ABSTRACT
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.
Subject(s)
B-Cell Activating Factor , B-Cell Activation Factor Receptor , B-Cell Maturation Antigen , Interleukin-6 , Transmembrane Activator and CAML Interactor Protein , Tumor Necrosis Factor Ligand Superfamily Member 13 , Animals , B-Cell Activating Factor/immunology , B-Cell Activating Factor/metabolism , B-Cell Activating Factor/genetics , Tumor Necrosis Factor Ligand Superfamily Member 13/metabolism , Tumor Necrosis Factor Ligand Superfamily Member 13/immunology , Tumor Necrosis Factor Ligand Superfamily Member 13/genetics , B-Cell Maturation Antigen/immunology , B-Cell Maturation Antigen/metabolism , Transmembrane Activator and CAML Interactor Protein/metabolism , Transmembrane Activator and CAML Interactor Protein/genetics , Transmembrane Activator and CAML Interactor Protein/immunology , Interleukin-6/metabolism , Interleukin-6/immunology , Mice , B-Cell Activation Factor Receptor/metabolism , B-Cell Activation Factor Receptor/immunology , B-Cell Activation Factor Receptor/genetics , Plasma Cells/immunology , Plasma Cells/metabolism , Mice, Knockout , Antibody-Producing Cells/immunology , Antibody-Producing Cells/metabolism , Mice, Inbred C57BLABSTRACT
In mature B cells, TACI controls class-switch recombination and differentiation into plasma cells during T cell-independent antibody responses. TACI binds the ligands BAFF and APRIL. Approximately 10% of patients with common variable immunodeficiency (CVID) carry TACI mutations, of which A181E and C172Y are in the transmembrane domain. Residues A181 and C172 are located on distinct sides of the transmembrane helix, which is predicted by molecular modeling to spontaneously assemble into trimers and dimers. In human B cells, these mutations impair ligand-dependent (C172Y) and -independent (A181E) TACI multimerization and signaling, as well as TACI-enhanced proliferation and/or IgA production. Genetic inactivation of TACI in primary human B cells impaired survival of CpG-activated cells in the absence of ligand. These results identify the transmembrane region of TACI as an active interface for TACI multimerization in signal transduction, in particular for ligand-independent signals. These functions are perturbed by CVID-associated mutations.
Subject(s)
Common Variable Immunodeficiency , Transmembrane Activator and CAML Interactor Protein , B-Lymphocytes , Cell Proliferation , Common Variable Immunodeficiency/genetics , Common Variable Immunodeficiency/metabolism , Humans , Ligands , Transmembrane Activator and CAML Interactor Protein/genetics , Transmembrane Activator and CAML Interactor Protein/metabolismABSTRACT
Belimumab (BLM) is a B lymphocyte stimulator (BLyS) inhibitor approved for the treatment of systemic lupus erythematosus (SLE). Autophagy is a cell survival mechanism involved in the pathogenesis of SLE. Citrullination is a post-translational modification catalyzed by peptidylarginine deiminase (PAD) enzymes. Autophagy and citrullination may generate neoepitopes, evoking an autoimmune response. No previous studies have investigated the connection of these processes, and how BLM could affect them, in SLE. Ex vivo autophagy and protein citrullination were analyzed by western blot in lysates from 26 SLE patients' PBMCs at baseline and after 2, 4, and 12 weeks of BLM administration, and from 16 healthy donors' PBMCs. Autophagic PBMCs were identified by the immunofluorescent detection of the autophagy-associated proteins LC3B (LC3 puncta) and LAMP-1. Autophagosome accumulation was evaluated in CD14- (PBLs) and CD14+ (monocytes) SLE cells. The presence of the BLyS receptors BAFF-R, BCMA, and TACI on SLE CD4+, CD8+ T cells and monocytes, as well as serum IL-18 levels, was also assessed. Following BLM administration, we observed a decrease in autophagy and citrullination, with a lowering of LC3-II, citrullinated vimentin, and PAD4 expression levels in PBMCs from SLE patients. LC3-II levels showed a correlation with the SLE Disease Activity Index 2000 (SLEDAI-2K) after 12 weeks of therapy. The LC3B/LAMP-1 analysis confirmed the reduction in autophagy. A lesser autophagosome accumulation occurred in PBLs and monocytes which, in turn, seemed to be the main cellular populations contributing to autophagy. A reduction in patients' serum IL-18 concentrations occurred. CD4+ and CD8+ cells weakly expressed BAFF receptors; monocytes expressed only BAFF-R. BLM could impact on autophagy and citrullination, offering an opportunity for a deeper understanding of these mechanisms in SLE, and a possible tool for the clinical management of SLE.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Autophagy , Citrullination , Leukocytes, Mononuclear/metabolism , Lupus Erythematosus, Systemic/blood , Lupus Erythematosus, Systemic/drug therapy , Adult , Antibodies, Monoclonal, Humanized/pharmacology , Antigens, CD/metabolism , Autophagy/drug effects , B-Cell Activation Factor Receptor/metabolism , B-Cell Maturation Antigen/metabolism , Biomarkers/blood , Cell Membrane/drug effects , Cell Membrane/metabolism , Citrullination/drug effects , Female , Humans , Interleukin-18/blood , Leukocytes, Mononuclear/drug effects , Lupus Erythematosus, Systemic/pathology , Lysosomal Membrane Proteins/metabolism , Male , Microtubule-Associated Proteins/metabolism , Middle Aged , Transmembrane Activator and CAML Interactor Protein/metabolismABSTRACT
