Unique and redundant roles of mouse BCMA, TACI, BAFF, APRIL, and IL-6 in supporting antibody-producing cells in different tissues.

Antibody-producing plasma cells fuel humoral immune responses. They also contribute to autoimmune diseases such as systemic lupus erythematosus or IgA nephropathy. Interleukin-6 and the tumor necrosis factor (TNF) family ligands BAFF (B cell-activating factor) and APRIL (a proliferation-inducing ligand) participate in plasma cell survival. BAFF binds to three receptors, BAFFR (BAFF receptor), TACI (transmembrane activator and CAML interactor), and BCMA (B cell maturation antigen), while APRIL binds to TACI, BCMA, and proteoglycans. However, which ligand-receptor pair(s) are required to maintain plasma cells in different body locations remains unknown. Here, by combining mouse genetic and pharmacological approaches, we found that plasma cells required BCMA and/or TACI but not BAFFR. BCMA responded exclusively to APRIL, while TACI responded to both BAFF and APRIL, identifying three self-sufficient ligand-receptor pairs for plasma cell maintenance: BAFF-TACI, APRIL-TACI, and APRIL-BCMA. Together, these actors accounted for 90% of circulating antibodies. In BAFF-ko mice, the reduction of plasma cells upon APRIL inhibition indicated that APRIL could function in the absence of BAFF-APRIL heteromers. No evidence was found that in the absence of BCMA and TACI, binding of APRIL to proteoglycans would help maintain plasma cells. IL-6, alone or together with BAFF and APRIL, supported mainly splenic plasmablasts and plasma cells and contributed to circulating IgG but not IgA levels. In conclusion, survival factors for plasma cells can vary with body location and with the antibody isotype that plasma cells produce. To efficiently target plasma cells, in particular IgA-producing ones, dual inhibition of BAFF and APRIL is required.

Trailblazing in adjuvant research: succinate's uncharted territory with neutrophils.

The purpose of this study is to investigate the previously unknown connection that succinate has with neutrophils in the setting of adjuvant-mediated immunological enhancement. It has been discovered that succinates stimulate the recruitment of neutrophils in immunization sites, which in turn induces the expression of what is known as neutrophil-derived B cell-activating factor (BAFF). Further amplification of vaccine-induced antibody responses is provided via the succinate receptor 1-interferon regulatory factor 5 (SUCNR1-IRF5)-BAFF signaling pathway, which provides insights into a unique mechanism for immunological enhancement.NEW & NOTEWORTHY This study explores the role of succinate as a vaccine adjuvant, revealing its capacity to enhance neutrophil recruitment at immunization sites, which boosts B cell activation through the succinate receptor 1-interferon regulatory factor 5-B cell-activating factor (SUCNR1-IRF5-BAFF) signaling pathway. Results demonstrate succinate's potential to amplify vaccine-induced antibody responses, highlighting its significance in immunological enhancement and offering new insights into the adjuvant mechanisms of action, particularly in neutrophil-mediated immune responses.

B cell activating factor levels are linked to distinct B cell markers in multiple sclerosis and following B cell depletion and repopulation.

Recent studies have highlighted the important role of B cells in the pathogenesis of multiple sclerosis (MS). B cell activating factor (BAFF) and A proliferation inducing ligand (APRIL) play a major role in B cell survival and homeostasis. Here, we studied the association of BAFF and APRIL with B cell immune markers in MS and following B cell depletion and repopulation. We found that BAFF but not APRIL was significantly higher in plasma in untreated MS compared to controls. BAFF increased after rituximab treatment and decreased again during repopulation displaying an inverse correlation with B cell numbers, and more specifically switched memory B cell numbers. Cerebrospinal fluid BAFF inversely correlated with IgG index. BAFF displayed an inverse association to anti-EBV-CA antibodies. In summary, our study identified immune cells and factors that might regulate or be regulated by BAFF and APRIL levels in MS, and during B cell depletion and repopulation.

Neutrophil depletion attenuates antibody-mediated rejection in a renal transplantation mouse model.

