BAFF Levels Research Articles

Soluble markers of B cell activation suggest a role of B cells in the pathogenesis of systemic sclerosis-associated pulmonary arterial hypertension.

IntroductionSoluble markers of B cell activation are interesting diagnostic and prognostic tools in autoimmune diseases. Data in systemic sclerosis (SSc) are scarce and few studies focused on their association with disease characteristics.Methods1. Serum levels of 14 B cell biomarkers (β2-microglobulin, rheumatoid factor (RF), immunoglobulins (Ig) G, IgA, IgM, BAFF, APRIL, soluble (s)TACI, sBCMA sCD21, sCD23, sCD25, sCD27, CXCL13) were measured in SSc patients and healthy controls (HC). 2. Associations between these biomarkers and SSc characteristics were assessed. 3. The pathophysiological relevance of identified associations was explored by studying protein production in B cell culture supernatant.ResultsIn a discovery panel of 80 SSc patients encompassing the broad spectrum of disease manifestations, we observed a higher frequency of RF positivity, and increased levels of β2-microglobulin, IgG and CXCL13 compared with HC. We found significant associations between several biomarkers and SSc characteristics related to disease phenotype, activity and severity. Especially, serum IgG levels were associated with pulmonary hypertension (PH); β2-microglobulin with Nt-pro-BNP and DLCO; and BAFF with peak tricuspid regurgitation velocity (TRV). In a validation cohort of limited cutaneous SSc patients without extensive ILD, we observed lower serum IgG levels, and higher β2-microglobulin, sBCMA, sCD23 and sCD27 levels in patients with pulmonary arterial hypertension (PAH). BAFF levels strongly correlated with Nt-pro-BNP levels, FVC/DLCO ratio and peak TRV in SSc-PAH patients. Cultured SSc B cells showed increased production of various angiogenic factors (angiogenin, angiopoietin-1, VEGFR-1, PDGF-AA, MMP-8, TIMP-1, L-selectin) and decreased production of angiopoietin-2 compared to HC.ConclusionSoluble markers of B cell activation could be relevant tools to assess organ involvements, activity and severity in SSc. Their associations with PAH could plead for a role of B cell activation in the pathogenesis of pulmonary microangiopathy. B cells may contribute to SSc vasculopathy through production of angiogenic mediators.

Elevated serum level of B-cell activating factor (BAFF) after rituximab therapy in pemphigus vulgaris patients suggests a possible therapeutic efficacy of B-cell depletion therapies combined with anti-BAFF agents.

Rituximab is widely used for treatment of pemphigus patients. B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) play key roles in B cell survival, maturation, and differentiation. Here, the effect of rituximab on BAFF and APRIL in patients with pemphigus vulgaris (PV) was studied. Fifty PV cases and 56 healthy individuals were recruited. Patients received rituximab for a period of 6 months. The levels of BAFF and APRIL were measured in the serum samples. The frequency of CD19+ B cells was measured by flow cytometry. The level of BAFF was significantly higher in the patients at the baseline level than controls (P = 0.0005). The level of BAFF was significantly higher at the 3rd month follow-up compared to the baseline (P = 0.033). There was a significant increase in the BAFF level at the 6th month follow-up compared to baseline (P = 0.0134). There was no significant difference in the CD19+ B cells/total lymphocytes ratio in the PV patients between the 3rd and 6th month follow-ups. Elevated BAFF in the sera could be associated with PV immunopathogenesis. Inhibition of BAFF after rituximab therapy might interfere with repopulation of B cells and confer a therapeutic approach in PV.

APRIL and BAFF play a key role in differentiating vitreoretinal lymphoma from uveitis