Atherosclerotic cardiovascular disease causes heart attacks and strokes, which are the leading causes of mortality worldwide1. The formation of atherosclerotic plaques is initiated when low-density lipoproteins bind to heparan-sulfate proteoglycans (HSPGs)2 and become trapped in the subendothelial space of large and medium size arteries, which leads to chronic inflammation and remodelling of the artery wall2. A proliferation-inducing ligand (APRIL) is a cytokine that binds to HSPGs3, but the physiology of this interaction is largely unknown. Here we show that genetic ablation or antibody-mediated depletion of APRIL aggravates atherosclerosis in mice. Mechanistically, we demonstrate that APRIL confers atheroprotection by binding to heparan sulfate chains of heparan-sulfate proteoglycan 2 (HSPG2), which limits the retention of low-density lipoproteins, accumulation of macrophages and formation of necrotic cores. Indeed, antibody-mediated depletion of APRIL in mice expressing heparan sulfate-deficient HSPG2 had no effect on the development of atherosclerosis. Treatment with a specific anti-APRIL antibody that promotes the binding of APRIL to HSPGs reduced experimental atherosclerosis. Furthermore, the serum levels of a form of human APRIL protein that binds to HSPGs, which we termed non-canonical APRIL (nc-APRIL), are associated independently of traditional risk factors with long-term cardiovascular mortality in patients with atherosclerosis. Our data reveal properties of APRIL that have broad pathophysiological implications for vascular homeostasis.
Subject(s)
Atherosclerosis/metabolism , Atherosclerosis/prevention & control , Heparan Sulfate Proteoglycans/metabolism , Tumor Necrosis Factor Ligand Superfamily Member 13/metabolism , Animals , B-Cell Maturation Antigen/metabolism , Binding Sites , Cardiovascular Diseases/blood , Cardiovascular Diseases/mortality , Female , Humans , Male , Mice , Mice, Inbred C57BL , Protein Binding , Transmembrane Activator and CAML Interactor Protein/metabolism , Tumor Necrosis Factor Ligand Superfamily Member 13/blood , Tumor Necrosis Factor Ligand Superfamily Member 13/deficiencyABSTRACT
Host genes define the severity of inflammation and immunity but specific loci doing so are unknown. Here we show that TNF receptor superfamily member 13B (TNFRSF13B) variants, which enhance defense against certain pathogens, also control immune-mediated injury of transplants, by regulating innate B cells' functions. Analysis of TNFRSF13B in human kidney transplant recipients revealed that 33% of those with antibody-mediated rejection (AMR) but fewer than 6% of those with stable graft function had TNFRSF13B missense mutations. To explore mechanisms underlying aggressive immune responses, we investigated alloimmunity and rejection in mice. Cardiac allografts in Tnfrsf13b-mutant mice underwent early and severe AMR. The dominance and precocity of AMR in Tnfrsf13b-deficient mice were not caused by increased alloantibodies. Rather, Tnfrsf13b mutations decreased "natural" IgM and compromised complement regulation, leading to complement deposition in allografted hearts and autogenous kidneys. Thus, WT TNFRSF13B and Tnfrsf13b support innate B cell functions that limit complement-associated inflammation; in contrast, common variants of these genes intensify inflammatory responses that help clear microbial infections but allow inadvertent tissue injury to ensue. The wide variation in inflammatory reactions associated with TNFRSF13B diversity suggests polymorphisms could underlie variation in host defense and explosive inflammatory responses that sometimes enhance morbidity associated with immune responses.
Subject(s)
B-Lymphocytes/immunology , Graft Rejection/genetics , Immunity, Innate , Isoantibodies/immunology , Kidney Transplantation/adverse effects , Mutation, Missense , Transmembrane Activator and CAML Interactor Protein/genetics , Animals , B-Lymphocytes/pathology , DNA/genetics , DNA Mutational Analysis , Disease Models, Animal , Female , Genotype , Graft Rejection/immunology , Graft Rejection/pathology , Humans , Lymphocyte Count , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Transgenic , Transmembrane Activator and CAML Interactor Protein/metabolismABSTRACT
Although fingolimod and interferon-ß are two mechanistically different multiple sclerosis (MS) treatments, they both induce B cell activating factor (BAFF) and shift the B cell pool towards a regulatory phenotype. However, whether there is a shared mechanism between both treatments in how they influence the B cell compartment remains elusive. In this study, we collected a cross-sectional study population of 112 MS patients (41 untreated, 42 interferon-ß, 29 fingolimod) and determined B cell subsets, cell-surface and RNA expression of BAFF-receptor (BAFF-R) and transmembrane activator and cyclophilin ligand interactor (TACI) as well as plasma and/or RNA levels of BAFF, BAFF splice forms and interleukin-10 (IL-10) and -35 (IL-35). We added an in vitro B cell culture with four stimulus conditions (Medium, CpG, BAFF and CpG+BAFF) for untreated and interferon-ß treated patients including measurement of intracellular IL-10 levels. Our flow experiments showed that interferon-ß and fingolimod induced BAFF protein and mRNA expression (P ≤ 3.15 x 10-4) without disproportional change in the antagonizing splice form. Protein BAFF correlated with an increase in transitional B cells (P = 5.70 x 10-6), decrease in switched B cells (P = 3.29 x 10-4), and reduction in B cell-surface BAFF-R expression (P = 2.70 x 10-10), both on TACI-positive and -negative cells. TACI and BAFF-R RNA levels remained unaltered. RNA, plasma and in vitro experiments demonstrated that BAFF was not associated with increased IL-10 and IL-35 levels. In conclusion, treatment-induced BAFF correlates with a shift towards transitional B cells which are enriched for cells with an immunoregulatory function. However, BAFF does not directly influence the expression of the immunoregulatory cytokines IL-10 and IL-35. Furthermore, the post-translational mechanism of BAFF-induced BAFF-R cell surface loss was TACI-independent. These observations put the failure of pharmaceutical anti-BAFF strategies in perspective and provide insights for targeted B cell therapies.