Antibody-mediated rejection (AMR) can cause graft failure following renal transplantation. Neutrophils play a key role in AMR progression, but the exact mechanism remains unclear. We investigated the effect of neutrophils on AMR in a mouse kidney transplantation model. The mice were divided into five groups: syngeneic transplantation (Syn), allograft transplantation (Allo), and three differently treated AMR groups. The AMR mouse model was established using skin grafts to pre-sensitize recipient mice. Based on the AMR model, Ly6G-specific monoclonal antibodies were administered to deplete neutrophils (NEUT-/- + AMR) and TACI-Fc was used to block B-cell-activating factor (BAFF)/a proliferation-inducing ligand (APRIL) signaling (TACI-Fc + AMR). Pathological changes were assessed using hematoxylin-eosin and immunohistochemical staining. Banff values were evaluated using the Banff 2015 criteria. Donor-specific antibody (DSA) levels were assessed using flow cytometry, and BAFF and APRIL concentrations were measured using ELISA. Compared to the Syn and Allo groups, a significantly increased number of neutrophils and increased C4d and IgG deposition were observed in AMR mice, accompanied by elevated DSA levels. Neutrophil depletion inhibited inflammatory cell infiltration and reduced C4d and IgG deposition. Neutrophil depletion significantly decreased DSA levels after transplantation and suppressed BAFF and APRIL concentrations, suggesting a mechanism for attenuating AMR-induced graft damage. Similar results were obtained after blockading BAFF/APRIL using a TACI-Fc fusion protein. In summary, neutrophil infiltration increased in the AMR mouse renal transplantation model. Neutrophil depletion or blockading the BAFF/APRIL signaling pathway significantly alleviated AMR and may provide better options for the clinical treatment of AMR.

Anti-CD40L therapy prevents the formation of precursor lesions to gastric B-cell MALT lymphoma in a mouse model.

Mucosa-associated lymphoid tissue (MALT) lymphoma is a B-cell tumour that develops over many decades in the stomachs of individuals with chronic Helicobacter pylori infection. We developed a new mouse model of human gastric MALT lymphoma in which mice with a myeloid-specific deletion of the innate immune molecule, Nlrc5, develop precursor B-cell lesions to MALT lymphoma at only 3 months post-Helicobacter infection versus 9-24 months in existing models. The gastric B-cell lesions in the Nlrc5 knockout mice had the histopathological features of the human disease, notably lymphoepithelial-like lesions, centrocyte-like cells, and were infiltrated by dendritic cells (DCs), macrophages, and T-cells (CD4+ , CD8+ and Foxp3+ ). Mouse and human gastric tissues contained immune cells expressing immune checkpoint receptor programmed death 1 (PD-1) and its ligand PD-L1, indicating an immunosuppressive tissue microenvironment. We next determined whether CD40L, overexpressed in a range of B-cell malignancies, may be a potential drug target for the treatment of gastric MALT lymphoma. Importantly, we showed that the administration of anti-CD40L antibody either coincident with or after establishment of Helicobacter infection prevented gastric B-cell lesions in mice, when compared with the control antibody treatment. Mice administered the CD40L antibody also had significantly reduced numbers of gastric DCs, CD8+ and Foxp3+ T-cells, as well as decreased gastric expression of B-cell lymphoma genes. These findings validate the potential of CD40L as a therapeutic target in the treatment of human gastric B-cell MALT lymphoma. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Transcriptome Analysis of BAFF/BAFF-R System in Murine Nephrotoxic Serum Nephritis.