BackgroundEarly diagnosis of vitreoretinal lymphoma (VRL) is critical for the successful treatment of this rare intraocular malignancy. However, fast and reliable diagnosis of VRL in patients presenting with intermediate or posterior non-infectious uveitis remains a challenge. A proliferation-inducing ligand (APRIL) and B-cell activating factor (BAFF) are vital factors in the pathophysiology, diagnosis, and prognosis of primary central nervous system lymphoma (PCNSL) and systemic autoimmune diseases. However, their utility as biomarkers for the diagnosis of VRL and uveitis remains unclear. MethodsIn this retrospective study, we analyzed APRIL and BAFF levels in the aqueous humor (AH) of 43 eyes of 40 patients, including 23 eyes of 20 patients with VRL, eight eyes of eight patients with uveitis, and 12 eyes of 12 patients with other ocular diseases (OODs). Additionally, we measured their levels after induction of chemotherapy in five eyes of five patients with VRL. ResultsAH levels of APRIL reliably distinguished VRL from uveitis, with a specificity of 78.3% and sensitivity of 75%. BAFF also showed similar potential. Serial AH analysis of patients with VRL during chemotherapy demonstrated a corresponding decline in AH levels of APRIL and BAFF. ConclusionThis study extends the spectrum of valuable diagnostic biomarkers for VRL and uveitis. In patients with uveitis, the assessment of AH APRIL may help accelerate the diagnosis of VRL. Moreover, our results underline the important role of APRIL and BAFF in therapeutic monitoring of VRL.

Serum B cell activating factor (BAFF) as a biomarker for induction of remission with rituximab in ANCA-associated vasculitis

We examined whether serum B cell activating factor (BAFF) is useful for predicting the remission of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) following rituximab treatment. We used the Birmingham Vasculitis Activity Score (BVAS) 2008 version 3 for the evaluation of 27 patients with AAV 6 months after rituximab treatment. Those with BVAS = 0 achieved remission, whereas those with BVAS score > 0 did not achieve remission. We considered changes in serum BAFF before rituximab treatment, 1 month after treatment, and 6 months after treatment. In the remission group, the serum BAFF increased consistently. In the non-achieved group, serum BAFF was within the normal range. In addition, there was no statistically significant difference between the two groups in terms of serum BAFF before and 1 month after rituximab treatment. However, the serum BAFF level at 6 months after rituximab treatment was significantly higher in the remission group than in the non-achieved group. If serum BAFF does not increase after 6 months of rituximab in AAV, it may be assumed that there are residual B cells and plasma cells in the tissues. Enhanced treatment targeting B cells, including re-administration of rituximab or the addition of other immunosuppressive drugs, should be considered.

Protein and functional isoform levels and genetic variants of the BAFF and APRIL pathway components in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is the prototype of an autoimmune disease. Belimumab, a monoclonal antibody targets BAFF, is the only biologic approved for SLE and active lupus nephritis. BAFF is a cytokine with a key-regulatory role in the B cell homeostasis, which acts by binding to three receptors: BAFF-R, TACI and BCMA. TACI and BCMA also bind APRIL. Many studies reported elevated soluble BAFF and APRIL levels in the sera of SLE patients, but other questions about the role of this system in the disease remain open. The study aimed to investigate the utility of the cytokine levels in serum and urine as biomarkers, the role of non-functional isoforms, and the association of gene variants with the disease. This case–control study includes a cohort (women, 18–60 years old) of 100 patients (48% with nephritis) and 100 healthy controls. We used ELISA assays to measure the cytokine concentrations in serum (sBAFF and sAPRIL) and urine (uBAFF and uAPRIL); TaqMan Gene Expression Assays to quantify the relative mRNA expression of ΔBAFF, βAPRIL, and εAPRIL, and next-generation sequencing to genotype the cytokine (TNFSF13 and TNFSF13B) and receptor (TNFRSF13B, TNFRSF17 and TNFRSF13C) genes. The statistical tests used were: Kruskal–Wallis (qualitative variables), the Spearman Rho coefficient (correlations), the Chi-square and SKAT (association of common and rare genetic variants, respectively). As expected, sBAFF and sAPRIL levels were higher in patients than in controls (p ≤ 0.001) but found differences between patient subgroups. sBAFF and sAPRIL significantly correlated only in patients with nephritis (rs = 0.67, p ≤ 0.001) and βAPRIL levels were lower in patients with nephritis (p = 0.04), and ΔBAFF levels were lower in patients with dsDNA antibodies (p = 0.04). Rare variants of TNFSF13 and TNFRSF13B and TNFSF13 p.Gly67Arg and TNFRSF13B p.Val220Ala were associated with SLE. Our study supports differences among SLE patient subgroups with diverse clinical features in the BAFF/APRIL pathway. In addition, it suggests the involvement of genetic variants in the susceptibility to the disease.