Subject(s)
B-Cell Activating Factor/metabolism , B-Lymphocyte Subsets/immunology , Fingolimod Hydrochloride/therapeutic use , Immunosuppressive Agents/therapeutic use , Interferon-beta/therapeutic use , Multiple Sclerosis/drug therapy , Multiple Sclerosis/immunology , Precursor Cells, B-Lymphoid/immunology , Signal Transduction/drug effects , Adult , Aged , B-Cell Activating Factor/genetics , B-Cell Activation Factor Receptor/genetics , B-Cell Activation Factor Receptor/metabolism , B-Lymphocyte Subsets/drug effects , Cells, Cultured , Cross-Sectional Studies , Female , Follow-Up Studies , Humans , Interleukin-10/metabolism , Interleukins , Male , Middle Aged , Precursor Cells, B-Lymphoid/drug effects , RNA, Messenger/genetics , Transmembrane Activator and CAML Interactor Protein/genetics , Transmembrane Activator and CAML Interactor Protein/metabolism , Treatment OutcomeABSTRACT
TNFRSF13B encodes the transmembrane activator and CAML interactor (TACI) receptor, which drives plasma cell differentiation. Although TNFRSF13B supports host defense, dominant-negative TNFRSF13B alleles are common in humans and other species and only rarely associate with disease. We reasoned that the high frequency of disruptive TNFRSF13B alleles reflects balancing selection, the loss of function conferring advantage in some settings. Testing that concept, we investigated how a common human dominant-negative variant, TNFRSF13B A181E, imparts resistance to enteric pathogens. Mice engineered to express mono- or biallelic A144E variants of tnrsf13B, corresponding to A181E, exhibited a striking resistance to pathogenicity and transmission of Citrobacter rodentium, a murine pathogen that models enterohemorrhagic Escherichia coli, and resistance was principally owed to natural IgA deficiency in the intestine. In WT mice with gut IgA and in mutant mice reconstituted with enteric IgA obtained from WT mice, IgA induces LEE expression of encoded virulence genes, which confer pathogenicity and transmission. Taken together, our results show that C. rodentium and most likely other enteric organisms appropriated binding of otherwise protective antibodies to signal induction of the virulence program. Additionally, the high prevalence of TNFRSF13B dominant-negative variants reflects balancing selection.
Subject(s)
Citrobacter rodentium/immunology , Colitis/immunology , Enterobacteriaceae Infections/immunology , Immunoglobulin A/immunology , Transmembrane Activator and CAML Interactor Protein/genetics , Alleles , Animals , B-Lymphocytes , Colitis/microbiology , Disease Models, Animal , Disease Resistance/genetics , Enterobacteriaceae Infections/microbiology , Female , Humans , Immunoglobulin A/metabolism , Loss of Function Mutation , Lymphocyte Activation/genetics , Male , Polymorphism, Single Nucleotide/immunology , Transmembrane Activator and CAML Interactor Protein/metabolismABSTRACT
Selective IgA deficiency (SIgAD), characterized by a serum IgA level below 0.07 mg/ml, while displaying normal serum levels of IgM and IgG antibodies, is the most frequently occurring primary immunodeficiency that reveals itself after the first four years after birth. These individuals with SIgAD are for the majority healthy and even when they are identified they are usually not investigated further or followed up. However, recent studies show that newborns and young infants already display clinical manifestations of this condition due to aberrancies in their immune defense. Interestingly, there is a huge heterogeneity in the clinical symptoms of the affected individuals. More than 50% of the affected individuals do not have clinical symptoms, while the individuals that do show clinical symptoms can suffer from mild to severe infections, allergies and autoimmune diseases. However, the reason for this heterogeneity in the manifestation of clinical symptoms of the individuals with SIgAD is unknown. Therefore, this review focusses on the characteristics of innate immune system driving T-cell independent IgA production and providing a mechanism underlying the development of SIgAD. Thereby, we focus on some important genes, including TNFRSF13B (encoding TACI), associated with SIgAD and the involvement of epigenetics, which will cover the methylation degree of TNFRSF13B, and environmental factors, including the gut microbiota, in the development of SIgAD. Currently, no specific treatment for SIgAD exists and novel therapeutic strategies could be developed based on the discussed information.