Chronic kidney disease (CKD) is an emerging cause for morbidity and mortality worldwide. Acute kidney injury (AKI) can transition to CKD and finally to end-stage renal disease (ESRD). Targeted treatment is still unavailable. NF-κB signaling is associated with CKD and activated by B cell activating factor (BAFF) via BAFF-R binding. In turn, renal tubular epithelial cells (TECs) are critical for the progression of fibrosis and producing BAFF. Therefore, the direct involvement of the BAFF/BAFF-R system to the pathogenesis of CKD is conceivable. We performed non-accelerated nephrotoxic serum nephritis (NTN) as the CKD model in BAFF KO (B6.129S2-Tnfsf13btm1Msc/J), BAFF-R KO (B6(Cg)-Tnfrsf13ctm1Mass/J) and wildtype (C57BL/6J) mice to analyze the BAFF/BAFF-R system in anti-glomerular basement membrane (GBM) disease using high throughput RNA sequencing. We found that BAFF signaling is directly involved in the upregulation of collagen III as BAFF ko mice showed a reduced expression. However, these effects were not mediated via BAFF-R. We identified several upregulated genes that could explain the effects of BAFF in chronic kidney injury such as Txnip, Gpx3, Igfbp7, Ccn2, Kap, Umod and Ren1. Thus, we conclude that targeted treatment with anti-BAFF drugs such as belimumab may reduce chronic kidney damage. Furthermore, upregulated genes may be useful prognostic CKD biomarkers.

B-Cell Activation Biomarkers in Salivary Glands Are Related to Lymphomagenesis in Primary Sjögren's Disease: A Pilot Monocentric Exploratory Study.

Primary Sjögren's disease is primarily driven by B-cell activation and is associated with a high risk of developing non-Hodgkin's lymphoma (NHL). Over the last few decades, microRNA-155 (miR-155) has arisen as a key regulator of B-cells. Nevertheless, its role in primary Sjögren's disease remains elusive. Thus, the purpose of this study was (i) to explore miR-155, B-cell activating factor (BAFF)-receptor (BAFF-R), and Interleukin 6 receptor (IL-6R) expression in the labial salivary glands (LSG) of patients with primary Sjögren's disease, aiming to identify potential B-cell activation biomarkers related to NHL development. Twenty-four patients with primary Sjögren's disease, and with available tissue blocks from a LSG biopsy performed at diagnosis, were enrolled. Among them, five patients developed B-cell NHL during follow-up (7.3 ± 3.1 years). A comparison group of 20 individuals with sicca disease was included. Clinical and laboratory parameters were recorded and the LSG biopsies were evaluated to assess local inflammation in terms of miR-155/BAFF-R and IL-6R expression. Stratifying the primary Sjögren's disease cohort according to lymphomagenesis, miR-155 was upregulated in primary Sjögren's disease patients who experienced NHL, more so than those who did not experience NHL. Moreover, miR-155 expression correlated with the focus score (FS), as well as BAFF-R and IL-6R expression, which were increased in primary Sjögren's disease patients and in turn related to neoplastic evolution. In conclusion, epigenetic modulation may play a crucial role in the aberrant activation of B-cells in primary Sjögren's disease, profoundly impacting the risk of NHL development.

Polymorphonuclear myeloid-derived suppressor cells play a proinflammatory role via TNF-α+ B cells through BAFF/BTK/NF-κB signalling pathway in the pathogenesis of collagen-induced arthritis mice.

Although various studies have been performed on the function of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in RA, the results were conflicting. Here we were trying to clarify the role of PMN-MDSCs in the pathogenesis of RA and its specific mechanisms. We detected the frequencies and counts of PMN-MDSCs, TNF-α+ B cells and Ki67+ B cells in spleen and inflamed joints of collagen-induced arthritis (CIA) mice using flow cytometry. The pathological role of PMN-MDSCs was examined by anti-Ly6G neutralizing antibodies against PMN-MDSCs or adoptive transfer of PMN-MDSCs. And the modulation of PMN-MDSCs on B cells was conducted by coculture assays, RNA-Seq, RT-qPCR, and so on. The mechanism of BAFF regulating B cells was verified through western blot and flow cytometry. PMN-MDSCs accumulated in the spleen and joints of CIA mice. PMN-MDSCs depletion could alleviate the arthritis severity, which was accompanied by decreased TNF-α secretion and proliferation of B cells. And its adoptive transfer also facilitated disease progress. Furthermore, PMN-MDSCs from CIA mice had higher expression level of BAFF, which regulated TNF-α expression, proliferation and apoptosis of B cells in vitro. What's more, BAFF promoted phosphorylation of BTK/NF-κB signalling pathway. And Ibrutinib (BTK inhibitor) could reverse the effect of BAFF on TNF-α expression of B cells. Our study suggested that PMN-MDSCs enhanced disease severity of CIA and manipulated TNF-α expression, proliferation and apoptosis of B cells via BAFF, furthermore, BAFF promoted TNF-α expression through BTK/NF-κB signalling pathway, which demonstrated a novel pathogenesis of PMN-MDSCs in CIA.