Serum Cytokine Levels of Systemic Lupus Erythematosus Patients in the Presence of Concomitant Cardiovascular Diseases.

Systemic lupus erythematosus (SLE) is known to be associated with an increased risk of cardiovascular diseases (CVD). SLE patients suffer from CVD 3.5 times more often than healthy people. Cytokine-mediated inflammation is actively involved in the development of cardiovascular pathology. Here, we analyzed serum levels of nine cytokines of steroids-treated SLE patients depending on the presence of concomitant CVD. The levels of interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-10, IL-21, tumor necrosis factor α (TNFα), B-cell activating factor (BAFF), and a proliferation-inducing ligand (APRIL) were analyzed using multiplex immunoassay. In the total group of SLE patients (n=29), the concentrations of IL-6 and IL-10 were higher, and the APRIL level decreased compared to healthy donors (n=39, p<0.05). The same changes were observed in the group of patients without CVD (n=15); the levels of IL-6 and IL- 10 were found to be increased, and the level of APRIL was lower than in healthy individuals (p<0.05). In the group of SLE patients with CVD (n=14), the concentrations of IL-4, IL-6, IL- 10, and TNFα were found to be increased (p<0.05). Interestingly, the levels of TNFα and BAFF in SLE patients with CVD were higher than in patients without cardiovascular pathology. Thus, TNFα and BAFF levels were significantly altered in SLE with concomitant CVD compared to SLE without CVD. These findings suggest that cytokine profiles in SLE with concomitant CVD and SLE without CVD are different, which should be considered in further research with large samples.

Anti-EBNA1 IgG titre is not associated with fatigue in multiple sclerosis patients.

Fatigue is the most frequent symptom in multiple sclerosis (MS), although it is still poorly understood due to its complexity and subjective nature. There is an urgent need to identify reliable biomarkers to improve disease prognosis and therapeutic strategies. Epstein-Barr virus (EBV) is the major environmental risk factor associated with MS aetiology, and trials with EBV-targeted T cell therapies have reduced fatigue severity in MS patients. We investigated whether the serum amount of immunoglobulin (Ig)G-specific for EBV antigens could be a suitable prognostic marker for the assessment of MS-related fatigue. A total of 194 MS patients were enrolled. We quantified EBV nuclear antigen 1 (EBNA1) and EBV viral capsid antigen (VCA) immunoglobulin (Ig) G levels and B cell-activating factor of the tumour necrosis factor family (BAFF) concentration in the serum of patients with relapsing-remitting MS (RRMS) and chronic progressive MS (CPMS), and we analysed their correlation with aspects of fatigue and other clinical disease parameters. A complete EBV seropositivity could be detected in our cohort. After adjusting for confounding variables and covariates, neither EBNA1 nor VCA antibody titres were associated with levels of fatigue, sleepiness, depression, or with any of the clinical values such as expanded disability status scale, lesion count, annual relapse rate, or disease duration. However, patients with RRMS had significantly higher EBNA1 IgG titre than those with CPMS, whereas this was not the case under therapies targeting CD20+ cells. BAFF levels in serum were inversely proportional to anti-EBNA1 IgG. Our results show that EBNA1 IgG titre is not associated with the presence or level of fatigue. Whether the increased EBNA1 titre in RRMS plays a direct role in disease progression, or is only a consequence of excessive B cell activation, remains to be answered in future studies.

Development of approaches to stratification of patients with schizophrenia based on cytokine levels using cluster analysis