Subject(s)
IgA Deficiency/immunology , Immunity, Innate/immunology , Immunoglobulin A/immunology , Transmembrane Activator and CAML Interactor Protein/immunology , Epigenesis, Genetic/genetics , Epigenesis, Genetic/immunology , Gastrointestinal Microbiome/immunology , Humans , IgA Deficiency/genetics , IgA Deficiency/metabolism , Immunity, Innate/genetics , Immunoglobulin A/blood , Infant , Infant, Newborn , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Transmembrane Activator and CAML Interactor Protein/genetics , Transmembrane Activator and CAML Interactor Protein/metabolismABSTRACT
BACKGROUND: Kidney transplantation is the best treatment option for end stage renal disease (ESRD), but graft rejection is still a big obstacle that occurs in spite of immunosuppressive therapy. B cells are considered as the major reason for renal graft rejection because of antibody production. Due to their roles in B cell function, we intended to evaluate the B cell activating factor (BAFF) and its receptors including BAFF receptor (BAFF-R), B cell maturation antigen (BCMA), and transmembrane activator and cyclophilin ligand interactor (TACI) in renal transplant patients. METHOD: The study included 40 kidney allograft patients with cAMR, 40 stable kidney allograft patients, and 8 healthy volunteers with normal kidney function. The percentage and absolute number of CD19+ B cells were analyzed by flow cytometry, the serum level of BAFF was analyzed by ELISA, and mRNA expressions of BAFF and BAFF receptors (BAFF-R, BCMA, and TACI) were measured using quantitative real-time PCR. RESULTS: The percentage and the absolute number of B cells decreased significantly in stable and cAMR patients compared to healthy individuals. The serum level and gene expression of BAFF, as well as the mRNA level of BCMA, were increased significantly in both cAMR and stable patients compared to healthy volunteers. There was an overexpression of TACI mRNA in cAMR patients compared to stable patients. CONCLUSIONS: Both soluble protein and mRNA transcript of BAFF increased in transplant recipients. However, BAFF neither at the serum level nor at the mRNA transcript level cannot be a good biomarker for the prediction of cAMR. In addition, expression of TACI, compared to other receptors of BAFF, confers a potential to be used in distinguishing cAMR and stable kidney transplant patients.
Subject(s)
B-Cell Activating Factor/metabolism , Graft Rejection/immunology , Kidney Transplantation , Adolescent , Adult , Aged , Aged, 80 and over , B-Cell Activating Factor/genetics , B-Cell Activation Factor Receptor/genetics , B-Cell Activation Factor Receptor/metabolism , B-Cell Maturation Antigen/genetics , B-Cell Maturation Antigen/metabolism , Chronic Disease , Female , Graft Survival , Humans , Isoantibodies/metabolism , Male , Middle Aged , Transmembrane Activator and CAML Interactor Protein/genetics , Transmembrane Activator and CAML Interactor Protein/metabolism , Young AdultABSTRACT
PURPOSE: While B-cell activating factor (BAFF) was identified to promote the invasion in other malignancies, its role in the progression of uveal melanoma (UM) still remains unexplored. Here, we analysed the serum level of BAFF in UM patients with regard to its significance as biomarker for the metastases. METHODS: In this retrospective study, serum BAFF levels in 173 UM patients (36 with metastases and 137 without), and 23 healthy controls were measured with a multiplexed sandwich ELISA system and then correlated with clinicopathological characteristics such as primary tumor size, tumor location, histological cell type, sex, cancer stage, cytogenetic alterations of chromosome 3, and the metastatic burden. Immunohistochemical staining of 50 UM tissue specimens was also performed to evaluate the expression of BAFF and its receptors BAFF-R and TACI. RESULTS: The metastatic patients were identified to have significantly higher serum BAFF levels (mean ± SD, 1520.8 ± 1182.1 pg/ml) than those without metastases (950.4 ± 494.6 pg/ml) and controls (810.3 ± 140.5 pg/ml). While no distinctions were detected with regard to tumor location, histological cell type, gender, and monosomy 3, the patients in cancer stages II, III, and IV displayed higher serum BAFF levels than those in stage I. The serum BAFF level was significantly correlated with the metastatic burden. The serum BAFF level of 1120 pg/ml was identified to have the best performance for distinguishing the metastatic patients from non-metastatic patients. In the kinetic study, we noticed that 20.8% of the analysed patients already demonstrated elevated serum BAFF concentrations before the clinical diagnosis of metastases. Positive BAFF staining was detected in the cytoplasm of single tumor cells (in 13 specimens), macrophages (in 12 specimens), and tumor-infiltrating lymphocytes (TILs) (in 13 specimens). The expressions of BAFF-R and TACI were also observed in 17 and 36 of the 50 tested UM specimens, respectively. CONCLUSIONS: Our study first suggests that BAFF might be a promising serum marker for the detection of UM metastases.