Excess BAFF May Impact HIV-1-Specific Antibodies and May Promote Polyclonal Responses Including Those from First-Line Marginal Zone B-Cell Populations.

We have previously shown that blood levels of B-cell Activating Factor (BAFF) rise relatively to disease progression status in the context of HIV-1 infection. Excess BAFF was concomitant with hyperglobulinemia and the deregulation of blood B-cell populations, notably with increased frequencies of a population sharing characteristics of transitional immature and marginal zone (MZ) B-cells, which we defined as marginal zone precursor-like" (MZp). In HIV-uninfected individuals, MZp present a B-cell regulatory (Breg) profile and function, which are lost in classic-progressors. Moreover, RNASeq analyses of blood MZp from classic-progressors depict a hyperactive state and signs of exhaustion, as well as an interferon signature similar to that observed in autoimmune disorders such as Systemic Lupus Erythematosus (SLE) and Sjögren Syndrome (SS), in which excess BAFF and deregulated MZ populations have also been documented. Based on the above, we hypothesize that excess BAFF may preclude the generation of HIV-1-specific IgG responses and drive polyclonal responses, including those from MZ populations, endowed with polyreactivity/autoreactivity. As such, we show that the quantity of HIV-1-specific IgG varies with disease progression status. In vitro, excess BAFF promotes polyclonal IgM and IgG responses, including those from MZp. RNASeq analyses reveal that blood MZp from classic-progressors are prone to Ig production and preferentially make usage of IGHV genes associated with some HIV broadly neutralizing antibodies (bNAbs), but also with autoantibodies, and whose impact in the battle against HIV-1 has yet to be determined.

B-cell activating factor gene variants in multiple sclerosis: Possible associations with disease susceptibility among females.

Although B cells and B cell activating factor (BAFF) have been previously implicated in MS pathogenesis, data regarding the genetic influence of BAFF polymorphisms on MS susceptibility are limited. Here we aim to explore whether BAFF polymorphisms could contribute to MS susceptibility. 156 RRMS patients fulfilling the revised McDonald criteria for MS diagnosis and 220 HCs were enrolled. Clinical, laboratory, and imaging characteristics were recorded. BAFF rs9514827, rs1041569, and rs9514828 polymorphisms were assessed by RFLP-PCR in DNA samples extracted from whole peripheral blood. The BAFF rs1041569 TT genotype along with the CTT and TTC haplotypes were associated with significantly increased risk for MS development in female MS patients compared to healthy female counterparts. These findings were not confirmed in males. The rs1041569 BAFF variant together with the CTT and TTC BAFF haplotypes derived from the BAFF rs9514827, rs1041569, and rs9514828 polymorphisms may represent novel genetic contributors to the development of MS in females.

CVID-Associated B Cell Activating Factor Receptor Variants Change Receptor Oligomerization, Ligand Binding, and Signaling Responses.

