RESUMO
B cell-activating factor (BAFF) is a critical TNF-family cytokine that regulates homeostasis and peripheral tolerance of B2 cells. BAFF overproduction promotes autoantibody generation and autoimmune diseases. During obesity, BAFF is predominantly produced by white adipose tissue (WAT), and IgG autoantibodies against adipocytes are identified in the WAT of obese humans. However, it remains to be determined if the autoantibodies formed during obesity affect WAT remodeling and systemic insulin resistance. Here, we show that IgG autoantibodies are generated in high-fat diet (HFD)-induced obese mice that bind to apoptotic adipocytes and promote their phagocytosis by macrophages. Next, using murine models of obesity in which the gonadal WAT undergoes remodeling, we found that BAFF neutralization depleted IgG autoantibodies, increased the number of dead adipocytes, and exacerbated WAT inflammation and insulin resistance. RNA sequencing of the stromal vascular fraction from the WAT revealed decreased expression of immunoglobulin light-chain and heavy-chain variable genes suggesting a decreased repertoire of B cells after BAFF neutralization. Further, the B cell activation and the phagocytosis pathways were impaired in the WAT of BAFF-neutralized mice. In vitro, plasma IgG fractions from BAFF-neutralized mice reduced the phagocytic clearance of apoptotic adipocytes. Altogether, our study suggests that IgG autoantibodies developed during obesity, at least in part, dampens exacerbated WAT inflammation and systemic insulin resistance.
Assuntos
Adipócitos , Autoanticorpos , Fator Ativador de Células B , Imunoglobulina G , Resistência à Insulina , Obesidade , Fagocitose , Animais , Resistência à Insulina/imunologia , Fator Ativador de Células B/metabolismo , Fator Ativador de Células B/imunologia , Camundongos , Obesidade/imunologia , Obesidade/metabolismo , Autoanticorpos/imunologia , Adipócitos/imunologia , Adipócitos/metabolismo , Fagocitose/imunologia , Imunoglobulina G/imunologia , Masculino , Dieta Hiperlipídica/efeitos adversos , Camundongos Endogâmicos C57BL , Apoptose/imunologia , Tecido Adiposo Branco/imunologia , Tecido Adiposo Branco/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Modelos Animais de DoençasRESUMO
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.
Assuntos
Fator Ativador de Células B , Receptor do Fator Ativador de Células B , Antígeno de Maturação de Linfócitos B , Interleucina-6 , Proteína Transmembrana Ativadora e Interagente do CAML , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral , Animais , Fator Ativador de Células B/imunologia , Fator Ativador de Células B/metabolismo , Fator Ativador de Células B/genética , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/imunologia , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Antígeno de Maturação de Linfócitos B/imunologia , Antígeno de Maturação de Linfócitos B/metabolismo , Proteína Transmembrana Ativadora e Interagente do CAML/metabolismo , Proteína Transmembrana Ativadora e Interagente do CAML/genética , Proteína Transmembrana Ativadora e Interagente do CAML/imunologia , Interleucina-6/metabolismo , Interleucina-6/imunologia , Camundongos , Receptor do Fator Ativador de Células B/metabolismo , Receptor do Fator Ativador de Células B/imunologia , Receptor do Fator Ativador de Células B/genética , Plasmócitos/imunologia , Plasmócitos/metabolismo , Camundongos Knockout , Células Produtoras de Anticorpos/imunologia , Células Produtoras de Anticorpos/metabolismo , Camundongos Endogâmicos C57BLRESUMO
It has been rediscovered in the last fifteen years that B-cells play an active role in autoimmune etiology rather than just being spectators. The clinical success of B-cell depletion therapies (BCDTs) has contributed to this. BCDTs, including those that target CD20, CD19, and BAFF, were first developed to eradicate malignant B-cells. These days, they treat autoimmune conditions like multiple sclerosis and systemic lupus erythematosus. Particular surprises have resulted from the use of BCDTs in autoimmune diseases. For example, even in cases where BCDT is used to treat the condition, its effects on antibody-secreting plasma cells and antibody levels are restricted, even though these cells are regarded to play a detrimental pathogenic role in autoimmune diseases. In this Review, we provide an update on our knowledge of the biology of B-cells, examine the outcomes of clinical studies employing BCDT for autoimmune reasons, talk about potential explanations for the drug's mode of action, and make predictions about future approaches to targeting B-cells other than depletion.
