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• B-cell activating factor is essential for the modulation of immune humoral responses. • BAFF was repeatedly associated with non-psychiatric inflammatory and autoimmune conditions. • High levels of soluble BAFF characterize both acute and stabilized patients with SZ and BD and under a genetic control. • sBAFF levels are correlated with positivity of stigma of infection and of autoimmune comorbidities. • BAFF appears as a promising marker of inflammatory processes in SZ and BD. Immune dysregulation is an important aspect of schizophrenia (SZ) and bipolar disorders (BD) pathophysiology, including not only inflammatory but also autoimmune process reflective of abnormal humoral immune responses. Given that B cell-activating factor (BAFF) is an integral aspect of B lymphocyte regulation, the current study investigated BAFF in SZ and BD. 255 SZ patients, 407 BD patients and 185 healthy controls (HC) were investigated across three aspects of soluble BAFF (sBAFF) by (i) comparing sBAFF circulatory levels across SZ, BD and HC, (ii) determining potential correlations between the circulating levels of sBAFF and the genotype distribution of a functionally relevant polymorphism, namely the TNFSF13B 3′UTR insertion-deletion polymorphism (GCTGT>A), (iii) analyzing relationships between both sBAFF levels and 3′UTR insertion-deletion genotypes and disease risk, patients clinical characteristics and circulating levels of potent inflammatory molecules. In addition, in subsets of patients, we also searched for possible correlations between sBAFF levels and stigma of past infectious events as well as positivity for circulating systemic autoantibodies or those directed against central nervous system (CNS) structures. Studying blood derived serum and DNA, we observed that circulating sBAFF levels were significantly higher in SZ and BD patients, versus HC (p = 5.3*10-10 and p = 4.4*10-09). Patients experiencing acute episodes, versus stable patients, in between acute episodes, exhibited higher sBAFF levels (p = 0.017). In SZ patients, positive correlations were observed between elevated sBAFF levels and: (i) elevated positive psychotic symptoms (PANSS pos), (ii) history of childhood trauma (physical abuse), and (iii) low scores on global functioning (GAF) (p = 0.024, p = 0.024, and p = 0.041). We also found that the distribution of the BAFF Ins/Del genotypes was significantly correlated with circulating sBAFF levels in SZ and BD patients (p = 0.0004). Elevated sBAFF levels were also correlated with increased levels of pro-inflammatory markers in both SZ and BD cohorts (p < 0.001). Regarding infectious stigma, only patients seropositive, versus seronegative, for herpes simplex virus (HSV)1 immunoglobulin (Ig)G antibodies exhibited a significant association with high sBAFF levels (p = 0.013). In contrast, positivity for systemic or CNS autoantibodies was significantly associated with reduced sBAFF levels, compared to patients without autoantibodies (p = 0.0017). Overall, our findings indicate that BAFF may be a promising trans -nosographic biomarker of inflammation that is likely to offer predictive, diagnostic, and prognostic tools for the management of SZ and BD. The results therefore have practicable clinical utility given the availability of immunotherapeutic treatment options including targeted monoclonal antibodies against BAFF. [ABSTRACT FROM AUTHOR]

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.

Clinical evidence points to a function for B cell-activating factor (BAFF) in pregnancy. However, direct roles for BAFF-axis members in pregnancy have not been examined. Here, via utility of genetically modified mice, we report that BAFF promotes inflammatory responsiveness and increases susceptibility to inflammation-induced preterm birth (PTB). In contrast, we show that the closely related A proliferation-inducing ligand (APRIL) decreases inflammatory responsiveness and susceptibility to PTB. Known BAFF-axis receptors serve a redundant function in signaling BAFF/APRIL presence in pregnancy. Treatment with anti-BAFF/APRIL monoclonal antibodies or BAFF/APRIL recombinant proteins is sufficient to manipulate susceptibility to PTB. Notably, macrophages at the maternal-fetal interface produce BAFF, while BAFF and APRIL presence divergently shape macrophage gene expression and inflammatory function. Overall, our findings demonstrate that BAFF and APRIL play divergent inflammatory roles in pregnancy and provide therapeutic targets for mitigating risk of inflammation-induced PTB.

Background: Refractory generalized myasthenia gravis (GMG) remains a substantial therapeutic challenge. Telitacicept, a recombinant human B-lymphocyte stimulator receptor-antibody fusion protein, holds promise for interrupting the immunopathology of this condition. Objectives: This study retrospectively assessed the effectiveness and safety of telitacicept in patients with refractory GMG. Design: A single-center retrospective study. Methods: Patients with refractory GMG receiving telitacicept (160 mg/week or biweekly) from January to September in 2023 were included. We assessed effectiveness using Myasthenia Gravis Foundation of America post-intervention status (MGFA-PIS), myasthenia gravis treatment status and intensity (MGSTI), quantitative myasthenia gravis (QMG), and MG-activity of daily living (ADL) scores, alongside reductions in prednisone dosage at 3- and 6-month intervals. Safety profiles were also evaluated. Results: Sixteen patients with MGFA class II–V refractory GMG were included, with eight females and eight males. All patients were followed up for at least 3 months, and 11 patients reached 6 months follow-up. At the 3-month evaluation, 75% (12/16) demonstrated clinical improvement with MGFA-PIS. One patient achieved pharmacological remission, two attained minimal manifestation status, and nine showed functional improvement; three remained unchanged, and one deteriorated. By the 6-month visit, 90.1% (10/11) sustained significant symptomatic improvement. MGSTI scores and prednisone dosages significantly reduced at both follow-ups (p < 0.05). MG-ADL and QMG scores showed marked improvement at 6 months (p < 0.05). The treatment was well tolerated, with no severe adverse events such as allergy or infection reported. Conclusion: Our exploratory investigation suggests that telitacicept is a feasible and well-tolerated add-on therapy for refractory GMG, offering valuable clinical evidence for this novel treatment option. [ABSTRACT FROM AUTHOR]

Copyright of Chinese Journal of Contemporary Pediatrics is the property of Xiangya Medical Periodical Press and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

BackgroundAlterations in the gut microbiome have been associated with HIV infection, but the relative impact of HIV versus other factors on the gut microbiome has been difficult to determine in cross-sectional studies.MethodsTo address this, we examined the gut microbiome, serum metabolome, and cytokines longitudinally within 27 individuals before and during acute HIV using samples collected from several ongoing cohort studies. Matched control participants (n=28) from the same cohort studies without HIV but at similar behavioral risk were used for comparison.FindingsWe identified few changes in the microbiome during acute HIV infection, but did find alterations in serum metabolites involving secondary bile acid (lithocholate sulfate, glycocholenate sulfate) and amino acid metabolism (3-methyl-2-oxovalerate, serine, cysteine, N-acetylputrescine). Greater microbiome differences, including decreased Bacteroides spp and increased Megasphaera elsdenii, were seen when comparing pre-HIV infection visits to matched at-risk controls. Those who acquired HIV also had elevated inflammatory cytokines (TNF-α, B cell activating factor, IL-8) and bioactive lipids (palmitoyl-sphingosine-phosphoethanolamide and glycerophosphoinositol) prior to HIV acquisition compared to matched controls.InterpretationLongitudinal sampling identified pre-existing microbiome differences in participants with acute HIV compared to matched control participants observed over the same period. These data highlight the importance of increasing understanding of the role of the microbiome in HIV susceptibility.FundingThis work was supported by NIH/NIAID (K08AI124979; P30AI117943), NIH/NIDA (U01DA036267; U01DA036939; U01DA036926; U24DA044554), and NIH/NIMH (P30MH058107; R34MH105272).