PURPOSE: Binding of the B cell activating factor (BAFF) to its receptor (BAFFR) activates in mature B cells many essential pro-survival functions. Null mutations in the BAFFR gene result in complete BAFFR deficiency and cause a block in B cell development at the transition from immature to mature B cells leading therefore to B lymphopenia and hypogammaglobulinemia. In addition to complete BAFFR deficiency, single nucleotide variants encoding BAFFR missense mutations were found in patients suffering from common variable immunodeficiency (CVID), autoimmunity, or B cell lymphomas. As it remained unclear to which extent such variants disturb the activity of BAFFR, we performed genetic association studies and developed a cellular system that allows the unbiased analysis of BAFFR variants regarding oligomerization, signaling, and ectodomain shedding. METHODS: In addition to genetic association studies, the BAFFR variants P21R, A52T, G64V, DUP92-95, P146S, and H159Y were expressed by lentiviral gene transfer in DG-75 Burkitt's lymphoma cells and analyzed for their impacts on BAFFR function. RESULTS: Binding of BAFF to BAFFR was affected by P21R and A52T. Spontaneous oligomerization of BAFFR was disturbed by P21R, A52T, G64V, and P146S. BAFF-dependent activation of NF-κB2 was reduced by P21R and P146S, while interactions between BAFFR and the B cell antigen receptor component CD79B and AKT phosphorylation were impaired by P21R, A52T, G64V, and DUP92-95. P21R, G64V, and DUP92-95 interfered with phosphorylation of ERK1/2, while BAFF-induced shedding of the BAFFR ectodomain was only impaired by P21R. CONCLUSION: Although all variants change BAFFR function and have the potential to contribute as modifiers to the development of primary antibody deficiencies, autoimmunity, and lymphoma, P21R is the only variant that was found to correlate positively with CVID.

Translational development of a novel BAFF-R CAR-T therapy targeting B-cell lymphoid malignancies.

Several CD19-targeting CAR-T cells are used to treat leukemias and lymphomas; however, relapsed and/or refractory (R/R) disease is still observed in a significant number of patients. Additionally, the success of CD19-CAR-T cell therapies is not uniform across hematological malignancies, particularly in chronic lymphocytic leukemia (CLL). In this study, we present the development of a novel CAR-T cell therapy targeting B-cell activating factor receptor (BAFF-R), a key regulator of B-cell proliferation and maturation. A new monoclonal antibody against BAFF-R was generated from a hybridoma clone and used to create a novel MC10029 CAR construct. Through a series of in vitro and in vivo models using the Nalm-6 cell line for leukemia and the Z138 cell line for lymphoma, we demonstrated the antigen-specific cytotoxicity of MC10029 CAR-T cells against tumor cells. Additionally, MC10029 CAR-T cells exhibited potent antitumor effects against CD19 knockout tumor cells, mimicking CD19-negative R/R disease. MC10029 CAR-T cells were specifically targeted to CLL, in which BAFF-R is nearly always expressed. The cytotoxicity of MC10029 CAR-T cells was first shown in the MEC-1 CLL cell line, before we turned our efforts to subject-derived samples. Using healthy donor-engineered MC10029 CAR-T cells against enriched primary tumor cells, followed by subject-derived MC10029 CAR-T cells against autologous tumor cells, we showed the efficacy of MC10029 CAR-T cells against CLL subject samples. With these robust data, we have advanced to the production of MC10029 CAR-T cells, using GMP lentivirus, and obtained an IND approval in preparation for a Phase 1 clinical trial.

Myeloid-derived suppressor cells cross-talk with B10 cells by BAFF/BAFF-R pathway to promote immunosuppression in cervical cancer.

Immunosuppression induced by myeloid-derived suppressor cells (MDSCs) is one of the main obstacles to the efficacy of immunotherapy for cervical cancer. Recent studies on the immunosuppressive ability of MDSCs have primarily focused on T cells, but the effect of MDSCs on B cells function is still unclear. In a study of clinical specimens, we found that the accumulation of MDSCs in patients with cervical cancer was accompanied by high expression of B cell activating factor (BAFF) on the surface and high expression of interleukin (IL)-10-producing B cells (B10) in vivo. We found that the absence of BAFF could significantly inhibit tumor growth in a cervical cancer model using BAFF KO mice. Further studies showed that abundant MDSCs in cervical cancer induced B cells to differentiate into B10 cells by regulating BAFF which acted on the BAFF receptor (BAFF-R) of them. In this process, we found that a large amount of IL-10 secreted by B10 cells can activate STAT3 signaling pathway in MDSCs, and then form a positive feedback loop to promote the differentiation of B10 cells. Therefore, this study reveals a new mechanism of BAFF-mediated mutual immune regulation between MDSCs and B cells in the occurrence and development of cervical cancer.