Assuntos
Doenças Autoimunes , Linfócitos B , Depleção Linfocítica , Animais , Humanos , Antígenos CD19/imunologia , Antígenos CD20/imunologia , Doenças Autoimunes/imunologia , Doenças Autoimunes/terapia , Fator Ativador de Células B/imunologia , Linfócitos B/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/terapia , Depleção Linfocítica/métodos , Esclerose Múltipla/imunologia , Esclerose Múltipla/terapiaRESUMO
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.
Assuntos
Adjuvantes Imunológicos , Neutrófilos , Transdução de Sinais , Ácido Succínico , Neutrófilos/imunologia , Neutrófilos/metabolismo , Animais , Ácido Succínico/metabolismo , Adjuvantes Imunológicos/farmacologia , Humanos , Camundongos , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linfócitos B/efeitos dos fármacos , Infiltração de Neutrófilos/efeitos dos fármacos , Fator Ativador de Células B/metabolismo , Fator Ativador de Células B/imunologia , Fator Ativador de Células B/genética , Camundongos Endogâmicos C57BL , FemininoRESUMO
Binding of BAFF to BAFFR activates in mature B cells PI3K/AKT signaling regulating protein synthesis, metabolic fitness, and survival. In humans, naive and memory B cells express the same levels of BAFFR, but only memory B cells seem to survive without BAFF. Here, we show that BAFF activates PI3K/AKT only in naive B cells and changes the expression of genes regulating migration, proliferation, growth, and survival. BAFF-induced PI3K/AKT activation requires direct interactions between BAFFR and the B cell antigen receptor (BCR) components CD79A and CD79B and is enhanced by the AKT coactivator TCL1A. Compared to memory B cells, naive B cells express more surface BCRs, which interact better with BAFFR than IgG or IgA, thus allowing stronger responses to BAFF. As ablation of BAFFR in naive and memory B cells causes cell death independent of BAFF-induced signaling, BAFFR seems to act also as an intrinsic factor for B cell survival.
Assuntos
Receptor do Fator Ativador de Células B , Células B de Memória , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Receptores de Antígenos de Linfócitos B , Fator Ativador de Células B/imunologia , Fator Ativador de Células B/metabolismo , Receptor do Fator Ativador de Células B/imunologia , Receptor do Fator Ativador de Células B/metabolismo , Humanos , Células B de Memória/imunologia , Células B de Memória/metabolismo , Fosfatidilinositol 3-Quinases/imunologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/imunologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Antígenos de Linfócitos B/imunologia , Receptores de Antígenos de Linfócitos B/metabolismoRESUMO
B cell-activating factor (BAFF) binds the three receptors BAFF-R, BCMA, and TACI, predominantly expressed on mature B cells. Almost all B cell cancers are reported to express at least one of these receptors. Here we develop a BAFF ligand-based chimeric antigen receptor (CAR) and generate BAFF CAR-T cells using a non-viral gene delivery method. We show that BAFF CAR-T cells bind specifically to each of the three BAFF receptors and are effective at killing multiple B cell cancers, including mantle cell lymphoma (MCL), multiple myeloma (MM), and acute lymphoblastic leukemia (ALL), in vitro and in vivo using different xenograft models. Co-culture of BAFF CAR-T cells with these tumor cells results in induction of activation marker CD69, degranulation marker CD107a, and multiple proinflammatory cytokines. In summary, we report a ligand-based BAFF CAR-T capable of binding three different receptors, minimizing the potential for antigen escape in the treatment of B cell cancers.