Objective: B‐cell activating factor (BAFF) is a key regulator of primary Sjögren's syndrome (pSS), which is characterized by B‐lymphocyte hyperactivity. BAFF, also known as tumor necrosis factor ligand superfamily member 13B, is encoded by TNFSF13B. This study aimed to explore the possible relationships between five single‐nucleotide polymorphisms (SNPs) of TNFSF13B (rs9514827, rs1041569, rs9514828, rs1224141, and rs12583006) and pSS susceptibility. Methods: We searched the following databases for articles on TNFSF13B polymorphism and pSS published up to January 2023: PubMed, Cochrane, Elsevier, Web of Science, CNKI, CQVIP, and WanFang. The odds ratios (with 95% confidence intervals) of genotypes and SNP alleles of TNFSF13B were investigated in patients with pSS to determine their relationships with pSS. Results: This meta‐analysis employing the fixed‐effect model comprised three studies of pSS patients and randomly selected healthy controls (HCs), revealing statistically significant relationships between pSS susceptibility and two SNPs: rs1041569 and rs12583006. Because rs1041569 was not in Hardy‐Weinberg equilibrium in the HC group, it was eliminated from the analysis. Conclusions: Polymorphisms in the BAFF (TNFSF13B) gene were related to vulnerability to pSS among pSS patients and HCs alike. The SNP rs12583006 was significantly related to pSS susceptibility in pSS patients. [ABSTRACT FROM AUTHOR]

As a member of the tumor necrosis factor (TNF) superfamily, the B-cell activating factor (BAFF) plays a crucial role in B-cell survival and differentiation. Overexpression of this protein has been closely linked to autoimmune disorders and some B-cell malignancies. Using monoclonal antibodies (mAbs) against the BAFF soluble domain appears to be a complementary treatment for some of these diseases. This study aimed to produce and develop a specific Nanobody (Nb), a variable camelid antibody domain, against the soluble domain of BAFF protein. After camel immunization with recombinant protein and preparing cDNA from total RNAs separated from camel lymphocytes, an Nb library was developed. Individual colonies capable of binding selectively to rBAFF were obtained by periplasmic-ELISA, sequenced, and expressed in a bacterial expression system. The specificity and affinity of selected Nb were determined and its target identification and functionality were evaluated using flow cytometry. [ABSTRACT FROM AUTHOR]

Abstract Objective B‐cell activating factor (BAFF) is a key regulator of primary Sjögren's syndrome (pSS), which is characterized by B‐lymphocyte hyperactivity. BAFF, also known as tumor necrosis factor ligand superfamily member 13B, is encoded by TNFSF13B. This study aimed to explore the possible relationships between five single‐nucleotide polymorphisms (SNPs) of TNFSF13B (rs9514827, rs1041569, rs9514828, rs1224141, and rs12583006) and pSS susceptibility. Methods We searched the following databases for articles on TNFSF13B polymorphism and pSS published up to January 2023: PubMed, Cochrane, Elsevier, Web of Science, CNKI, CQVIP, and WanFang. The odds ratios (with 95% confidence intervals) of genotypes and SNP alleles of TNFSF13B were investigated in patients with pSS to determine their relationships with pSS. Results This meta‐analysis employing the fixed‐effect model comprised three studies of pSS patients and randomly selected healthy controls (HCs), revealing statistically significant relationships between pSS susceptibility and two SNPs: rs1041569 and rs12583006. Because rs1041569 was not in Hardy‐Weinberg equilibrium in the HC group, it was eliminated from the analysis. Conclusions Polymorphisms in the BAFF (TNFSF13B) gene were related to vulnerability to pSS among pSS patients and HCs alike. The SNP rs12583006 was significantly related to pSS susceptibility in pSS patients.

Background Immune thrombocytopenic purpura (ITP) is a hematological autoimmune bleeding disorder that characterized by isolated thrombocytopenia (platelet count <100 × 109/L) with unclear pathophysiology due to contribution of many cytokines, one of them is B-cell activating factor (BAFF) which affect both B-cell and T-cell activation and survival. Objectives This work aimed to study serum BAFF levels in the Egyptian ITP patients, and the relation between its level and response to steroid therapy, as well its value as a predictive marker for steroid response in ITP patients. Patients and methods 90 subjects were recruited, and divided into 45 patients with primary ITP, and 45 healthy subjects. Serum BAFF was estimated using the ELISA technique. Results BAFF level was significantly higher in the ITP patients than in the control group. Serum BAFF level was significantly higher in newly diagnosed ITP cases and steroids-resistant ITP cases. BAFF was negatively correlated with platelet count, while MPV, PDW, and LDH were positively correlated, BAFF level at a cut-off 201.01 pg/ml is a good predictive for steroid resistance in ITP cases. Conclusion BAFF could be a good inexpensive helper to determine the response to steroid treatment in ITP cases. [ABSTRACT FROM AUTHOR]

Progression of chronic lymphocytic leukemia (CLL) and resistance to therapy are affected by tumor microenvironmental factors. One such factor is B-cell activating factor (BAFF), a cytokine that is produced mainly by nurse-like cells (NLC) and enhances CLL cells survival and modulates response to therapy. In CLL cells, BAFF activates NF-κB signaling, but how NF-κB supports CLL survival is not entirely clear. In this study we show that BAFF induces accumulation of the signaling and autophagy adaptor p62/SQSTM1 in a manner dependent on NF-κB activation. p62 potentiates mTORC1 signaling and activates NRF2, the master regulator of the anti-oxidant response. We found that expression of NRF2 target genes, such as NAD(P)H quinone oxidoreductase 1 (NQO1), is particularly enriched in CLL cells with high ROR1 surface expression (ROR1Hi). ROR1Hi CLL cells with elevated NQO1 expression exhibit resistance to drugs that induce ROS accumulation, such venetoclax. However, such cells are more sensitive to compound 29h, a pro-drug that only becomes active after being metabolized by NQO1. Accordingly, 29h sensitizes high NQO1 CLL cells to venetoclax. Collectively, our study unravels a previously unknown signaling network through which the NF-κB-p62-NRF2 axis protects ROR1-high CLL cells from ROS-inducing therapeutics.

Background: India ranks first in the global share of tuberculosis (TB). Active TB is also associated with elevated levels of B-Cell growth factors like B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL). We aimed to study the circulating levels of ferritin, high-sensitivity C-reactive protein (hsCRP), BAFF, and APRIL in sputum-positive and sputum-negative active pulmonary TB (PTB) patients. Materials and Methods: We enrolled 90 sputum positive and 90 sputum-negative newly diagnosed PTB patients. All the patients underwent estimation of serum ferritin, hsCRP, BAFF, and APRIL before initiation of f Anti-Tubercular therapy (ATT), after 1 month of ATT, and after 2 months of ATT. We compared the change in the cytokines mentioned above in PTB subjects at baseline, after 01 and 02 months of the intensive phase of standard anti-tubercular therapy. Results: There was a significant difference between the serum BAFF levels at all times between the sputum-positive and sputum-negative groups (P < 0.001). There was a considerable increase in the APRIL level 2 months after initiation of ATT in both the groups (sputum positive group P = 0.004) (sputum negative group P < 0.001). There was a significant decrease in serum ferritin level and hsCRP after 2 months of ATT compared to baseline (P < 0.001) in both sputum positive and negative groups. Conclusion: Serum ferritin, hsCRP, and APRIL levels can be used to assess the treatment response in both sputum-positive and sputum-negative cases. Serum BAFF levels >587 pg/ml at baseline implies high probability of sputum smear positivity in a patient with PTB.

To explore the correlations of B cell-activating factor (BAFF), aquaporin-4 antibody (AQP4-Ab) and brain-derived neurotrophic factor (BDNF) with the severity of neuromyelitis optica spectrum disorder (NMOSD).