IntroductionAlterations in a variety of immune parameters, including abnormal cytokine levels, are known to be found in schizophrenia. These changes can be useful in identifying patients with the most severe immune abnormalities.ObjectivesTo develop approaches to stratification of schizophrenia patients based on cytokine levels using cluster analysis.MethodsWe recruited 53 patients (25 women/28 men) with a verified diagnosis of simple or paranoid schizophrenia and 37 healthy individuals (19 women/18 men) in our study. Serum levels of IL-1β, IL-2, IL-4, IL-6, TNFα, INFα, BAFF, GM-CSF, NGFβ, NRG1, and GDNF were determined using a MAGPIX multiplex analyzer (Luminex, USA). Statistical analysis was performed in Statistica 10.ResultsPrincipal component analysis and partial least-squares discriminant analysis showed that the combined multi-cytokine profiles of the studied groups differ. The results of the k-means cluster analysis are presented in Table 1 The most reliable results are obtained by a combination of 4 variable: IL-1β, IL- 4, BAFF and GDNF. Table 1 Percent of individuals classified in different clusters depending of number of parameters using for classification.Number of variables for classification Healthy individualsSchizophrenia patientsCluster 1Cluster 2Cluster 1Cluster 210 variables5,496,426,473,64 variables010011,188,93 variables2,797,329,670,42 variables8,191,920,479,6ConclusionsA subgroup (сluster 1) of schizophrenic patients with severe immune abnormalities was identified using data on the levels of IL-1β, IL-4, BAFF and GDNF. Anti-inflammatory therapy is recommended for this subgroup of patients. Support by Grant of RSF № 21-75-00102.DisclosureNo significant relationships.

Coding joint: kappa-deleting recombination excision circle ratio and B cell activating factor level: predicting juvenile dermatomyositis rituximab response, a proof-of-concept study

BackgroundThis pilot study’s primary aim was to determine if oligoclonal B cell expansion in children with Juvenile Dermatomyositis (JDM) predicts response to Rituximab therapy. We evaluated: (1) tissue B cell depletion efficacy by measuring the ratio of Coding joint (CJ) to Kappa-deleting recombination excision circle (KREC) DNA, and (2) serum BAFF level upon B cell recovery.MethodsCJ and KREC values were measured via qPCR assessment of serial PBMC stored (− 80 °C) in the CureJM Center’s BioRepository. Serum BAFF was quantitated by Mesoscale® technology. Oligoclonal B cell expansion was defined as a CJ:KREC ≥ 8 prior to Rituximab therapy. Detection of a CJ:KREC ratio ≤ 2.5 in the first sample after Rituximab was designated as adequate B cell depletion. A significant clinical response to therapy was defined as improvement in Disease Activity Score (DAS) by at least 2 points on consecutive visits within the first 12 months of therapy.ResultsSix out of nine children with JDM showed oligoclonal B cell expansion prior to Rituximab (CJ:KREC ≥ 8). Of those 6 patients, 4 had evidence of effective B cell depletion after Rituximab (CJ:KREC ≤ 2.5), and all 4 of those subjects displayed a significant clinical response to Rituximab. Serum BAFF level increased in 8/9 children after Rituximab.ConclusionsIn this proof-of-concept study, JDM patients with oligoclonal B cell expansion prior to Rituximab have more favorable clinical outcomes after Rituximab. We speculate: (1) B cell depletion post-Rituximab predicts JDM clinical response; (2) increased BAFF post-Rituximab may contribute to disease flare.

Circulating C-X-C Motif Ligand 13 as a Biomarker for Early Predicting Efficacy of Subcutaneous Immunotherapy in Children With Chronic Allergic Rhinitis.

BackgroundC-X-C motif ligand 13 (CXCL13) and B cell-activating factor (BAFF) are proven to be involved in inflammatory diseases, but their role in allergic rhinitis (AR) remains unclear. The aim of this study was to investigate the role of serum CXCL13 and BAFF in AR and their clinical values as objective biomarkers to predict the efficacy of subcutaneous immunotherapy (SCIT).MethodsWe prospectively recruited 90 children with AR treated with SCIT and collected their serum specimens before SCIT. One-year follow-up was conducted for all patients, and they were categorized into effective and ineffective groups based on efficacy. The serum concentrations of CXCL13 and BAFF were detected and compared between the two groups. A validation cohort of 52 responders and 26 non-responders were further assessed for both cytokines and serum CXCL13 and BAFF levels were assayed by enzyme-linked immunosorbent assay (ELISA).ResultsEighty children completed the follow-up schedule, and 56 children were categorized into the effective group and 24 children into the ineffective group. The serum levels of CXCL13 in the effective group were clearly higher than those in the ineffective group (P < 0.05). Receiver operating characteristic (ROC) curves revealed the potential values of CXCL13 as a biomarker in predicting the response of SCIT. Further, in the validation cohort, ELISA results demonstrated that serum CXCL13 levels were increased in responders than non-responders (P < 0.05). ROC curves showed good accuracy of serum CXCL13 in predicting the efficacy of SCIT.ConclusionOur discovery–validation study demonstrated that circulating CXCL13 might serve as a novel biomarker to predict the outcome of SCIT in childhood AR. The findings indicated that CXCL13 was involved in the pathological mechanisms of AR and made help to the fundamental therapeutic mechanism of SCIT.