Assuntos
Fator Ativador de Células B/genética , Receptor do Fator Ativador de Células B/genética , Antígeno de Maturação de Linfócitos B/genética , Linfoma de Célula do Manto/terapia , Mieloma Múltiplo/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Proteína Transmembrana Ativadora e Interagente do CAML/genética , Animais , Antígenos CD/genética , Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos T/genética , Antígenos de Diferenciação de Linfócitos T/imunologia , Fator Ativador de Células B/imunologia , Receptor do Fator Ativador de Células B/imunologia , Antígeno de Maturação de Linfócitos B/imunologia , Linfócitos B/imunologia , Linfócitos B/patologia , Linhagem Celular Tumoral , Técnicas de Cocultura , Citotoxicidade Imunológica , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Lectinas Tipo C/genética , Lectinas Tipo C/imunologia , Ativação Linfocitária , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/imunologia , Linfoma de Célula do Manto/patologia , Proteína 1 de Membrana Associada ao Lisossomo/genética , Proteína 1 de Membrana Associada ao Lisossomo/imunologia , Masculino , Camundongos , Mieloma Múltiplo/genética , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Ligação Proteica , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Transdução de Sinais , Linfócitos T/imunologia , Linfócitos T/transplante , Proteína Transmembrana Ativadora e Interagente do CAML/imunologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Activation-induced cytidine deaminase (AID) initiates class-switch recombination and somatic hypermutation (SHM) in antibody genes. Protein expression and activity are tightly controlled by various mechanisms. However, it remains unknown whether a signal from the extracellular environment directly affects the AID activity in the nucleus where it works. Here, we demonstrated that a deubiquitinase USP10, which specifically stabilizes nuclear AID protein, can translocate into the nucleus after AKT-mediated phosphorylation at its T674 within the NLS domain. Interestingly, the signals from BCR and TLR1/2 synergistically promoted this phosphorylation. The deficiency of USP10 in B cells significantly decreased AID protein levels, subsequently reducing neutralizing antibody production after immunization with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or human immunodeficiency virus type 1 (HIV-1) nanoparticle vaccines. Collectively, we demonstrated that USP10 functions as an integrator for both BCR and TLR signals and directly regulates nuclear AID activity. Its manipulation could be used for the development of vaccines and adjuvants.
Assuntos
Vacinas contra a AIDS/imunologia , Fator Ativador de Células B/imunologia , Vacinas contra COVID-19/imunologia , Citidina Desaminase/imunologia , HIV-1/imunologia , Nanopartículas , SARS-CoV-2/imunologia , Transdução de Sinais/imunologia , Ubiquitina Tiolesterase/imunologia , Ubiquitinação/imunologia , Vacinas contra a AIDS/genética , Animais , Fator Ativador de Células B/genética , Vacinas contra COVID-19/genética , Citidina Desaminase/genética , Células HEK293 , HIV-1/genética , Humanos , Camundongos , Camundongos Knockout , SARS-CoV-2/genética , Transdução de Sinais/genética , Ubiquitina Tiolesterase/genéticaRESUMO
Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease. The disease is characterized by activation and dysregulation of both the innate and the adaptive immune systems. The autoimmune response targets self-molecules including cell nuclei, double stranded DNA and other intra and extracellular structures. Multiple susceptibility genes within the immune system have been identified, as well as disturbances in different immune pathways. SLE may affect different organs and organ systems, and organ involvement is diverse among individuals. A universal understanding of pathophysiological mechanism of the disease, as well as directed therapies, are still missing. Cytokines are immunomodulating molecules produced by cells of the immune system. Interferons (IFNs) are a broad group of cytokines, primarily produced by the innate immune system. The IFN system has been observed to be dysregulated in SLE, and therefore IFNs have been extensively studied with a hope to understand the disease mechanisms and identify novel targeted therapies. In several autoimmune diseases identification and subsequent blockade of specific cytokines has led to successful therapies, for example tumor necrosis factor-alpha (TNF-α) inhibition in rheumatoid arthritis. Authors of this review have sought corresponding developments in SLE. In the current review, we cover the actual knowledge on IFNs and other studied cytokines as biomarkers and treatment targets in SLE.