ObjectiveHIV-infected (HIV+) individuals may be at increased risk for sudden arrhythmic cardiac death. Some studies have reported an association between HIV infection and prolongation of the electrocardiographic QT interval, a measure of ventricular repolarisation, which could potentiate ventricular arrhythmias. We aimed to assess whether HIV+ men have longer QT intervals than HIV-uninfected (HIV-) men and to determine factors associated with QT duration.MethodsWe performed resting 12-lead ECGs in 774 HIV+ and 652 HIV- men in the Multicenter AIDS Cohort Study (MACS). We used multivariable linear and logistic regression analyses to assess associations between HIV serostatus and Framingham corrected QT interval (QTc), after accounting for potential confounders. We also determined associations among QTc interval and HIV-related factors in HIV+ men. In a subgroup of participants, levels of serum markers of inflammation were also assessed.ResultsAfter adjusting for demographics and risk factors, QTc was 4.0 ms longer in HIV+ than HIV- men (p

To understand how the interaction between an intracellular bacterium and the host immune system contributes to outcome at the site of infection, we studied leprosy, a disease that forms a clinical spectrum, in which progressive infection by the intracellular bacterium Mycobacterium leprae is characterized by the production of type I IFNs and antibody production. Dual RNA-seq on patient lesions identifies two independent molecular measures of M. leprae, each of which correlates with distinct aspects of the host immune response. The fraction of bacterial transcripts, reflecting bacterial burden, correlates with a host type I IFN gene signature, known to inhibit antimicrobial responses. Second, the bacterial mRNA:rRNA ratio, reflecting bacterial viability, links bacterial heat shock proteins with the BAFF-BCMA host antibody response pathway. Our findings provide a platform for the interrogation of host and pathogen transcriptomes at the site of infection, allowing insight into mechanisms of inflammation in human disease.

Humans always mount a robust immune response to the bacterial infection caused by Helicobacter pylori, which causes various gastrointestinal tract infections. Calprotectin (CALP) and B-Cell Activating Factor (BAFF) are inflammatory biomarkers having a role in the gastrointestinal neutrophilic response to bacterial infection. The study was designed to assess serum CALP and BAFF as inflammatory biomarkers in H. pylori infection and peptic ulcer patients. The current study comprised 112 people, including 62 H. pylori-infected patients (34 men and 28 women) who were clinically diagnosed with H. pylori infection via testing positive for the H. pylori stool antigen test; they were compared to a control group of 50 healthy people (34 men and 16 women) who were age and gender-matched to H. pylori-infected patients. The serum level of CALP and BAFF were assayed using the ELISA technique. The biochemical parameters were statistically compared between patients and controls by unpaired Man-Whitney U t-test and Receiver Operating Characteristic (ROC) curve analysis. There was a significant elevation of serum CALP in H. pylori-infected patients [116.4(120.7), p=0.0132] in comparison to healthy controls [99.50(115.8)]. Similarly, there was a significant elevation of serum BAFF concentration in H. pylori-infected patients [485.7(367.1), p=0.0014] in comparison to healthy controls [444.5(513.0)]. The ROC curve analysis suggests serum CALP and BAFF as reasonable inflammatory biomarkers for H. pylori infection with statistically significant (p=0.0135, p=0.0015) area under the ROC curve of (0.6361, 0.6748), respectively. CALP and BAFF are potent inflammatory biomarkers involved in the development and etiology of H. pylori infection. Serum CALP and BAFF levels could be used as biomarkers for chronic inflammation induced by H. pylori. CALP and BAFF biomarkers can be combined to diagnose and predict the prognosis of H. pylori infection.

Humans always mount a robust immune response to the bacterial infection caused by Helicobacter pylori, which causes various gastrointestinal tract infections. Calprotectin (CALP) and B-Cell Activating Factor (BAFF) are inflammatory biomarkers having a role in the gastrointestinal neutrophilic response to bacterial infection. The study was designed to assess serum CALP and BAFF as inflammatory biomarkers in H. pylori infection and peptic ulcer patients. The current study comprised 112 people, including 62 H. pylori-infected patients (34 men and 28 women) who were clinically diagnosed with H. pylori infection via testing positive for the H. pylori stool antigen test; they were compared to a control group of 50 healthy people (34 men and 16 women) who were age and gender- matched to H. pylori-infected patients. The serum level of CALP and BAFF were assayed using the ELISA technique. The biochemical parameters were statistically compared between patients and controls by unpaired Man-Whitney U t-test and Receiver Operating Characteristic (ROC) curve analysis. There was a significant elevation of serum CALP in H. pylori-infected patients [116.4(120.7), p=0.0132] in comparison to healthy controls [99.50(115.8)]. Similarly, there was a significant elevation of serum BAFF concentration in H. pylori-infected patients [485.7(367.1), p=0.0014] in comparison to healthy controls [444.5(513.0)]. The ROC curve analysis suggests serum CALP and BAFF as reasonable inflammatory biomarkers for H. pylori infection with statistically significant (p=0.0135, p=0.0015) area under the ROC curve of (0.6361, 0.6748), respectively. CALP and BAFF are potent inflammatory biomarkers involved in the development and etiology of H. pylori infection. Serum CALP and BAFF levels could be used as biomarkers for chronic inflammation induced by H. pylori. CALP and BAFF biomarkers can be combined to diagnose and predict the prognosis of H. pylori infection. [ABSTRACT FROM AUTHOR]

B-cell-activating factor (BAFF) is a crucial cytokine supporting survival and differentiation of B cells. Dysregulation of BAFF is involved in the pathogenesis of B-cell related autoimmune diseases including immune thrombocytopenia (ITP). The aim of this study was to evaluate the significance of BAFF expression in pediatric ITP patients. Eighty pediatric patients with ITP are subdivided in three groups. Group I included (32 patients) diagnosed with acute ITP less than 3 months, group II (48 patients) diagnosed with persistent ITP (from 3 to 12 months) and chronic ITP (more than 12 months) and group III 20 healthy controls. Complete blood picture, autoimmune profile, antiplatelet antibodies, coagulation profile, bone marrow examination, and RT-PCR were performed to detect the expression for BAF for all participants in this study. BAFF expression levels significantly increased in cases rather than in controls. BAFF Expression Value significantly increased in groups I & II (3.10 ± 1.99&3.29 ± 2.58) compared to controls (0.83 ± 0.45) as p <.001 for both. On the other hand, groups I & II were comparable in BAFF Expression Value (p =.470). BAFF expression increased in ITP patients, implying a function in the disease's pathogenesis. [ABSTRACT FROM AUTHOR]

Abstract Background and Aim Functional gastrointestinal disorders (FGIDs) and chronic fatigue syndrome (CFS) frequently occur as comorbid conditions to each other. A shared etiology of these syndromes has been proposed because of their shared symptomatology and triggering by infections. Antibodies against the bacterial antigens cytolethal distending toxin B (CdtB) and flagellin have been proposed to be biomarkers of irritable bowel syndrome (IBS), especially diarrhea‐predominant IBS (IBS‐D). It is unknown if they may also be associated with comorbid conditions such as CFS. On the other hand, elevated level of B‐cell activating factor (BAFF) has been associated with CFS and inflammatory bowel disease (IBD) and subjective food intolerance. Methods We evaluated serum levels of anti‐flagellin and anti‐CdtB using an in‐house enzyme‐linked immunosorbent assay (ELISA) and BAFF with a commercially available ELISA kit in a cohort of patients who developed fatigue syndromes and/or FGIDs after Giardia infection, by comparing them with healthy controls without these conditions. Results We did not find significant differences in circulating BAFF, anti‐CdtB, or anti‐flagellin antibody levels in these patient groups compared to healthy controls. Therefore, our results do not support a role for BAFF, anti‐CdtB, or anti‐flagellin antibodies as universal biomarkers for IBS or CFS. Conclusion BAFF, anti‐CdtB, or anti‐flagellin antibodies cannot be considered as universal biomarkers for IBS or CFS.