BAFF blockade in experimental autoimmune encephalomyelitis reduces inflammation in the meninges and synaptic and neuronal loss in adjacent brain regions.

Multiple sclerosis (MS) has traditionally been viewed as a chronic inflammatory disease affecting the white matter of the central nervous system. However, over the past two decades, increasing evidence has highlighted the role of gray matter pathology in MS-related disability. Numerous studies have linked the presence of leptomeningeal inflammation to a more severe disease course, underscoring its potential importance as a driver of gray matter pathology in MS. The major components of leptomeningeal inflammation include T cells, B cells, macrophages, follicular dendritic cells, and plasma cells. Since BAFF [B cell-activating factor of the tumor necrosis factor (TNF) family] promotes B cell survival and maturation and is a co-stimulator of T cells, we used anti-BAFF antibody 10F4 as a BAFF antagonist to study its effect on meningeal inflammation and adjacent brain regions in a relapsing-remitting PLP-EAE (rr-EAE) model of multiple sclerosis in SJL/J mice. rr-EAE mice were treated either with anti-BAFF antibody 10F4 or with IgG control antibody. We performed ultra-high field (11.7 T) MRI to identify areas of meningeal inflammation and track them over time in both treatment groups. We also performed histopathological analysis in brain sections of these mice to study the effects of the BAFF antagonist on leptomeningeal inflammation, and hippocampal and cortical neurons and synapses. We observed that BAFF antagonist treatment reduced B cells, T cells, and myeloid cells in regions of meningeal inflammation. Additionally, we noted that BAFF treatment protected against EAE-induced synaptic and neuronal loss in the adjacent cortex and in the CA1, CA3, and dentate gyrus regions of the hippocampus likely due to its effects on meningeal inflammation.

Features of BAFF and APRIL receptors on circulating B cells in antineutrophil cytoplasmic antibody-associated vasculitis.

To investigate the features of circulating B cells, their expressing receptors, serum levels of B-cell activation factor of the TNF family (BAFF), and a proliferation-inducing ligand (APRIL) in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Blood samples from 24 patients with active AAV (a-AAV), 13 with inactive AAV (i-AAV), and 19 healthy controls (HC) were included in this study. The proportion of B cells and their expressing BAFF receptor (BAFF-R), transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), and B-cell maturation antigen were analyzed via flow cytometry. Serum levels of BAFF, APRIL, and interleukin (IL)-4, IL-6, IL-10, and IL-13 were also evaluated using an enzyme-linked immunosorbent assay. The proportion of plasmablasts (PB)/plasma cells (PC) and serum levels of BAFF, APRIL, IL-4, and IL-6 were significantly higher in a-AAV than in HC. Higher serum levels of BAFF, APRIL, and IL-4 were observed in i-AAV than in HC. Lower expression of BAFF-R on memory B cells and higher expression of TACI on CD19+ cells, immature B cells, and PB/PC were demonstrated in a-AAV and i-AAV than in HC. The population of memory B cells was positively associated with serum APRIL levels and BAFF-R expression in a-AAV. In conclusion, decreased expression of BAFF-R on memory B cells and increased expression of TACI on CD19+ cells, immature B cells, and PB/PC, as well as increased serum levels of BAFF and APRIL, were sustained even in the remission phase of AAV. Persistent aberrant signaling of BAFF/APRIL may contribute to disease relapse.

Subclinical atherosclerosis profiles in rheumatoid arthritis and primary Sjögren's syndrome: the impact of BAFF genetic variations.