Assuntos
Citocinas/imunologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/imunologia , Animais , Fator Ativador de Células B/imunologia , Fator Ativador de Células B/metabolismo , Biomarcadores , Citocinas/metabolismo , Humanos , Interferons/imunologia , Interferons/metabolismo , Interleucinas/imunologia , Interleucinas/metabolismo , Lúpus Eritematoso Sistêmico/diagnóstico , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/imunologia , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: Belimumab was recently approved for treatment of lupus glomerulonephritis (LN). AIM: To evaluate renal response and its predictors in LN patients receiving belimumab in real-life. PATIENTS AND METHODS: We considered all patients fulfilling the SLEDAI-2K renal items and/or having estimated glomerular filtration rate (eGFR)≤60 ml/min/1.73 m2, with positive anti-dsDNA and/or low C3/C4 enrolled in the multicentre Italian lupus cohort BeRLiSS (BElimumab in Real LIfe Setting Study), treated with monthly IV Belimumab 10 mg/kg over standard treatment. Primary efficacy renal response (PERR), defined as proteinuria ≤0.7 g/24 h, eGFR≥60 ml/min/1.73 m2 without rescue therapy, was considered as primary outcome. Complete renal response (CRR; proteinuria <0.5 g/24 h, eGFR≥90 ml/min/1.73 m2) was considered as secondary outcome. Prevalence and predictors of PERR were evaluated at 6, 12, 24 months by multivariate logistic regression. RESULTS: Among the 466 SLE patients of BeRLiSS, 91 fulfilled the inclusion criteria, 79 females, median age 41.0 (33.0-47.0) years, median follow-up 22.0 (12.0-36.0) months. Sixty-four (70.3%) achieved PERR, of whom 38.4% reached CRR. Among patients achieving PERR at 6 months, 86.7% maintained response throughout the follow-up. At multivariable analysis, hypertension (OR [95%CI]: 0.28 [0.09-0.89], p = 0.032), high baseline serum creatinine (0.97 [0.95-0.99], p = 0.01) and high baseline proteinuria (0.37, [0.19-0.74], p = 0.005) negatively predicted PERR. Positive predictors of PERR at 12 and 24 months were baseline anti-Sm positivity (OR [95%CI]: 6.2 [1.21-31.7], p = 0.029; 19.8 [2.01-186.7], p = 0.009, respectively) and having achieved PERR at 6 months (14.4 [3.28-63.6]; 11.7 [2.7-48.7], p = 0.001 for both). CONCLUSIONS: Add-on therapy with belimumab led to durable renal response in patients with LN in a real-life setting.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Rim/efeitos dos fármacos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Nefrite Lúpica/tratamento farmacológico , Adulto , Fator Ativador de Células B/imunologia , Estudos de Coortes , Feminino , Seguimentos , Taxa de Filtração Glomerular , Humanos , Imunossupressores , Itália , Rim/metabolismo , Rim/patologia , Masculino , Pessoa de Meia-Idade , Proteinúria , Resultado do TratamentoRESUMO
The pathogenic roles for B cells in autoimmunity include produce pathogenic autoantibodies and modulate immune responses via the production of cytokines and chemokines. The B lymphocyte stimulator BLyS (also known as B-cell-activating factor, BAFF) and APRIL (a proliferation-inducing ligand) are critical factors in the maintenance of the B-cell pool and humoral immunity, namely BLyS modulates the differentiation and maturation of immature B cell, while APRIL modulates the function and survival of long-lived plasma cell, which plays a prominent role in the pathogenesis of autoimmune diseases. Telitacicept is a novel recombinant fusion protein of both the ligand-binding domain of the TACI receptor and the Fc component of human IgG and which is a BLyS/APRIL dual inhibitor. Moreover, telitacicept was developed by Remegen Co., Ltd. in China and is approved to treat systemic lupus erythematosus in China. We review the rationale, clinical evidence, and future perspectives of telitacicept for the treatment of autoimmune disease.HighlightThe B lymphocyte stimulator BLyS (also known as B-cell-activating factor, BAFF) and APRIL (a proliferation-inducing ligand), members of tumor necrosis factor (TNF) family, and which are critical factors in the maintenance of the B-cell pool and humoral immunity.BAFF and APRIL are implicated in the pathogenesis of several human autoimmune diseases with autoreactive B-cell involvement, and targeting both is beneficial for the treatment of autoimmune diseases.Telitacicept is a novel recombinant fusion protein of both the ligand-binding domain of the TACI receptor and the Fc component of human IgG, as a BLyS/APRIL dual inhibitor and which has been approved by National Medical Products Administration (MNPA) for the treatment of patients with SLE in China.With more clinical trials underway, telitacicept may also be approved for the treatment of other autoimmune diseases in the future.