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

ObjectiveTo investigate the role of serum B-cell activating factor (BAFF) and lung ultrasound (LUS) B-lines in connective tissue disease related interstitial lung disease (CTD-ILD), and their association with different ILD patterns on high resolution computed tomography (HRCT) of chest.MethodsWe measured the levels of BAFF and KL-6 by ELISA in the sera of 63 CTD-ILD patients [26 with fibrotic ILD (F-ILD), 37 with non-fibrotic ILD (NF-ILD)], 30 CTD patients without ILD, and 26 healthy controls. All patients underwent chest HRCT and LUS examination.ResultsSerum BAFF levels were significantly higher in CTD patients compared to healthy subjects (617.6 ± 288.1 pg/ml vs. 269.0 ± 60.4 pg/ml, p < 0.01). BAFF concentrations were significantly different between ILD group and non-ILD group (698.3 ± 627.4 pg/ml vs. 448.3 ± 188.6 pg/ml, p < 0.01). In patients with ILD, BAFF concentrations were significantly correlated with B-lines number (r = 0.37, 95% CI 0.13–0.56, p < 0.01), KL-6 level (r = 0.26, 95% CI 0.01–0.48, p < 0.05), and Warrick score (r = 0.33, 95% CI 0.09–0.53, p < 0.01), although all correlations were only low to moderate. B-lines number correlated with Warrick score (r = 0.65, 95% CI 0.48–0.78, p < 0.01), and KL-6 levels (r = 0.43, 95% CI 0.21–0.61, p < 0.01). Patients with F-ILD had higher serum BAFF concentrations (957.5 ± 811.0 pg/ml vs. 516.1 ± 357.5 pg/ml, p < 0.05), KL-6 levels (750.7 ± 759.0 U/ml vs. 432.5 ± 277.5 U/ml, p < 0.05), B-lines numbers (174.1 ± 82 vs. 52.3 ± 57.5, p < 0.01), and Warrick score (19.9 ± 4.6 vs. 13.6 ± 3.4, p < 0.01) vs. NF-ILD patients. The best cut-off values to separate F-ILD from NF-ILD using ROC curves were 408 pg/ml for BAFF (AUC = 0.73, p < 0.01), 367 U/ml for KL-6 (AUC = 0.72, p < 0.05), 122 for B-lines number (AUC = 0.89, p < 0.01), and 14 for Warrick score (AUC = 0.87, p < 0.01) respectively.ConclusionSerum BAFF levels and LUS B-lines number could be useful supportive biomarkers for detecting and evaluating the severity and/or subsets of CTD-ILD. If corroborated, combining imaging, serological, and sonographic biomarkers might be beneficial and comprehensive in management of CTD-ILD.

Copyright of Rheuma Plus is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Cryoglobulinemic Vasculitis (CV) is an autoimmune/lymphoproliferative disorder associated with HCV infection that in 5%–10% of cases evolves into a B cell Non‐Hodgkin's Lymphoma (NHL). B‐cell activating factor (BAFF) is a key regulator in B‐cell development and survival. Particular genetic variants are responsible for BAFF signaling impairment in autoimmune and neoplastic diseases. We evaluated BAFF and BAFF‐receptor (BAFF‐R) polymorphisms in order to determine if they predispose to HCV‐related CV and NHL. The analysis was performed on 416 HCV‐chronically infected patients: 136 HCV without signs/symptoms of lymphoproliferations/autoimmunity (HCV), 166 HCV with CV (HCV‐CV) and 114 HCV with NHL (HCV‐NHL). Rs9514828 SNP on BAFF promoter, rs61756766 on BAFF‐R and rs12428930 on the BAFF gene were evaluated by Real‐Time PCR. Concerning rs9514828, the frequency of C/T genotype was significantly higher in HCV‐CV than in HCV. The difference in the distribution of the T/T mutant genotype in HCV‐CV compared to HCV was significant as well as the distribution of C/T and T/T genotype in HCV‐NHL versus HCV. T minor allele was more frequent in HCV‐NHL and HCV‐CV than in HCV. The distribution of C/T + T/T (for the dominant model of penetrance C/T + T/T vs. C/C) was significantly higher in HCV‐CV and HCV‐NHL than in HCV. Genotyping of rs61756766 on BAFF‐R coding gene, revealed C/T heterozygosis at a frequency of 11% in HCV‐NHL versus 3% in HCV. The T minor allele frequency was higher in HCV‐NHL than in HCV. No differences emerged by genotyping rs12428930 SNP on BAFF coding gene. Our results reinforce the hypothesis that BAFF/BAFF‐R genetic pattern has a role in the pathogenesis of HCV‐related lymphoproliferations. BAFF/BAFF‐R variants could identify a risk haplotype for HCV related CV and NHL and a BAFF/BAFF‐R genetic profile assessment could potentially contribute to tailoring anti‐BAFF therapy by identifying patients with BAFF alterations in which the treatment could be more beneficial. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the association between vascular inflammation, as detected by positron emission tomography (PET) imaging and interleukin-6 (IL-6), pentraxin3, and B-cell-activating factor (BAFF) in subjects with LVV. Methods: The study included newly diagnosed giant cell arteritis (GCA, n=27) or Takayasu arteritis (n=9) patients and healthy control (HC, n=31) subjects. PET scan and blood samples were obtained before the introduction of treatments. IL-6, PTX3, and BAFF levels were determined quantitatively by enzyme-linked immunosorbent assay kits. Results: Thirty-six patients with LVV (20 females, 16 males; age 64.5±16.6 years) and 31 HC (14 females, 17 males; age 37.1±9.6 years) were included. Serum levels of IL-6, PTX3, and BAFF were increased in patients with newly diagnosed LVV compared with healthy control subjects. In receiver operating characteristics (ROC) analysis, serum IL-6 and BAFF provided excellent discrimination of newly diagnosed LVV patients from HC (area under the ROC curve of >0.90 and >0.80, respectively). None of the inflammatory markers correlated with vascular inflammatory activity determined by PET scanning. Conclusions: Our results suggest that IL-6 and BAFF may serve as markers of large vessel vasculitis, while PTX3 is not useful. None of the inflammatory markers correlated with PET assessed vasculitis activity. [ABSTRACT FROM AUTHOR]

Introduction: Interferon (IFN)-β is known as an environmental trigger for the occurrence of autoimmune thyroid disease (AITD). However, the association of another type-1 IFN, IFN-β, with AITD is unknown.Material and methods: In the study, we explored the association of serum IFN-β levels with AITD in an ethnic Chinese (i.e., Taiwanese) population. We enrolled 160 patients with Graves' disease (GD), 47 patients with Hashimoto's thyroiditis (HT), and 119 healthy controls. Serum IFN-β and B-cell activating factor (BAFF) levels were quantified in healthy controls at the baseline and in patients with AITD either prior to receiving medication or while under medication. Thyroid function and thyroid-stimulating hormone receptor antibody (TSHRAb) levels were measured at the time of serum collection.Results: Serum IFN-β levels were lower in the HT group than in the control group (p = 0.031). A significant inverse correlation was observed between IFN-β and TSHRAb levels in men with GD (r = -0.433, p = 0.044). Serum IFN-β levels were also negatively associated with BAFF levels in men with GD, HT, and AITD (r = -0.320, p = 0.032; r = -0.817, p = 0.047; and r = -0.354, p = 0.011, respectively), but not in women with GD, HT, or AITD.Conclusions: Serum IFN-β levels were lower in HT patients. Correlations of serum IFN-β with TSHRAb and BAFF levels were found to be gender-specific. Further well-designed studies with larger sample sizes are required to confirm our findings. [ABSTRACT FROM AUTHOR]

