound BAFF and residual soluble BAFF as efficiently as atacicept. These reagents did not activate complement or antibody-dependent cell cytotoxicity upon binding to membrane-bound BAFF in vitro. In conclusion, our data show that belimumab can inhibit membrane-bound BAFF, and that BAFF in U937 cells is processed by furin.
TL;DR: It is demonstrated that the BAFF levels in both the serum and bronchoalveolar lavage fluid were positively correlated with the disease activity markers and disease severity.
Abstract: B-cell activating factor (BAFF) plays an important role in the survival and differentiation of B-cells and production of antibodies. Recent studies show that the serum BAFF levels are elevated in patients with sarcoidosis; however, they have not studied the relationship of the finding with the clinical features of the disease. The purpose of the present study is to analyze the BAFF and to elucidate the relationship between BAFF levels and the disease activity or severity of sarcoidosis. Eighty-eight patients with sarcoidosis and 21 healthy volunteers were enrolled in the present study. The BAFF levels were measured by an enzyme-linked immunosorbent assay. To assess the disease severity, we examined the number of affected organs, Schadding stages, respiratory function impairment (RFI), and the scoring system developed by Wasfi et al. The serum BAFF levels in sarcoidosis patients were significantly higher than those in healthy volunteers (median 1553.0 vs 984.6 pg/ml, p < 0.001). There were positive correlations between the serum BAFF level and disease activity markers. In addition, there were positive correlations between the BAFF levels and the disease severity score in both the serum (R = 0.367, p < 0.001) and bronchoalveolar lavage fluid (BALF) (R = 0.376, p < 0.001). This study demonstrated that the BAFF levels in both the serum and BALF were positively correlated with the disease activity markers and disease severity. BAFF may be useful as an indicator of both the disease activity and severity.
TL;DR: It is shown in a mouse model of RSV infection that IFN-α plays a dual role as an antiviral and immune modulator and age-related differences in IgA production upon RSV Infection can be overcome by IFn-α administration.
Abstract: Respiratory syncytial virus (RSV) infection is the most frequent cause of hospitalization in infants and young children worldwide Although mucosal RSV vaccines can reduce RSV disease burden, little is known about mucosal immune response capabilities in children Neonatal or adult mice were infected with RSV; a subset of neonatal mice received interferon alpha (IFN-α) (intranasal) prior to RSV infection B cells, B cell activating factor (BAFF) and IgA were measured by flow cytometry RSV specific IgA was measured in nasal washes Nasal associated lymphoid tissue (NALT) and lungs were stained for BAFF and IgA Herein, we show in a mouse model of RSV infection that IFN-α plays a dual role as an antiviral and immune modulator and age-related differences in IgA production upon RSV infection can be overcome by IFN-α administration IFN-α administration before RSV infection in neonatal mice increased RSV-specific IgA production in the nasal mucosa and induced expression of the B-cell activating factor BAFF in NALT These findings are important, as mucosal antibodies at the infection site, and not serum antibodies, have been shown to protect human adults from experimental RSV infection
TL;DR: The roles of TRAFs in NF-κB signaling pathway mediated by BAFF are reviewed and TRAF7 is involved in signal transduction pathways that lead either to activation or repression of NF-σκB transcription factor.
TL;DR: The objective of this study was to study the correlations between stress and disease‐specific, negative prognostic cellular, cytokine, and chemokine markers in patients with CLL.
Abstract: BACKGROUND Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia, with profound disease-related cellular, humoral, and innate immune suppression. The objective of this study was to study the correlations between stress and disease-specific, negative prognostic cellular, cytokine, and chemokine markers in patients with CLL. METHODS A single-group, observational design was used. Patients with relapsed/refractory CLL (N = 96) who were entering a phase 2 trial of an experimental therapy (ibrutinib) were studied. Before the first dose, a validated self-report measure of stress (the Impact of Event Scale) was completed, and blood was drawn for absolute lymphocyte counts (ALCs) and for cytokine and chemokine enzyme-linked immunosorbent assays. Multiple linear regression models tested stress as a concurrent predictor of ALCs; of cytokines (tumor necrosis factor α [TNFα], a proliferation-inducing ligand [APRIL], B-cell activating factor [BAFF], interleukin 6 [IL-6], IL-10, IL-16, and vascular endothelial growth factor [VEGF]); and of the chemokine (C-C motif) ligand 3 (CCL3). RESULTS Controlling for relevant demographic variables, comorbidities, CLL genetic risk (deletion of the short arm of chromosome 17 [del17p]), and correlates of inflammation, stress predicted higher ALCs (P < .05), and higher levels of TNFα (P < .05), IL-16 (P < .01), and CCL3 (P < .05). Stress was not associated with APRIL, BAFF, IL-6, IL-10, or VEGF. CONCLUSIONS Novel biobehavioral data from patients with relapsed/refractory CLL demonstrate that stress is related to heightened levels of cellular, cytokine, and chemokine markers associated previously with progressive disease in CLL. The current results indicate that stress is related to immune and inflammatory processes that contribute to cancer cell proliferation and survival. These data provide a first look into these processes. Cancer 2018. © 2018 American Cancer Society.