Cytokine responses of immunosuppressed and immunocompetent patients with Neoehrlichia mikurensis infection

PurposeThe tick-borne bacterium Neoehrlichia mikurensis causes the infectious disease neoehrlichiosis in humans. Vascular endothelium is one of the target cells of the infection. Neoehrlichiosis patients with compromised B cell immunity present with more severe inflammation than immunocompetent patients. The aim of this study was to compare the cytokine profiles of immunocompetent and immunosuppressed patients with neoehrlichiosis.MethodsBlood samples from Swedish and Norwegian immunosuppressed (N = 30) and immunocompetent (N = 16) patients with neoehrlichiosis were analyzed for the levels of 30 cytokines, using a multiplex cytokine assay and ELISA. A gender-matched healthy control group (N = 14) was analyzed in parallel. Data were analyzed using the multivariate method OPLS-DA.ResultsThe multiplex cytokine analyses generated more cytokine results than did the uniplex ELISA analyses. Multivariate analysis of the multiplex cytokine results established that increased levels of FGF2, GM-CSF, CXCL10, and IFN-γ were associated with immunosuppressed patients, whereas increased levels of IL-15 and VEGF were associated with immunocompetent neoehrlichiosis patients. When multivariate analysis findings were confirmed with uniplex ELISA, it was found that both groups of patients had similarly elevated levels of VEGF, FGF2 and IFN-γ. In contrast, the immunosuppressed patients had clearly elevated levels of CXCL10, CXCL13 and BAFF, whereas the immunocompetent patients had the same levels as healthy controls.ConclusionPro-angiogenic and type 1 cytokines were produced as part of the host response of neoehrlichiosis independent of immune status, whereas immunosuppressed neoehrlichiosis patients produced cytokines required for B cell-mediated defense.

Increased B Cell-Activating Factor Expression Is Associated with Postoperative Recurrence of Chronic Rhinosinusitis with Nasal Polyps.

Background Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common upper airway inflammatory disease with a high postoperative recurrence rate. This study is aimed at exploring the expression of B cell-activating factor (BAFF) in CRSwNP and its association with postoperative recurrence. Methods A total of 80 CRSwNP patients, including 40 primary CRSwNP patients and 40 recurrent CRSwNP patients, 40 chronic rhinosinusitis without nasal polyps (CRSsNP) patients, and 40 healthy controls (HC) were enrolled in this study, and the serum and tissue samples were collected. The circulating and tissue BAFF expressions were detected by enzyme-linked immunosorbent assay reverse transcription-polymerase chain reaction and immunohistochemistry. Their clinical values for predicting postoperative recurrence of CRSwNP were evaluated. Results We determined serum levels of BAFF were remarkably increased in the CRSwNP group than the CRSsNP and HC groups (P < 0.05), and higher concentrations of BAFF were associated with peripheral eosinophil percentage (r = 0.614, P < 0.001). The serum BAFF concentrations were significantly higher in the recurrent CRSwNP group in comparison with the primary group (P < 0.05). Multivariate analysis and receiver operating characteristic (ROC) curve presented that serum BAFF levels were associated with the postoperative recurrence in CRSwNP patients (P < 0.05). Moreover, tissue BAFF levels were significantly increased in the CRSwNP group than the HC group, especially in the recurrent CRSwNP group (P < 0.05), and enhanced BAFF RNA expressions were correlated with serum BAFF levels (r = 0.703, P < 0.001). Conclusion Our results elucidated that the BAFF expression was enhanced in CRSwNP patients and associated with postoperative recurrence. BAFF could be a serologic biomarker for predicting postoperative recurrence in CRSwNP patients.