The study examined changes in the plasma proteome, metabolome, and lipidome of N = 14 patients with relapsing-remitting multiple sclerosis (RRMS) initiating treatment with ocrelizumab, assayed at baseline, 6 months, and 12 months. Analyses of >4000 circulating biomarkers identified depletion of B-cell associated proteins as the early effect observed following ocrelizumab (OCR) initiation, accompanied by the reduction in plasma abundance of cytokines and cytotoxic proteins, markers of neuronaxonal damage, and biologically active lipids including ceramides and lysophospholipids, at 6 months. B-cell depletion was accompanied by decreases in B-cell receptor and cytokine signaling but a pronounced increase in circulating plasma B-cell activating factor (BAFF). This was followed by an upregulation of a number of signaling and metabolic pathways at 12 months. Patients with higher baseline brain MRI lesion load demonstrated both higher levels of cytotoxic and structural proteins in plasma at baseline and more pronounced biomarker change trajectories over time. Digital cytometry identified a putative increase in myeloid cells and a pro-inflammatory subset of T-cells. Therapeutic effects of ocrelizumab extend beyond CD20-mediated B-cell lysis and implicate metabolic reprogramming, juxtaposing the early normalization of immune activation, cytokine signaling and metabolite and lipid turnover in periphery with changes in the dynamics of immune cell activation or composition. We identify BAFF increase following CD20 depletion as a tentative compensatory mechanism that contributes to the reconstitution of targeted B-cells, necessitating further research., (Copyright © 2024 Elsevier B.V. All rights reserved.)

B-cell activating factor belonging to the TNF family (BAFF), also known as B-lymphocyte stimulator (BLyS), plays a crucial role in B-cell development. It has multiple receptors, including BCMA, TACI, and BAFF-R, with diverse roles in different cell types. BAFF induces B-cell proliferation and immunoglobulin secretion, and acts as a survival factor for immature, naive, and activated B cells. Consequently, BAFF-deficient mice often show suppressed humoral responses, while BAFF-overexpressing mice show the higher number of mature B cells and may develop autoimmune-like manifestations and B-cell lymphoproliferative diseases. Elevated BAFF levels are also associated with various hematological malignancies, and its expression correlates with disease progression in some cases. Therefore, BAFF-targeted therapies, such as belimumab, atacicept, and tabalumab, are being explored in clinical trials for conditions like chronic lymphocytic leukemia (CLL) and multiple myeloma. Belimumab, an anti-BAFF monoclonal antibody, is being investigated in combination with rituximab/venetoclax for CLL. Atacicept, a decoy receptor for BAFF and APRIL, showed tolerability in a phase 1b trial for CLL. Tabalumab, another monoclonal antibody targeting BAFF, did not demonstrate significant efficacy in a phase 2 study for relapsed/refractory multiple myeloma. BAFF ligand-based CAR-T cells are designed to target BAFF receptors and show promise in preclinical studies, particularly for B-cell malignancies. The review emphasizes the importance of understanding the roles of BAFF and its receptors in the microenvironment of hematologic malignancies. Targeting BAFF and its receptors presents potential therapeutic avenues, and ongoing clinical trials provide valuable insights., (© 2024. The Author(s).)

Abstract Introduction The low frequency of ectopic germinal center in labial salivary glands of patients with human T‐cell leukemia virus type 1 (HTLV‐1) antibody‐positive Sjögren's syndrome (SS) suggests that HTLV‐1 has some effects on follicular dendritic cells (FDCs). Methods We used flow cytometry, immunofluorescence, and enzyme‐linked immunosorbent assays (ELISAs) to investigate the direct effect of HTLV‐1 on B‐cell activating factors produced by established FDC like cells obtained from excised human tonsils. We then measured the serum B‐cell activating factor (BAFF) and C‐X‐C motif ligand (CXCL) 13 concentrations of the HTLV‐1‐seropositive SS patients and the HTLV‐1‐seronegative SS patients by ELISA. Results Among the 31 isolated specimens, 22 showed morphological characteristics of FDCs. Day 2‐cultured specimens showed expressions of CD14, CD23, CD40, intracellular adhesion molecule‐1 (ICAM‐1), and vascular cell adhesion molecule‐1. After 2 weeks, 12 of these specimens expressed ICAM‐1, FDC, and fibroblast cell marker. Intracellular BAFF and CXCL13 were constitutively expressed regardless of stimulation. After direct coculture with the HTLV‐1‐infected T‐cell line HCT‐5 or MT‐2, the BAFF and CXCL13 expressions on the FDC‐like cells were decreased in accord with the increased number of HCT‐5 and MT‐2 cells with styliform change and without HTLV‐1 Gag protein expression. Interferons upregulated the concentration of BAFF (but not CXCL13) in the culture supernatant, which showed a declining trend under the presence of HCT‐5 or MT‐2. The serum concentrations of BAFF and CXCL13 in the HTLV‐1‐seropositive SS patients were lower than those of the HTLV‐1 seronegative SS patients. Conclusions HTLV‐1 partially inhibited the BAFF and CXCL13 expressions of established FDC‐like cells.

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. [ABSTRACT FROM AUTHOR]

ObjectiveTo assess the relationship between treatment response, baseline biomarker levels, and atacicept exposure in patients with systemic lupus erythematosus (SLE) in the phase II/III APRIL-SLE study.MethodsWe performed a post hoc analysis of patients who received placebo, atacicept 75 mg, or atacicept 150 mg in a randomized, controlled, 52-week trial. Serum levels of BlyS and APRIL were measured at baseline, and serum levels of Ig and the numbers of naive B cells and plasma cells were measured at baseline and during treatment. Atacicept exposure was determined by assessment of the serum trough concentrations throughout the 52-week trial period. Associations between these parameters, treatment response (reduction in British Isles Lupus Assessment Group A or B flare), and infection rates were explored.ResultsRecurrent high baseline levels of both BLyS (≥1.6 ng/ml) and APRIL (≥2.2 ng/ml) correlated with a greater treatment response (flare rate 75.7% with placebo, and 50.0% and 32.0% with atacicept 75 mg and atacicept 150 mg, respectively) compared with lower baseline levels of both. Increased atacicept exposure correlated with reduced flare rates (60.5% with placebo; 63.4%, 61.0%, 48.8%, and 29.3% in the 4 quartiles, from lowest to highest atacicept exposure). Greater pharmacodynamic responses (reduced Ig levels and naive B cell and plasma cell numbers) were associated with greater reductions in the flare rate. Infection rates were similar regardless of biomarker levels at baseline or at the time of atacicept exposure.ConclusionThese post hoc analyses demonstrate a dose-response relationship between atacicept concentrations, reduced Ig levels, and reduced flare rates and suggest that baseline biomarkers such as elevated serum levels of BLyS and APRIL may help to identify the patients who are most likely to benefit from atacicept treatment.