OBJECTIVES: RA and primary SS carry increased atherosclerotic risk, while B-cell activating factor holds a vital role in disease pathogenesis and atherosclerosis. We aimed to compare subclinical atherosclerosis profiles between the two clinical entities and define whether BAFF genetic variants alter atherosclerotic risk. METHODS: DNA from 166 RA, 148 primary SS patients and 200 healthy controls of similar age and sex distribution was subjected to PCR-based assay for the detection of five single nucleotide polymorphisms of the BAFF gene (rs1224141, rs12583006, rs9514828, rs1041569 and rs9514827). Genotype and haplotype frequencies were determined by SNPStats software and statistical analysis was performed by SPSS and Graphpad Software. Subclinical atherosclerosis was defined by the presence of carotid/femoral plaque formation and arterial wall thickening. RESULTS: Atherosclerotic plaque formation was more frequently detected in the RA vs primary SS group (80.7% vs 62.2%, P-value <0.001), along with higher rates of family CVD history, current steroid dose and serum inflammatory markers. The TT genotype of the rs1224141 variant was more prevalent in RA but not primary SS patients with plaque and arterial wall thickening vs their counterparts without. Regarding the rs1014569 variant, among RA patients the TT genotype increased the risk for plaque formation while in primary SS patients the AT genotype conferred increased risk. Haplotype GTTTT was protective in the RA cohort, while TATTT and TTCTT haplotypes increased susceptibility for arterial wall thickening in the primary SS cohort. CONCLUSIONS: Increased inflammatory burden, higher steroid doses and distinct BAFF gene variations imply chronic inflammation and B-cell hyperactivity as key contributors for the augmented atherosclerotic risk among autoimmune patients.

SLE stratification based on BAFF and IFN-I bioactivity for biologics and implications of BAFF produced by glomeruli in lupus nephritis.

OBJECTIVE: B-cell activating factor (BAFF) is implicated in SLE pathogenesis. Blocking BAFF signalling has contributed to reducing glucocorticoid dosage and preventing organ damage. However, clinical characteristics of patients who may benefit from this therapy are not yet fully elucidated. Therefore, we identified patients with high BAFF-bioactivity to investigate their clinical characteristics and BAFF-producing cells. METHODS: We established the reporter cell for BAFF and investigated the clinical characteristics of SLE patients with high BAFF-bioactivity. We identified BAFF-expressing kidney cells using publicly available scRNA-seq data and immunohistological analysis. SLE patients were stratified based on the bioactivity of BAFF and type-I IFN (IFN-I) to identify associated characteristic clinical manifestations. RESULTS: SLE patients, especially patients with LN, had significantly higher serum BAFF-bioactivity than healthy controls (HC) and non-LN patients. Additionally, single-cell-RNA-seq data and immunohistological analysis of kidney samples from LN patients revealed that BAFF is expressed in glomerular macrophages and mesangial cells. Notably, BAFF bioactivity was elevated in the urine of LN patients compared with that of non-LN patients, while no IFN-I bioactivity was detected in the urine. Furthermore, SLE stratification based on bioactivities of serum BAFF and IFN-I revealed the clinical characteristics of patients: high BAFF represented patients with LN and high IFN-I represented patients with blood and skin manifestations. CONCLUSIONS: Monitoring urinary BAFF-bioactivity may be valuable in diagnosing LN. Furthermore, stratification based on serum BAFF and IFN-I bioactivities may allow the identification of appropriate patients for biologics targeting BAFF and IFN-I.

Translational implications of humoral and cellular immune dysfunction in granulomatosis with polyangiitis.

Granulomatosis with polyangiitis (GPA) is a rare systemic ANCA (Anti-neutrophil cytoplasmic antibodies) associated vasculitis (AAV). In the last couple of decades, GPA has emerged as a disease of concern due to rapid increase in the prevalence and incidence especially in developing countries. Unknown aetiology and rapid progression have made GPA a critical disease. Thus, establishing specific tools to facilitate early and faster disease diagnosis and efficient disease management has immense importance. GPA may develop in genetically predisposed individuals on receiving the external stimulus (i.e. microbial pathogen, pollutant etc.) that triggers the immune response. B-cell activating factor (BAFF) produced by the neutrophils, promotes the B-cell maturation and survival which leads to increased ANCA production. Abnormal B-cell and T-cell proliferation and their cytokine response plays a major role in disease pathogenesis and granuloma formation. ANCA interacts with neutrophils and induces the neutrophil extracellular traps (NETs) formation and reactive oxygen species (ROS) production which leads to the endothelial cell injury. This review article summarizes the critical pathological events and how cytokines and immune cells shape the GPA pathogenesis. Decoding this complex network would facilitate in developing tools for diagnosis, prognosis and disease management. Recently developed specific monoclonal antibodies (MAbs) targeting cytokines and immune cells are being used for safer treatment and achieving longer remission.