Assuntos
Doenças Autoimunes/tratamento farmacológico , Fator Ativador de Células B/antagonistas & inibidores , Imunossupressores/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/antagonistas & inibidores , Animais , Doenças Autoimunes/imunologia , Fator Ativador de Células B/imunologia , Ensaios Clínicos como Assunto/métodos , Humanos , Imunossupressores/farmacologia , Proteínas Recombinantes de Fusão/farmacologia , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/imunologiaRESUMO
B cell-activating factor (BAFF), part of a tumor necrosis factor family of cytokines, was recently identified as a regulator of atherosclerosis; however, its role in aortic aneurysm has not been determined. Here, the study examined the effect of selective BAFF antagonism using an anti-BAFF antibody (blocks binding of BAFF to receptors BAFF receptor 3, transmembrane activator and CAML interactor, and B-cell maturation antigen) and mBaffR-mFc (blocks binding of BAFF to BAFF receptor 3) on a murine model of abdominal aortic aneurysm (AAA). In a prevention strategy, the antagonists were injected before the induction of AAA, and in an intervention strategy, the antagonists were injected after the induction of AAA. Both strategies attenuated the formation of AAA. In the intervention group, BAFF antagonism depleted most of the mature B-cell subsets in spleen and circulation, leading to enhanced resolution of inflammation in AAA as indicated by decreased infiltration of B cells and proinflammatory macrophages and a reduced number of apoptotic cells. In AAA tissues, B cells and macrophages were found in close contact. In vitro, B cells, irrespective of treatment with BAFF, impaired the efferocytosis activity of macrophages, suggesting a direct innate role of B cells on macrophage function. Altogether, BAFF antagonism affects survival of the mature B cells, promotes resolution of inflammation in the aorta, and attenuates the growth of AAA in mice.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Aneurisma da Aorta Abdominal/terapia , Fator Ativador de Células B/antagonistas & inibidores , Animais , Anticorpos Monoclonais/farmacologia , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/imunologia , Aneurisma da Aorta Abdominal/patologia , Fator Ativador de Células B/genética , Fator Ativador de Células B/imunologia , Fator Ativador de Células B/fisiologia , Subpopulações de Linfócitos B/patologia , Contagem de Células , Células Cultivadas , Quimiotaxia de Leucócito/fisiologia , Modelos Animais de Doenças , Progressão da Doença , Humanos , Fragmentos Fc das Imunoglobulinas/farmacologia , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
BAFF is a critical cytokine supporting the survival of mature naïve B cells, acting through the BAFFR receptor. Recent studies show that BAFF and BAFFR are also required for the survival of memory B cells, autoimmune B cells as well as malignant chronic lymphocytic leukaemia (CLL) cells. BAFFR cooperates with other receptors, notably the B cell antigen receptor (BCR), a process which is critical for the expansion of autoimmune and CLL cells. This crosstalk may be mediated by TRAF3 which interacts with BAFFR and with CD79A, a signalling subunit of the BCR and the downstream SYK kinase, inhibiting its activity. BAFF binding to BAFFR leads to degradation of TRAF3 which may relieve inhibition of SYK activity transducing signals to pathways required for B cell survival. BAFFR activates both canonical and non-canonical NF-κB signalling and both pathways play important roles in the survival of B cells and CLL cells.
Assuntos
Fator Ativador de Células B/imunologia , Receptor do Fator Ativador de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/imunologia , Linfócitos B/imunologia , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Transdução de Sinais/imunologiaRESUMO
The B cell activating factor BAFF has gained importance in the context of kidney transplantation due to its role in B cell survival. Studies have shown that BAFF correlates with an increased incidence of antibody-mediated rejection and the development of donor-specific antibodies. In this study, we analyzed a defined cohort of kidney transplant recipients who were treated with standardized immunosuppressive regimens according to their immunological risk profile. The aim was to add BAFF as an awareness marker in the course after transplantation to consider patient's individual immunological risk profile. Included patients were transplanted between 2016 and 2018. Baseline data, graft function, the occurrence of rejection episodes, signs of microvascular infiltration, and DSA kinetics were recorded over 3 years. BAFF levels were determined 14 d, 3 and 12 months post transplantation. Although no difference in graft function could be observed, medium-risk patients showed a clear dynamic in their BAFF levels with low levels shortly after transplantation and an increase in values of 123% over the course of 1 year. Patients with high BAFF values were more susceptible to rejection, especially antibody-mediated rejection and displayed intensified microvascular inflammation; the combination of high BAFF + DSA puts patients at risk. The changing BAFF kinetics of the medium risk group as well as the increased occurrence of rejections at high BAFF values enables BAFF to be seen as an awareness factor. To compensate the changing immunological risk, a switch from a weaker induction therapy to an intensified maintenance therapy is required.