Subject(s)
B-Cell Activating Factor/metabolism , Biomarkers, Tumor/metabolism , Melanoma/metabolism , Neoplasm Metastasis/pathology , Uveal Neoplasms/metabolism , Adult , Aged , Aged, 80 and over , Case-Control Studies , Chromosomes, Human, Pair 3/metabolism , Cytoplasm/metabolism , Female , Humans , Lymphocytes, Tumor-Infiltrating/metabolism , Lymphocytes, Tumor-Infiltrating/pathology , Macrophages/metabolism , Male , Melanoma/pathology , Middle Aged , Retrospective Studies , Transmembrane Activator and CAML Interactor Protein/metabolism , Uveal Neoplasms/pathologyABSTRACT
B cell differentiation and memory are controlled by the transmembrane activator and CAML interactor (TACI), a receptor encoded by TNFRSF13B. TNFRSF13B mutations are frequently found in common variable immunodeficiency (CVID) and in IgA -deficiency; yet, ~98% of those with mutant TNFRSF13B are healthy. Indeed, TNFRSF13B is among the 5% most polymorphic genes in man. Other mammals evidence polymorphism at comparable loci. We hypothesize that TNFRSF13B diversity might promote rather than detract from well-being by controlling key elements of innate immunity. We shall discuss how extraordinary diversity of TNFRSF13B could have evolved and persisted across diverse species of mammals by controlling innate and adaptive B cell responses in apparently paradoxical ways.
Subject(s)
Adaptive Immunity/genetics , B-Lymphocytes/immunology , Common Variable Immunodeficiency/genetics , Evolution, Molecular , IgA Deficiency/genetics , Immunity, Innate/genetics , Mutation , Transmembrane Activator and CAML Interactor Protein/genetics , Animals , Antibodies/metabolism , B-Lymphocytes/metabolism , Common Variable Immunodeficiency/immunology , Common Variable Immunodeficiency/metabolism , Genetic Predisposition to Disease , Humans , IgA Deficiency/immunology , IgA Deficiency/metabolism , Phenotype , Transmembrane Activator and CAML Interactor Protein/metabolismABSTRACT
B-cell follicles constitute large reservoirs of infectious HIV/SIV associated to follicular dendritic cells and infecting follicular helper (TFH) and regulatory (TFR) T-cells in germinal centers (GCs). Thus, follicular and GC B-cells are persistently exposed to viral antigens. Despite recent development of potent HIV immunogens, numerous questions are still open regarding GC reaction during early HIV/SIV infection. Here, we dissect the dynamics of B- and T-cells in GCs of macaques acutely infected by SIV (Group SIV+) or vaccinated with Tetanus Toxoid (Group TT), a T-dependent model antigen. Systemic inflammation and mobilization of antigen-presenting cells in inguinal lymph nodes and spleen are lower in Group TT than in Group SIV+. Despite spleen GC reaction of higher magnitude in Group SIV+, the development of protective immunity could be limited by abnormal helper functions of TFH massively polarized into TFH1-like cells, by inflammation-induced recruitment of fCD8 (either regulatory or cytotoxic) and by low numbers of TFR limiting TFH/TFR competition for high affinity B-cells. Increased GC B-cells apoptosis and accumulation of CD21lo memory B-cells, unable to further participate to GC reaction, likely contribute to eliminate SIV-specific B-cells and decrease antibody affinity maturation. Surprisingly, functional GCs and potent TT-specific antibodies develop despite low levels of CXCL13.
Subject(s)
Germinal Center/immunology , Simian Acquired Immunodeficiency Syndrome/immunology , Simian Immunodeficiency Virus/immunology , Animals , B-Cell Activation Factor Receptor/metabolism , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Immunity, Humoral , Immunologic Memory , Inflammation , Macaca mulatta , Male , Spleen/immunology , T Follicular Helper Cells/immunology , T Follicular Helper Cells/metabolism , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Tetanus Toxoid/administration & dosage , Tetanus Toxoid/immunology , Transmembrane Activator and CAML Interactor Protein/metabolismABSTRACT
Background Recently, some studies reported the pulmonary artery hypertension (PAH)-associated genes. However, a majority of patients with familial or sporadic PAH lack variants in the known pathogenic genes. In this study, we investigated the new causative gene variants associated with PAH. Methods and Results Whole-exome sequencing in 242 Japanese patients with familial or sporadic PAH identified a heterozygous substitution change involving c.226G>A (p.Gly76Ser) in tumor necrotic factor receptor superfamily 13B gene (TNFRSF13B) in 6 (2.5%) patients. TNFRSF13B controls the differentiation of B cell and secretion of inflammatory cytokines and may be involved in vascular inflammation. In silico structural analysis simulation demonstrated the structural instability of the N-terminal region of the protein synthesized from TNFRSF13B p.Gly76Ser variant. These suggest that the TNFRSF13B p.Gly76Ser variant may be involved in the development of PAH via aberrant inflammation in pulmonary vessels. Conclusions TNFRSF13B p.Gly76Ser variant is a candidate of novel causative gene variant for PAH.