Intravenous Immunoglobulin is Associated with Lower Rates of Reinfection in Solid Organ Recipients with Infection and Secondary Antibody Deficiency: A Multicenter Randomized Clinical Trial

<h3>Purpose</h3> In a multicenter randomized clinical trial we evaluated the safety and efficacy of an intravenous immunoglobulin (IVIG) protocol to decrease the rate of reinfection in solid organ recipients with severe infections and secondary antibody deficiency. <h3>Methods</h3> Distribution: Heart 20, Lung 15, Kidney 5, Liver transplantation 4 were randomized. Patients with post transplant severe infections and secondary antibody deficiency (defined as IgG < 600 mg/dL) were included. IVIG protocol: Two doses of 15 grams (interval between doses 7-15 days) followed by another 3 doses of 20 grams (interval between doses 15-30 days) of a 5% IVIG product. 39 patients that completed the protocol were analysed [IVIG in combination with conventional antimicrobial therapy (n=21) versus conventional antimicrobial therapy alone (n=18)]. Specific antibodies were tested at inclusion in the clinical trial (V1) and 30-45 days after last IVIG dose (last-visit, V7) in a subgroup of patients to assess the kinetics of humoral immunity reconstitution. <h3>Results</h3> The primary outcome measure (rate of reinfection) was significantly lower in patients randomized to receive IVIG as compared with patients receiving only conventional antimicrobial therapy (28.6 vs 66.7%, chi-square test, p=0.017). Mean number of reinfections tended to be lower in IVIG group (0.47, interval 1-3, versus 0.89, interval 1-4, Mann-Whitney test, p=0.056). IVIG recipients tended to have lower IgG levels in V1 but disclosed significantly higher IgG concentrations at distinct visits during follow-up. Significantly higher levels of specific IgG anti-cytomegalovirus, IgG anti-clostridium difficile toxins A and B and IgG1 anti-tetanus toxoid antibodies was demonstrated at V7 in patients who received IVIG as compared with patient that were treated with antimicrobial therapy alone. A significant decrease of serum IL6 and BAFF levels (V1 versus V7) was demostrated in IVIG treated patients. IVIG infusions were well tolerated. <h3>Conclusion</h3> In a multicenter randomized clinical trial we have demonstrated that IVIG is associated with a lower rate of reinfection in solid organ transplantation with severe infection and secondary IgG hypogammaglobulinemia.

Toll-like receptor 10 expression in B cells is negatively correlated with the progression of primary Sjögren's disease

Primary Sjögren's Disease (pSjD) is considered a B cell-mediated disease. Toll-like receptor 10 (TLR10) is highly expressed in human B cells, indicating that TLR10 probably plays a vital role in pSjD. We examined TLR10 expression in peripheral B subsets of pSjD patients and analyzed their association with disease activity. We observed that TLR10 expression in total, naïve, memory, and switched memory B cells was significantly increased in low-activity pSjD patients as compared with healthy controls and high-activity patients. TLR10 expression in the above mentioned B subsets (except naïve B) was negatively correlated with serum levels of anti-SSA antibody and BAFF, respectively. Moreover, a higher proportion of high-activity pSjD patients was observed in TLR10 low- than high-expressed patients. Our study concluded that TLR10 expression in CD19+ B and memory B was negatively correlated with pSjD disease activity, suggesting that TLR10 might take part in the progression of pSjD.

BAFF rs9514828 gene polymorphism and the risk of the development of inhibitors in children with severe haemophilia A.

Haemophilia A (HA) is an x-linked recessive disease due to deficiency of coagulation factor VIII (FVIII). The development of neutralizing antibodies (inhibitors) against infused FVIII is a major concern. B cell activating factor (BAFF) has been implicated in several autoimmune diseases. We aimed to evaluate the possible association of BAFF rs9514828 gene polymorphism and the risk of the development of FVIII inhibitor in children with severe HA. This cohort study was carried out on 100 newly diagnosed boys with severe HA who were never treated before with FVIII concentrate. Assessment of serum levels of BAFF and BAFF rs9514828 genotyping at first diagnosis was performed and the patients were followed up for the completion of a total of 50 exposure days or the development of inhibitors whichever occurred first. The patients were divided as positive or negative according to the presence or absence of inhibitors. The risk allele for BAFF rs9514828 (T) was significantly more frequent in the inhibitor positive patients than the inhibitor negative patients (P=.003). In addition, CT+TT genotypes were associated with increased risk of FVIII inhibitor development. Receiver operating characteristics (ROC) analysis showed that BAFF levels could predict the development of FVIII inhibitors at a cut-off value of ≥ .92 with a sensitivity of 85.9% and a specificity of 80.2%. BAFF rs9514828 gene polymorphism could be independent risk factor and elevated BAFF levels might be useful prognostic marker for the development of FVIII inhibitor in newly diagnosed children with severe HA.