Small heterodimer partner interacting leucine zipper protein (SMILE) ameliorates autoimmune arthritis via AMPK signaling pathway and the regulation of B cell activation.

Rheumatoid arthritis (RA) is an autoimmune disease that causes joint swelling and inflammation and can involve the entire body. RA is characterized by the increase of pro-inflammatory cytokines such as interleukin (IL) and tumor necrosis factor, and the over-activation of T lymphocytes and B lymphocytes, which may lead to severe chronic inflammation of joints. However, despite numerous studies the pathogenesis and treatment of RA remain unresolved. This study investigated the use of small heterodimer partner-interacting leucine zipper protein (SMILE) overexpression to treat a mouse model of RA. SMILE is an insulin-inducible corepressor through adenosine monophosphate-activated kinase (AMPK) signaling pathway. The injection of a SMILE overexpression vector to mice with collagen induced-arthritis resulted in a milder clinical pathology and a reduced incidence of arthritis, less joint tissue damage, and lower levels of Th17 cells and plasma B cells in the spleen. Immunohistochemistry of the joint tissue showed that SMILE decreased B-cell activating factor (BAFF) receptor (BAFF-R), mTOR, and STAT3 expression but increased AMPK expression. In SMILE-overexpressing transgenic mice with collagen antibody-induced arthritis (CAIA), a decrease in the arthritis score and reductions in tissue damage, the number of B cells, and antibody production were observed. The treatment of immune cells in vitro with curcumin, a known SMILE-inducing agent, led to decreases in plasma B cells, germinal center B cells, IL-17-producing B cells, and BAFF-R-positive B cells. Taken together, our findings demonstrate the therapeutic potential of SMILE in RA, based on its inhibition of B cell activation mediated by the AMPK/mTOR and STAT3 signaling pathway and BAFF-R expression. Video abstract.

Low-grade inflammation is associated with a heterogeneous lipoprotein subclass profile in an apparently healthy population sample.

BACKGROUND AND AIMS: Prevention measures for cardiovascular diseases (CVD) have shifted their focus from lipoproteins to the immune system. However, low-grade inflammation and dyslipidemia are tightly entangled. The objective of this study was to assess the relations between a broad panel of inflammatory biomarkers and lipoprotein subclass parameters. METHODS: We utilized data from the population-based Study of Health in Pomerania (SHIP-TREND, n = 403). Plasma concentrations of 37 inflammatory markers were measured by a bead-based assay. Furthermore, we employed nuclear magnetic resonance spectroscopy to measure total cholesterol, total triglycerides, total phospholipids as well as the fractional concentrations of cholesterol, triglycerides, phospholipids, ApoA1, ApoA2 and ApoB in all major lipoprotein subclasses. Associations between inflammatory biomarkers and lipoprotein subclasses were analyzed by adjusted linear regression models. RESULTS: APRIL, BAFF, TWEAK, sCD30, Pentraxin-3, sTNFR1, sTNFR2, Osteocalcin, Chitinase 3-like 1, IFN-alpha2, IFN-gamma, IL-11, IL-12p40, IL-29, IL-32, IL-35, TSLP, MMP1 and MMP2 were related with lipoprotein subclass components, forming two distinct clusters. APRIL had inverse relations to HDL-C (total and subclasses) and HDL Apo-A1 and Apo-A2 content. MMP-2 was inversely related to VLDL-C (total and subclasses), IDL-C as well as LDL5/6-C and VLDL-TG, IDL-TG, total triglycerides as well as LDL5/5-TG and HDL4-TG. Additionally, we identified a cluster of cytokines linked to the Th1-immune response, which were associated with an atherogenic lipoprotein profile. CONCLUSION: Our findings expand the existing knowledge of inflammation-lipoprotein interactions, many of which are suggested to be involved in the pathogeneses of chronic non-communicable diseases. The results of our study support the use of immunomodulatory substances for the treatment and possibly prevention of CVD.