Subject(s)
DNA/genetics , Genetic Predisposition to Disease , Mutation , Pulmonary Arterial Hypertension/genetics , Transmembrane Activator and CAML Interactor Protein/genetics , Adult , Exome , Female , Humans , Male , Pedigree , Pulmonary Arterial Hypertension/metabolism , Transmembrane Activator and CAML Interactor Protein/metabolism , Exome Sequencing/methodsABSTRACT
B cell activating factor of TNF family (BAFF) is a member of TNF ligand superfamily and plays a key role in B cell homeostasis, proliferation, maturation, and survival. In this study, we detected BAFF level, the expressions of BAFF receptors and important molecules in NF-κB pathway in rheumatoid arthritis (RA) patients and analyzed the correlation between BAFF level and clinical variables, laboratory parameters or X-ray scores in order to elucidate the roles of BAFF in RA. A total of 50 RA patients and 50 healthy controls (HCs) were enrolled. We showed that the serum BAFF level in RA patients was significantly higher than that of HCs, and the percentages of B cell subsets (CD19+ B cells, CD19+CD27+ B cells, CD19+CD20+CD27+ B cells, and CD19+CD20-CD27+ B cells) in the serum of RA patients were significantly increased compared with those of HCs. The percentages of CD19+BAFFR+ B cells, CD19+ BCMA+ B cells, and CD19+ TACI+ B cells in RA patients were significantly increased compared with those in HCs. The expression of important molecules in the NF-κB pathway (MKK3, MKK6, p-P38, p-P65, TRAF2, and p52) was significantly higher in RA patients than in HCs, but p100 level in RA patients was lower than that in HCs. The serum BAFF level was positively correlated with C-reactive protein, rheumatoid factor, disease activity score (in 28 joints), swollen joint counts, tender joint counts, and X-ray scores. When normal B cells were treated with BAFF in vitro, the percentages of the B cell subset and the expression of BAFF receptors were significantly upregulated. BAFF also promoted the expression of MKK3, MKK6, p-P38, p-P65, TRAF2, and p52. In conclusion, this study demonstrates that BAFF level is correlated with the disease activity and bone destruction of RA. BAFF is involved in the differentiation, proliferation, and activation of B cells in RA through NF-κB signaling pathway, suggesting that BAFF might be an ideal therapeutic target for RA.
Subject(s)
Arthritis, Rheumatoid/metabolism , B-Cell Activating Factor/metabolism , B-Lymphocytes/metabolism , Lymphocyte Activation/physiology , NF-kappa B p50 Subunit/metabolism , Signal Transduction/physiology , Aged , B-Cell Activation Factor Receptor/metabolism , B-Cell Maturation Antigen/metabolism , Cell Differentiation/physiology , Cytokines/metabolism , Female , Humans , Immunoglobulins/metabolism , Male , Middle Aged , Transmembrane Activator and CAML Interactor Protein/metabolism , Up-Regulation/physiologyABSTRACT
OBJECTIVE: Cardiovascular disease (CVD) is the leading cause of death in systemic lupus erythematosus (SLE). B cells play a key role in the pathogenesis of lupus, and anti-BAFF therapy has been approved for use in SLE. Since mature B cells also promote atherosclerosis, we undertook this study to evaluate, in a mouse model and in SLE patients, whether BAFF neutralization has an atheroprotective effect in SLE. METHODS: The effect of BAFF on atherosclerosis associated with lupus was investigated in the atherosclerosis/lupus-prone apolipoprotein E-knockout D227K mouse model and in a cohort of SLE patients. Mice were treated with a blocking anti-BAFF monoclonal antibody (mAb), while fed a standard chow diet. Carotid plaque and carotid intima-media thickness were assessed by ultrasound at baseline and during follow-up in SLE patients who were asymptomatic for CVD. RESULTS: Anti-BAFF mAb in ApoE-/- D227K mice induced B cell depletion, efficiently treated lupus, and improved atherosclerosis lesions (21% decrease; P = 0.007) in mice with low plasma cholesterol levels but worsened the lesions (17% increase; P = 0.06) in mice with high cholesterol levels. The atheroprotective effect of the BAFF-BAFF receptor signaling inhibition on B cells was counterbalanced by the proatherogenic effect of the BAFF-TACI signaling inhibition on macrophages. In SLE patients, blood BAFF levels were associated with subclinical atherosclerosis (r = 0.26, P = 0.03). Anti-BAFF mAb treatment had a differential effect on the intima-media thickness progression in SLE patients depending on body mass index. CONCLUSION: Depending on the balance between lipid-induced and B cell-induced proatherogenic conditions, anti-BAFF could be detrimental or beneficial, respectively, to atherosclerosis development in SLE.