Obesity (OB) is a major healthcare problem that results from long-term energy imbalance. Adipokines and pro-inflammatory cytokines facilitate adipose tissue (AT) remodeling to safely store excess nutrients. B-cell activating factor (BAFF) is a newly described adipokine whose role in enhancing adipogenesis has been reported. The present study aimed to evaluate serum BAFF association with adiposity distribution, serum adipokines, pro-inflammatory cytokines, and metabolic and endothelial dysfunction markers. The study included 124 young Mexican adults with no diagnosed comorbidities, divided according to their BMI. Anthropometric measurements, blood counts, and serum molecules (i.e., glucose, lipid profile, insulin, leptin, pro- and anti-inflammatory cytokines, von Willebrand factor (vWF), and BAFF) were assessed. The analysis showed positive correlation between BAFF and increased fat mass in all anthropometric measurements (p < 0.0001). BAFF augmentation was related to systemic inflammatory environment (p < 0.05), and linked with insulin resistance status (p < 0.05). BAFF increment was also correlated with early endothelial damage markers such as vWF (p < 0.0001). Linear regression analysis showed a role for BAFF in predicting serum vWF concentrations (p < 0.01). In conclusion, our data show that BAFF is an adipokine dynamically related to OB progression, insulin resistance status, and systemic inflammatory environment, and is a predictor of soluble vWF augmentation, in young overweight and obese Mexican subjects. [ABSTRACT FROM AUTHOR]

Objectives: We aim to investigate the association between serum B-cell activating factor (BAFF) and A proliferation-inducing ligand (APRIL) levels with disease activity and clinical findings in SLE patients. Methods: Seventy-nine patients with SLE and 27 healthy controls were included into the study. Serum BAFF and APRIL levels were measured by using ELISA. In 19 patients with active disease at the time of the assessment, BAFF/APRIL levels were reassessed after 6 months of follow-up and disease activity was evaluated by using SLEDAI-2K. The relationship between renal histopathology index scores and lupus nephritis (LN) classes with serum BAFF/APRIL levels was examined in 16 patients who had recent renal involvement and underwent biopsy during the study. Results: Although both BAFF/APRIL levels were higher in patients with SLE compared to the control group (p < 0.001), no correlation was found between BAFF/APRIL levels and SLEDAI scores. Serum BAFF levels were higher in patients with renal disease activity (p = 0.01), and there was a significant correlation between APRIL levels and proteinuria (r = 0.42, p = 0.02). A weak inverse correlation was observed between BAFF and C3 levels (r = 0.25, p = 0.02). No correlation was found between BAFF/APRIL levels and renal SLEDAI scores, renal histopathology, activity, and chronicity index scores. In the active disease group after treatment, there was no significant change in serum BAFF levels, but a significant increase in serum APRIL levels was observed. Conclusion: These results suggest that both cytokines are involved in the pathogenesis of SLE and that serum BAFF can be valuable as a biomarker in SLE especially in patients with renal activity. [ABSTRACT FROM AUTHOR]

Background and Aim: Functional gastrointestinal disorders (FGIDs) and chronic fatigue syndrome (CFS) frequently occur as comorbid conditions to each other. A shared etiology of these syndromes has been proposed because of their shared symptomatology and triggering by infections. Antibodies against the bacterial antigens cytolethal distending toxin B (CdtB) and flagellin have been proposed to be biomarkers of irritable bowel syndrome (IBS), especially diarrhea‐predominant IBS (IBS‐D). It is unknown if they may also be associated with comorbid conditions such as CFS. On the other hand, elevated level of B‐cell activating factor (BAFF) has been associated with CFS and inflammatory bowel disease (IBD) and subjective food intolerance. Methods: We evaluated serum levels of anti‐flagellin and anti‐CdtB using an in‐house enzyme‐linked immunosorbent assay (ELISA) and BAFF with a commercially available ELISA kit in a cohort of patients who developed fatigue syndromes and/or FGIDs after Giardia infection, by comparing them with healthy controls without these conditions. Results: We did not find significant differences in circulating BAFF, anti‐CdtB, or anti‐flagellin antibody levels in these patient groups compared to healthy controls. Therefore, our results do not support a role for BAFF, anti‐CdtB, or anti‐flagellin antibodies as universal biomarkers for IBS or CFS. Conclusion: BAFF, anti‐CdtB, or anti‐flagellin antibodies cannot be considered as universal biomarkers for IBS or CFS. [ABSTRACT FROM AUTHOR]

Introduction Interferon (IFN)-β is known as an environmental trigger for the occurrence of autoimmune thyroid disease (AITD). However, the association of another type-1 IFN, IFN-β, with AITD is unknown. Material and methods In the study, we explored the association of serum IFN-β levels with AITD in an ethnic Chinese (i.e., Taiwanese) population. We enrolled 160 patients with Graves’ disease (GD), 47 patients with Hashimoto’s thyroiditis (HT), and 119 healthy controls. Serum IFN-β and B-cell activating factor (BAFF) levels were quantified in healthy controls at the baseline and in patients with AITD either prior to receiving medication or while under medication. Thyroid function and thyroid-stimulating hormone receptor antibody (TSHRAb) levels were measured at the time of serum collection. Results Serum IFN-β levels were lower in the HT group than in the control group (p = 0.031). A significant inverse correlation was observed between IFN-β and TSHRAb levels in men with GD (r = –0.433, p = 0.044). Serum IFN-β levels were also negatively associated with BAFF levels in men with GD, HT, and AITD (r = –0.320, p = 0.032; r = –0.817, p = 0.047; and r = –0.354, p = 0.011, respectively), but not in women with GD, HT, or AITD. Conclusions Serum IFN-β levels were lower in HT patients. Correlations of serum IFN-β with TSHRAb and BAFF levels were found to be gender-specific. Further well-designed studies with larger sample sizes are required to confirm our findings.

Abstract Background Irritable Bowel Syndrome (IBS) is a widespread disease with variable symptoms that have an important impact on the quality of life. Despite the prevalence of IBS, its etiology and pathophysiology are still to be fully understood, but immune response is known to be involved. In this study, we investigated the variation of two specific cytokines, B-cell activating factor (BAFF) and platelet-activating factor (PAF), the levels of food-specific IgG and the symptom severity, using Irritable Bowel Syndrome—Symptom Severity Score (IBS-SSS), following a personalized and unrestricted-calorie diet. Methods We enrolled 30 subjects with diagnosis of IBS, according to Rome-IV criteria, whose inflammatory markers were measured at baseline and after 6 weeks of dietary intervention. The subjects were monitored in a general practice outpatient setting and nutritional advice was offered remotely via two telephone sessions with a nutritionist. Results BAFF and PAF values did not differ between baseline and end of study, both in compliant (C) and non-compliant (NC) subjects. IgG levels significantly decreased only in compliant subjects: 37.32 (23.24–93.67) IU/mL; 27.9 (7.56–93.96) IU/mL (p = 0.02) and in non-compliant went from 51.83 (13.17–113.1) IU/mL to 44.06 (4.96–255.4) IU/mL (p = 0.97, ns). IBS-SSS significantly decreased in both compliant subjects, from 245 (110–480) to 110 (0–140) (p

Targeted deletion of BAFF causes severe deficiency of splenic B cells. BAFF-R is commonly thought to signal to nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB)-inducing kinase dependent noncanonical NF-κB RelB. However, RelB-deficient mice have normal B-cell numbers. Recent studies showed that BAFF also signals to the canonical NF-κB pathway, and we found that both RelB and cRel are persistently activated, suggesting BAFF signaling coordinates both pathways to ensure robust B-cell development. Indeed, we report now that combined loss of these 2 NF-κB family members leads to impaired BAFF-mediated survival and development in vitro. Although single deletion of RelB and cRel was dispensable for normal B-cell development, double knockout mice displayed an early B-cell developmental blockade and decreased mature B cells. Despite disorganized splenic architecture in Relb(-/-)cRel(-/-) mice, generation of mixed-mouse chimeras established the developmental phenotype to be B-cell intrinsic. Together, our results indicate that BAFF signals coordinate both RelB and cRel activities to ensure survival during peripheral B-cell maturation.