The relationship between serum A proliferation-inducing ligand and B-cell activating factor levels with disease activity and organ involvement in systemic lupus erythematosus.

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. 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 6months 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. 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. 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.

Increased vitreous levels of B cell activation factor (BAFF) and soluble interleukin-6 receptor in patients with macular edema due to uveitis related to Behçet's disease and sarcoidosis.

Uveitis accounts for 10-15% of all cases of blindness in the developed world. Uveitic macular edema (UME) is a primary cause of permanent visual impairment in patients with uveitis. Because proinflammatory mediators elicit inflammation and lead to UME, we determined the profiles of proinflammatory mediators associated with complications, such as ME, in the vitreous humor of patients with panuveitis related to Behçet's disease (BD) and sarcoidosis. In this retrospective study, we enrolled 21 patients with uveitis, including 6 with BD and 15 with sarcoidosis, and 15 patients with idiopathic epiretinal membrane (iERM) at the Department of Ophthalmology, Kyushu University Hospital, between January 2008 and April 2016. Vitreous concentrations of 32 proinflammatory mediators, including cytokines and soluble receptors of tumor necrosis factor (TNF) and interleukin (IL)-6 families, were assessed using a bead-based multiplex assay and their association with clinical data was examined. The levels of proinflammatory mediators, including a proliferation-inducing ligand (APRIL), B cell activating factor belonging to the TNF family (BAFF), soluble cluster of differentiation 30 (sCD30), soluble TNF receptor-1 (sTNFR1), sTNFR2, TNF-α, IL-6, and soluble IL-6 receptor-α (sIL-6Rα), were significantly higher in patients with uveitis. With regard to clinical parameters in patients with uveitis, vitreous levels of BAFF and sIL-6Rα were prominently elevated in patients with UME compared to in those without UME (P < 0.01, respectively). Our results suggest that elevated vitreous levels of BAFF and sIL-6Rα are associated with the pathogenesis of UME in patients with panuveitis related to BD and sarcoidosis.

B-cell activating factor and IL-21 levels predict treatment response in autoimmune hepatitis

Background & AimsIncreased serum IgG and autoantibodies suggest involvement of B cells in autoimmune hepatitis (AIH). The aim of this study was to assess levels of B cell activating factor of the tumour necrosis family (BAFF), IL-21, and circulating B cell populations in AIH and correlate these to treatment response.MethodsBAFF and IL-21 levels were determined in 66 patients with AIH before treatment and 10 healthy controls. Flow cytometry was performed on circulating B cells of 10 patients with AIH and 12 healthy controls.ResultsBased on BAFF and IL-21 levels, untreated patients with AIH were divided into 3 groups: 27 (41%) patients with normal BAFF and IL-21 (normal BAFF), 27 (41%) patients with elevated BAFF but normal IL-21 (high BAFF), and 12 (18%) patients with elevated IL-21 (high IL-21). The high BAFF group presented with higher bilirubin compared with the normal BAFF and high IL-21 groups (159 vs. 26 vs. 89 μmol/L; p = 0.001; Mann–Whitney U test). After 12 months of treatment, 54% of the high BAFF group reached remission compared with 34% of the normal BAFF group and 0% of the high IL-21 group (p = 0.006, Chi-square test). During follow-up, 3 patients (25%) with high IL-21 developed primary sclerosing cholangitis (PSC) variant syndrome. Autoimmune-associated B cells were increased in patients with AIH compared with healthy controls (4.4 vs. 1.4%; p = 0.003, Mann–Whitney U test). BAFF levels were correlated positively with naïve B cells (p = 0.01) and negatively with class-switched B cells (p = 0.003) and nonclass-switched B cells (p = 0.005, Spearman correlation).DiscussionUsing BAFF and IL-21, we identified different immunological phenotypes of AIH with a different presentation, treatment response, and outcome. Patients with high IL-21 had the poorest treatment response and a risk of developing PSC variant syndrome. BAFF level was related to shifts in circulating B-cell populations.Lay summaryIn patients with untreated autoimmune hepatitis (AIH), circulating B-cell activating factor of the tumour necrosis family (BAFF), IL-21, and B-cell populations were determined. Three subgroups were identified: with (1) normal BAFF and IL-21, (2) elevated BAFF and normal IL-21, and (3) elevated IL-21. Remission after 1-year treatment occurred in 54, 34, and 0% in Groups 1, 2, and 3, respectively. Group 2 had higher bilirubin, indicating more liver dysfunction. In 25% of patients with high IL-21, AIH-PSC variant syndrome developed, but none in the other groups. Autoimmune-associated B cells were elevated and BAFF levels correlated with certain B cells.