Subject(s)
Atherosclerosis/metabolism , B-Cell Activating Factor/antagonists & inhibitors , B-Cell Activating Factor/metabolism , B-Lymphocytes/immunology , Cholesterol/metabolism , Lupus Erythematosus, Systemic/metabolism , Transmembrane Activator and CAML Interactor Protein/metabolism , Adult , Adventitia/pathology , Animals , Antibodies, Neutralizing/pharmacology , Aorta/pathology , Atherosclerosis/diagnostic imaging , Atherosclerosis/immunology , Carotid Artery Diseases/diagnostic imaging , Carotid Artery Diseases/metabolism , Carotid Intima-Media Thickness , Cell Proliferation , Female , Foam Cells/drug effects , Foam Cells/metabolism , Humans , Lupus Erythematosus, Systemic/immunology , Male , Mice , Mice, Knockout, ApoE , Middle Aged , Phenotype , Plaque, Atherosclerotic/diagnostic imaging , Plaque, Atherosclerotic/metabolism , Signal Transduction , UltrasonographyABSTRACT
Abnormal B cells, which produce antibodies against self-antigens, play a key role in the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). B-cell activating factor (BAFF) is closely associated with abnormal B cells and participates in B cell-mediated autoimmune diseases; thus, neutralizing BAFF is an effective method for treating these diseases. Our group designed a novel fusion protein, BAFF-Trap, that contains the BAFF-binding domains of two BAFF receptors (TACI and BAFF-R) and the Fc domain of human IgG1. In this study, we showed that BAFF-Trap significantly decreased the autoantibody levels, BAFF concentrations and B cells numbers in MRL/lpr mice. BAFF-Trap suppressed the expression of pro-inflammatory cytokines in the kidney and decreased the frequencies of T cell subsets and dendritic cells. Furthermore, BAFF-Trap reduced proteinuria and IgG deposition, relieved glomerular damage in the kidney, and markedly improved the survival rate of mice. These results indicated that BAFF-Trap may be a potential drug for the treatment of SLE.
Subject(s)
B-Cell Activating Factor/antagonists & inhibitors , Lupus Erythematosus, Systemic/drug therapy , Lupus Erythematosus, Systemic/metabolism , Recombinant Fusion Proteins/pharmacology , Tartrate-Resistant Acid Phosphatase/metabolism , Animals , Autoantibodies/metabolism , B-Cell Activation Factor Receptor/metabolism , B-Lymphocytes/drug effects , Cytokines/metabolism , Dendritic Cells/drug effects , Dendritic Cells/metabolism , Disease Progression , Female , Humans , Immunoglobulin G/metabolism , Inflammation/drug therapy , Inflammation/metabolism , Kidney Diseases/drug therapy , Kidney Diseases/metabolism , Kidney Glomerulus/drug effects , Kidney Glomerulus/metabolism , Mice , Mice, Inbred MRL lpr , Survival Rate , T-Lymphocyte Subsets/drug effects , T-Lymphocyte Subsets/metabolism , Transmembrane Activator and CAML Interactor Protein/metabolismABSTRACT
The MRZ reaction (MRZR) comprises the three antibody indices (AIs) against measles, rubella, and varicella zoster virus, reflecting an intrathecal polyspecific B cell response highly specific for multiple sclerosis (MS). Thus, MRZR can be used to confirm a diagnosis of primary progressive MS (PPMS) but its pathophysiological and wider clinical relevance is unclear. This study aimed to investigate whether PPMS patients with a positive MRZR (MRZR+) differ from those with a negative MRZR (MRZR-) according to cerebrospinal fluid (CSF) biomarkers of B cell activity, neuroaxonal damage or glial activity, and clinical features. (1) Methods: In a multicenter PPMS cohort (n = 81) with known MRZR status, we measured B cell-activating factor (BAFF), chemokine CXC ligand 13 (CXCL-13), soluble B cell maturation antigen (sBCMA), soluble transmembrane activator and CAML interactor (sTACI), and chitinase-3-like protein 1 (CHI3L1) in the CSF with enzyme-linked immunosorbent assays (ELISAs). Glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) were detected in serum and CSF using single molecule array (SIMOA) technology. (2) Results: MRZR+ patients (45.7% of all PPMS patients) revealed higher levels of NfL in CSF compared to MRZR- patients (54.3%). There were positive correlations between each of sBCMA, sTACI, and intrathecal immunoglobin G (IgG) synthesis. Additionally, NfL concentrations in serum positively correlated with those in CSF and those of GFAP in serum. However, MRZR+ and MRZR- patients did not differ concerning clinical features (e.g., age, disease duration, Expanded Disability Status Scale (EDSS) at diagnosis and follow-up); CSF routine parameters; CSF concentrations of BAFF, CXCL-13, sBCMA, sTACI, CHI3L1, and GFAP; or serum concentrations of GFAP and NfL. (3) Conclusions: In PPMS patients, MRZR positivity might indicate a more pronounced axonal damage. Higher levels of the soluble B cell receptors BCMA and transmembrane activator and CAML interactor (TACI) in CSF are associated with a stronger intrathecal IgG synthesis in PPMS.