Multiple sclerosis (MS) is the most common immune-mediated CNS disease, characterised by demyelination and progressive neurological disability. The B-cell activating factor BAFF has been described as one important factor in the pathophysiology of different autoimmune diseases. We measured BAFF levels in the serum and cerebrospinal fluid (CSF) in 50 consecutive patients with MS and 35 patients with infectious CNS disease (ID). 52 patients with other, non-inflammatory disorders (OND), served as controls. BAFF-serum levels in ID patients were higher than in patients diagnosed with MS (ID 0.55 ± 0.24 ng/ml, MS 0.43 ± 0.14 ng/ml, OND 0.45 ± 0.24 ng/ml; p = 0.09). Interestingly, MS patients had lower BAFF CSF levels compared to the controls and ID patients, and the CSF levels in the latter were elevated compared to those of the controls (MS 0.17 ± 0.11 ng/ml, OND 0.25 ± 0.14 ng/ml, ID 0.97 ± 0.78 ng/ml; p < 0.001). The ID patients' having higher absolute BAFF levels in the CSF than in the serum indicates that the increased BAFF CSF levels were caused by intrathecal synthesis rather than passive transfer via a disturbed blood-brain-barrier. The significantly decreased BAFF CSF levels in MS patients were a surprising result of our study. Although it has been reported that astrocytes in active MS lesions can express BAFF, the soluble form was not increased in the CSF of MS patients. It remains unclear whether the inflammatory features of active MS plaques are truly represented by the CSF compartment. [ABSTRACT FROM AUTHOR]

Cytokines and growth factors participate in immune responses, and the pathogenesis of autoimmune diseases. Herein, we simultaneously examined differential levels of 29 circulating factors to determine their associations in female patients with overt autoimmune thyroid disease (AITD). We enrolled 40 patients with Graves’ disease (GD), 20 patients with Hashimoto’s thyroiditis (HT), and 14 healthy controls. Twenty-nine circulating factors were simultaneously measured. GD patients with low thyroid-stimulating hormone at the time of sample collection were defined as having active GD. B-cell activating factor (BAFF) levels were associated with GD and HT (p = .001 and .001, respectively) and interferon (IFN)-α levels were higher in the HT group than in the control group (p = .021). Significant associations of serum BAFF and tumour necrosis factor (TNF)-α levels with free thyroxin (FT4) were present in HT (r = −0.498, p = .026, and r = 0.544, p = .013, respectively). Meanwhile, there were significant associations of FT4 with interleukin (IL)-4 and eotaxin levels in GD (r = 0.354, p = .025 and r = 0.384, p = .014, respectively). In active GD, serum BAFF and eotaxin level were correlated with FT4 levels (r = 0.465, p = .034, and r = 0.463, p = .035, respectively). In conclusion, BAFF is the best circulating indicator to identify GD and HT among all chosen 29 biomarkers, and it could be used to predict the disease severity in HT and active GD. Meanwhile, IFN-α could be another reliable parameter for recognising HT.

ABSTRACT There are large gaps in understanding the molecular machinery accounting for the association of hepatitis C virus (HCV) infection with autoimmunity. Mixed cryoglobulinemia (MC) is the most common HCV-associated extrahepatic manifestation, which is characterized by B-cell lymphoproliferation and autoantibody production. B-cell activating factor (BAFF) is a member of the tumor necrosis factor family and plays an important role in B-cell proliferation. We explored the roles of hepatocyte-derived exosomal microRNAs (exo-miRNAs) and BAFF in the extrahepatic diseases of HCV infection. The exo-miRNA profiles were explored using a next-generation sequencing approach, followed by quantitative reverse transcription-PCR validation. The Toll-like receptor 7 (TLR7) polymorphism were analyzed using quantitative PCR. The biological function of exo-miRNAs and TLR7 polymorphism in BAFF expression was evaluated by using immunoblotting and enzyme-linked immunosorbent assay. Significantly increased levels of BAFF, exosomes, and TLR7 were found in HCV patients, particularly in those with MC (P

Background: The long-term use of rituximab (RTX) has been gaining ground in the treatment of systemic autoimmune diseases. The adverse events (AEs) associated with its use different to infections are being reported., Methods: A cohort of patients with SAIDs treated at a high-complexity center in Cali (southwestern Colombia) with follow-up from January 2008 to December 2022 were examined to search for potential AEs associated with prolonged use of RTX., Results: From 178 patients with long-term use of RTX 3 (1.68%) had lymphadenopathies with lymphoid follicular hyperplasia related to BAFF overexpression, 4 (2.24%) with bronchiectasis, and 4 (2.24%) with lymphoplasmacytic cystitis., Conclusion: Bronchiectasis, lymphoid follicular hyperplasia related to BAFF overexpression, and lymphoplasmacytic cystitis may be life-threatening long-term AEs in patients with prolonged use of RTX., (Copyright © 2024 Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI). All rights reserved.)

Peri-implantitis (PI) and periodontitis (PD) are common oral inflammatory diseases, which seem to exhibit critical differences in some of their molecular features. Thus, we assessed the immune cell composition of PI and PD lesions and the corresponding inflammatory profile in soft tissues and crevicular fluid. PI, PD, and control patients were recruited (n = 62), and soft tissue biopsies were collected during surgery. Crevicular fluid around implant or tooth was collected. The proportions of major immune cell populations in tissues were analyzed by flow cytometry, and the inflammatory profile in tissue and crevicular fluid by a multiplex immunoassay. No significant difference was seen between PI and PD lesions in the proportions of immune cells. PI tissues showed an increased frequency of B cells in comparison with control tissues, along with higher levels of IL-1β, TNF-α, IL-4, and BAFF in tissue and crevicular fluid. Moreover, TNF-α, IL-17A, and BAFF were higher in PI tissues, but not in PD, than in control tissues. The immune cell composition did not differ significantly between PI and PD, but an enhanced inflammatory profile was seen in PI tissue. PI lesions were enriched in B cells, and displayed increased levels of IL-1β, TNF-α, IL-4, and BAFF in both tissue and crevicular fluid., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Immunology.)

Problem: Immunologic, angiogenic, and anti‐angiogenic factors are associated with spontaneous abortion (SAB). B cell–activating factor (BAFF), a proliferation‐inducing ligand (APRIL), placental growth factor (PlGF), and soluble fms‐like tyrosine kinase‐1 (sFlt‐1) may play a role in SAB and may serve singly or in combination as an early biomarker of SAB. Method of Study: In this prospective observational study, serum sFlt‐1, PIGF, BAFF, and APRIL levels were measured in the first trimester of pregnancy in a medically diverse group of women and in non‐pregnant controls. Associations and discriminative values of first‐trimester sFlt‐1, PIGF, BAFF, and APRIL levels and the corresponding APRIL:BAFF, BAFF:sFlt‐1, and sFlt‐1:PlGF ratios with development of SAB were tested. Results: Median serum BAFF level was lower (p =.007) and median serum sFlt‐1 level was higher (p <.001), in the first trimester of pregnancy than in non‐pregnant controls. SAB developed in 27 of the pregnant women (11.3%), and first‐trimester levels of BAFF (but not APRIL) and sFlt‐1 (but not PIGF) were associated with SAB. Using optimal cutoffs determined through receiver operating characteristics curves, the best discriminator of SAB was the serum BAFF:sFlt‐1 ratio, specifically among non‐nulliparous women and women with prior SAB. Conclusion: First‐trimester serum BAFF:sFlt‐1 ratio is a candidate indicator/predictor of SAB among non‐nulliparous women and women with prior SAB. If validated through additional studies, then early identification of pregnant women at high risk for SAB through this simple blood test would assist in counseling and facilitate clinical trials of therapeutic interventions. [ABSTRACT FROM AUTHOR]