Correlation of Serum Levels of Interleukine-16, CCL27, Tumor Necrosis Factor-related Apoptosis-inducing Ligand, and B-cell Activating Factor with Multiple Sclerosis Severity.

The pathogenic roles of Interleukine-16 (IL-16), CCL27, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and B-cell activating factor (BAFF) has been shown in some autoimmune and inflammatory diseases. We aimed to correlate the circulatory changes of such factors with the severity of disease in patients with multiple sclerosis (MS). This case-control study was conducted on 84 MS patients and 83 healthy controls. We measured the serum levels of IL-16, CCL27, TRAIL, and BAFF in all participants by enzyme-linked immune sorbent assay. Using the expanded disability status scale (EDSS), we evaluated the severity of MS. Finally, we assessed the correlation between serum levels of such factors with the severity of MS. We found increased serum levels of CCL27, IL-16, and BAFF in patients with MS compared to those in healthy subjects. However, no difference was found in serum levels of TRAIL between the patients and controls. In addition, a significant positive correlation between serum levels of CCL27, IL-16, TRAIL, and BAFF with disease severity according to EDSS score was determined. We showed higher serum levels of CCL27, BAFF, TRAIL, and IL-16 in MS patients with more severe disabilities than mild forms. Such finding may represent their contribution to the pathogenesis of MS. Blocking such molecules may yield new treatments for MS.

Circulating BAFF as novel biomarker in distinguishing chronic rhinosinusitis with nasal polyps endotypes and predicting postoperative recurrence

BackgroundB cell-activating factor (BAFF) is a proinflammatory cytokine involved in inflammatory and allergic diseases, but its role in chronic rhinosinusitis with nasal polyps (CRSwNP) remains unclear. This study aims to explore the predictive value of circulating BAFF in CRSwNP endotypes and postoperative recurrence. MethodsWe recruited 120 CRSwNP patients, including 68 non-eosinophilic CRSwNP (neCRSwNP) patients, 52 eosinophilic CRSwNP (CRSwNP) patients, and 60 healthy controls (HCs). Circulating BAFF levels of all participants were measured by enzyme-linked immunosorbent assay (ELISA), and receiver-operating characteristic (ROC) and logistic regression analyses were applied to assess the predictive ability of BAFF levels in distinguishing CRSwNP endotypes. All CRSwNP patients were followed for more than 3 years, and the predictive value of circulating BAFF for postoperative recurrence was evaluated. ResultsSerum BAFF levels were elevated in CRSwNP patients compared with the HCs (P < 0.01) and significantly higher in eCRSwNP patients. The increased serum BAFF concentrations positively correlated with blood eosinophil counts and percentages, tissue eosinophil counts, and serum total IgE (P < 0.05). The ROC curve showed that serum BAFF exhibited strong discriminative ability for eCRSwNP. Finally, 99 CRSwNP patients completed the follow-up schedule, 65 patients were classified into non-recurrence group and the other 34 patients were categorized into recurrence group. Serum BAFF levels were significantly higher in recurrence group than non-recurrence group (P < 0.001), and the ROC curve suggested a high predictive value of serum BAFF in predicting postoperative recurrence. Moreover, logistic regression and Kaplan-Meier curves showed that serum BAFF was an independent risk factor for postoperative recurrence (P < 0.05). ConclusionOur data suggested that serum BAFF levels were upregulated in CRSwNP patients and correlated with mucosal eosinophil infiltration severity. Serum BAFF seemed to be a novel biomarker for preoperatively distinguishing CRSwNP endotypes and predicting postoperative recurrence.