Subject(s)
Biomarkers/metabolism , Cerebrospinal Fluid/metabolism , Multiple Sclerosis/metabolism , Adolescent , Adult , Axons/metabolism , B-Lymphocytes/metabolism , Chitinase-3-Like Protein 1/metabolism , Cohort Studies , Female , Glial Fibrillary Acidic Protein/metabolism , Humans , Immunoglobulin G/metabolism , Male , Middle Aged , Transmembrane Activator and CAML Interactor Protein/metabolism , Young AdultABSTRACT
B cell-activating factor (BAFF) is an essential cytokine in primary Sjögren's syndrome (pSS) physiopathology. It has been reported that pSS patients develop germinal center-like (GC-like) structures in their minor salivary glands (MSGs). BAFF, BAFF-R, TACI, and BCMA expression was analyzed in MSGs from 29 subjects (nonspecific chronic sialadenitis and focal lymphocytic sialadenitis with the presence [pSS-GC(+)] or absence [pSS-GC(-)] of GC-like structures). Twenty-four percent of patients showed ectopic GC-like structures and a high focus score [p < 0.001 vs pSS-GC(-)]. BAFF serum levels (sBAFF) were high in pSS patients (p = 0.025 vs healthy subjects). However, the pSS-GC(-) group showed higher sBAFF levels than pSS-GC(+) patients. BAFF and BAFF-R glandular expression levels were higher in pSS-GC(+) patients, without significant differences compared to pSS-GC(-) patients. Soluble levels of BAFF correlated with anti-La/SSB antibodies and disease duration. Our results showed that BAFF could contribute to focal lymphocytic infiltration. The role of BAFF-binding receptors in MSGs is proposed as a mechanism for the possible establishment of ectopic GC-like structures and disease progression in some patients. In conclusion, this study supports previous evidence that considers the active BAFF system role in the pathogenesis of pSS and the need for strong biomarkers in this disease.
Subject(s)
B-Cell Activating Factor/metabolism , B-Cell Activation Factor Receptor/metabolism , Salivary Glands, Minor/pathology , Sjogren's Syndrome/metabolism , Adult , Aged , B-Cell Activating Factor/blood , B-Cell Maturation Antigen/metabolism , Case-Control Studies , Female , Germinal Center/pathology , Humans , Immunophenotyping , Male , Middle Aged , Salivary Glands, Minor/physiology , Severity of Illness Index , Sjogren's Syndrome/etiology , Sjogren's Syndrome/immunology , Sjogren's Syndrome/pathology , Transmembrane Activator and CAML Interactor Protein/metabolismABSTRACT
The increasing availability of genetic testing for modern immunologists in the evaluation of immune diseases could provide a definite diagnosis in elusive cases. A 27-year-old white male patient presented to the clinic with recurrent sinopulmonary and cutaneous infections since childhood. The patient's mother had seronegative polyarthritis, and one of two sisters of the patient had chronic sinopulmonary infections. Serum immunoglobulins, immunoglobulin G (IgG) subclasses, lymphocyte subset markers, mannose-binding lectin, mitogen and antigen stimulation, bacteriophage study, and Streptococcus pneumoniae titers to 23 serotypes were all normal. B-cell phenotyping revealed a decrease in both nonswitched memory B cells (CD19+CD27+IgD+) and switched memory B-cells (CD19+CD27+IgD-). Genetic testing and the improvement of clinical symptoms after IgG replacement led to the final diagnosis.
Subject(s)
B-Lymphocytes/metabolism , Bronchitis/immunology , Common Variable Immunodeficiency/diagnosis , Sinusitis/immunology , Skin Diseases, Infectious/immunology , Transmembrane Activator and CAML Interactor Protein/genetics , Abscess/etiology , Abscess/immunology , Adult , B-Cell Activation Factor Receptor/metabolism , Bronchitis/etiology , Cellulitis/etiology , Cellulitis/immunology , Common Variable Immunodeficiency/complications , Common Variable Immunodeficiency/genetics , Common Variable Immunodeficiency/immunology , Diagnosis, Differential , Humans , Male , Mastoiditis/etiology , Mastoiditis/immunology , Mothers , Pedigree , Recurrence , Serratia Infections/etiology , Serratia Infections/immunology , Serratia marcescens , Siblings , Sinusitis/etiology , Skin Diseases, Infectious/etiology , Staphylococcal Infections/etiology , Staphylococcal Infections/immunology , Staphylococcus aureus , Transmembrane Activator and CAML Interactor Protein/metabolismABSTRACT
Background: Biological agents (also termed biologics or biologicals) play a growingly central role in the treatment of immunological diseases. However, the numerous studies published on biologics complicate the decision on the most appropriate biologic for a given disease. We aim to address this problem by publishing a series of systematic reviews evaluating the safety and efficacy of B cell-targeting biologics for the treatment of immune-mediated diseases. This article assesses the safety and efficacy of atacicept, a recombinant fusion protein consisting of the binding portion of transmembrane activator and CAML interactor (TACI; also known as tumor necrosis factor receptor superfamily member 13B), which is able to bind the cytokines B cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL). Objective: To evaluate atacicept's safety and efficacy for the treatment of immune-mediated disorders compared to placebo, conventional treatment or other biologics. Methods: The PRISMA checklist guided the reporting of the data. We searched the PubMed database between 4 October 2016 and 26 July 2018 concentrating on immune-mediated disorders. Results: The literature search identified 118 articles. After screening titles and abstracts against the inclusion and exclusion criteria and assessing full texts, ten articles were finally included in a narrative synthesis. Conclusions: Atacicept failed to show an effect in multiple sclerosis, optic neuritis, rheumatoid arthritis, and systemic lupus erythematosus. In patients with systemic lupus erythematosus, atacicept led to increased infection rates, but this adverse effect was not seen in the other treated diseases.