Introduction: The low frequency of ectopic germinal center in labial salivary glands of patients with human T‐cell leukemia virus type 1 (HTLV‐1) antibody‐positive Sjögren's syndrome (SS) suggests that HTLV‐1 has some effects on follicular dendritic cells (FDCs). Methods: We used flow cytometry, immunofluorescence, and enzyme‐linked immunosorbent assays (ELISAs) to investigate the direct effect of HTLV‐1 on B‐cell activating factors produced by established FDC like cells obtained from excised human tonsils. We then measured the serum B‐cell activating factor (BAFF) and C‐X‐C motif ligand (CXCL) 13 concentrations of the HTLV‐1‐seropositive SS patients and the HTLV‐1‐seronegative SS patients by ELISA. Results: Among the 31 isolated specimens, 22 showed morphological characteristics of FDCs. Day 2‐cultured specimens showed expressions of CD14, CD23, CD40, intracellular adhesion molecule‐1 (ICAM‐1), and vascular cell adhesion molecule‐1. After 2 weeks, 12 of these specimens expressed ICAM‐1, FDC, and fibroblast cell marker. Intracellular BAFF and CXCL13 were constitutively expressed regardless of stimulation. After direct coculture with the HTLV‐1‐infected T‐cell line HCT‐5 or MT‐2, the BAFF and CXCL13 expressions on the FDC‐like cells were decreased in accord with the increased number of HCT‐5 and MT‐2 cells with styliform change and without HTLV‐1 Gag protein expression. Interferons upregulated the concentration of BAFF (but not CXCL13) in the culture supernatant, which showed a declining trend under the presence of HCT‐5 or MT‐2. The serum concentrations of BAFF and CXCL13 in the HTLV‐1‐seropositive SS patients were lower than those of the HTLV‐1 seronegative SS patients. Conclusions: HTLV‐1 partially inhibited the BAFF and CXCL13 expressions of established FDC‐like cells. [ABSTRACT FROM AUTHOR]

The tumor microenvironment affects malignancy in hepatocellular carcinoma (HCC) cells, and cancer‐associated fibroblasts (CAFs) play an important role in the microenvironment. As recent studies indicated a difference between CAFs isolated from chemoresistant and non‐resistant cancer tissues, therefore we investigated the intracellular mechanism in resistant HCC co‐cultured CAFs and interactions between these CAFs with cancer cells. We established a sorafenib‐resistant (SR) Huh7 (human HCC) cell line, and characterized it with cytokine assays, then developed CAFs by co‐culturing human hepatic stellate cells with resistant or parental Huh7 cells. The 2 types of CAFs were co‐cultured with parental Huh7 cells, thereafter the cell viability of these Huh7 cells was checked under sorafenib treatment. The SR Huh7 (Huh7SR) cells expressed increased B‐cell activating factor (BAFF), which promoted high expression of CAF‐specific markers in Huh7SR‐co‐cultured CAFs, showed activated BAFF, BAFF‐R, and downstream of the NFκB‐Nrf2 pathway, and aggravated invasion, migration, and drug resistance in co‐cultured Huh7 cells. When we knocked down BAFF expression in Huh7SR cells, the previously increased malignancy and BAFF/NFκB axis in Huh7SR‐co‐cultured CAFs reversed, and enhanced chemoresistance in co‐cultured Huh7 cells returned as well. In conclusion, the BAFF/NFκB pathway was activated in CAFs co‐cultured with cell‐culture medium from resistant Huh7, which promoted chemoresistance, and increased the malignancy in co‐cultured non‐resistant Huh7 cells. This suggests that the BAFF/NFκB axis in CAFs might be a potential therapeutic target in chemoresistance of HCC. [ABSTRACT FROM AUTHOR]

BAFF, an activator of the noncanonical NFκB pathway, provides critical survival signals during B cell maturation and contributes to B cell proliferation. We found that the NFκB family member RelB is required ex vivo for B cell maturation, but cRel is required for proliferation. Combined molecular network modeling and experimentation revealed Nfkb2 p100 as a pathway switch; at moderate p100 synthesis rates in maturing B cells, BAFF fully utilizes p100 to generate the RelB:p52 dimer, whereas at high synthesis rates, p100 assembles into multimeric IκBsome complexes, which BAFF neutralizes in order to potentiate cRel activity and B cell expansion. Indeed, moderation of p100 expression or disruption of IκBsome assembly circumvented the BAFF requirement for full B cell expansion. Our studies emphasize the importance of p100 in determining distinct NFκB network states during B cell biology, which causes BAFF to have context-dependent functional consequences.

Problem: As maternal atopy represents a risk factor for the development of atopy in offspring, we aimed to assess how pregnancy affects B‐cell activation markers in women with atopic asthma and whether they correlate with risk manifestations for allergy in newborns from mothers with atopic asthma. Method of Study: Pregnant women with atopic asthma (AP) in the third trimester of gestation and nonpregnant women with atopic asthma (ANP) were prospectively recruited and compared to respective healthy counterparts (HP and HNP). All pregnant women were also assessed during the postpartum period until 6 weeks after delivery (HP/PP and AP/PP). Newborns were clinically evaluated at the age of 6 months. Peripheral blood samples were taken from each woman at each time point. Soluble CD23 (sCD23), B‐cell activating factor (BAFF), IgA, IgG, IgM, kappa (κ), and lambda (λ) free light chains (FLC) were quantified in serum samples. Results: The AP group presented increased sCD23 (p < 0.05) and BAFF (p < 0.001) levels compared to the ANP group and even higher levels of sCD23 during the postpartum period (p < 0.001). Moreover, the cutoffs of 6.74 g/L for IgG (sensitivity 90.9%, specificity 77.8%) and of 11.30 mg/L for λ FLC (sensitivity 81.8%, specificity 88.9%) in the AP group were predictive factors for the manifestation of allergy in their offspring. Conclusions: After delivery, the dynamics of sCD23 and BAFF changed significantly in the AP group. Furthermore, we found novel predictive factors for allergy manifestations in the children of these women, with potential clinical application. [ABSTRACT FROM AUTHOR]

• Immune thrombocytopenia (ITP) is an autoimmune condition characterized by a low platelet count triggered by antiplatelet autoantibodies. • B cell activating factor (BAFF) regulates B cell development and autoreactivity; crucial factors in ITP pathogenesis. • Belimumab, as a BAFF inhibitor, prohibits BAFF activity and long-lived plasma cell production. • Ianalumab, another BAFF inhibitor, inserts a dual mechanism by targeting BAFF-R and deleting peripheral BAFF-R+ B cells. Immune thrombocytopenia (ITP) is an autoimmune-driven disease characterized by increased destruction and impaired platelet production resulting in an enhanced risk of bleeding. Immunosuppressant agents are the most common treatment strategies for ITP. Despite their efficacy, these medications often cause unpredictable side effects. Recent investigations revealed that patients with ITP exhibit elevated B-cell activating factor (BAFF) levels in both their spleens and serum. Belimumab, a BAFF inhibitor, illustrated a promising therapeutic avenue for managing ITP by interfering with BAFF activity and long-lived plasma cell production. Both clinical and experimental studies have yielded positive outcomes when combining rituximab with an anti-BAFF monoclonal antibody in treating ITP. In addition, ianalumab, a monoclonal antibody with a dual mechanism that targets BAFF-R and deletes peripheral BAFF-R+ B cells, is currently being used for ITP treatment [NCT05885555]. The upcoming results from novel BAFF inhibitors, such as ianalumab, could offer clinicians an additional therapeutic option for treating ITP. [ABSTRACT FROM AUTHOR]