Assuntos
Fator Ativador de Células B , Rejeição de Enxerto , Sobrevivência de Enxerto/imunologia , Transplante de Rim , Adulto , Idoso , Fator Ativador de Células B/sangue , Fator Ativador de Células B/imunologia , Biomarcadores/sangue , Feminino , Seguimentos , Rejeição de Enxerto/sangue , Rejeição de Enxerto/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Medição de RiscoRESUMO
B-cell-activating factor (BAFF) mediates B-cell survival and, when deregulated, contributes to autoimmune diseases and B-cell malignancies. The mechanism connecting BAFF receptor (BAFFR) signal to downstream pathways and pathophysiological functions is not well understood. Here we identified DYRK1a as a kinase that responds to BAFF stimulation and mediates BAFF-induced B-cell survival. B-cell-specific DYRK1a deficiency causes peripheral B-cell reduction and ameliorates autoimmunity in a mouse model of lupus. An unbiased screen identified DYRK1a as a protein that interacts with TRAF3, a ubiquitin ligase component mediating degradation of the noncanonical nuclear factor (NF)-κB-inducing kinase (NIK). DYRK1a phosphorylates TRAF3 at serine-29 to interfere with its function in mediating NIK degradation, thereby facilitating BAFF-induced NIK accumulation and noncanonical NF-κB activation. Interestingly, B-cell acute lymphoblastic leukemia (B-ALL) cells express high levels of BAFFR and respond to BAFF for noncanonical NF-κB activation and survival in a DYRK1a-dependent manner. Furthermore, DYRK1a promotes a mouse model of B-ALL through activation of the noncanonical NF-κB pathway. These results establish DYRK1a as a critical BAFFR signaling mediator and provide novel insight into B-ALL pathogenesis.
Assuntos
Autoimunidade , Fator Ativador de Células B/imunologia , Leucemia de Células B/imunologia , NF-kappa B/imunologia , Proteínas Serina-Treonina Quinases/imunologia , Proteínas Tirosina Quinases/imunologia , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Linfócitos B/imunologia , Linfócitos B/patologia , Carcinogênese/imunologia , Carcinogênese/patologia , Linhagem Celular Tumoral , Humanos , Leucemia de Células B/patologia , Camundongos , Camundongos Endogâmicos C57BL , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Quinases DyrkRESUMO
Memory plasma cells, also called long-lived plasma cells, provide 'humoral immunity' by continued secretion of protective antibodies against pathogens, which the immune system has once encountered. They are maintained mainly in the bone marrow, docking on to stromal cells individually. In those niches they can apparently persist for decades (Chang et al., 2018 [1]). Integrin-mediated contact to the stromal cell provides an essential survival signal to the plasma cell, activating the PI3K signalling pathway, downregulating FoxO1/3a and repressing the activation of caspases 3 and 7. In a redundant form, the cytokines BAFF and APRIL, ligands of the plasma cell receptors TACI and BCMA, provide a second essential survival signal, preventing activation of caspase 12, as triggered by endoplasmic reticulum stress.
Assuntos
Anticorpos/imunologia , Fator Ativador de Células B/imunologia , Plasmócitos/imunologia , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/imunologia , Estresse do Retículo Endoplasmático/imunologia , HumanosRESUMO
The BAFF-receptor (BAFFR) is a member of the TNF-receptor family. It is expressed only by B cells and binds BAFF as single ligand, which activates key signaling pathways regulating essential cellular functions, including survival, protein synthesis, and metabolic fitness. In humans, BAFFR deficiency interrupts B cell development at the transition from immature to mature B cells and causes B lymphopenia, hypogammaglobulinemia, and impaired humoral immune responses. Polymorphisms in TNFRSF13C gene affecting BAFFR oligomerization and signaling have been described in patients with immunodeficiency, autoimmunity and B cell lymphomas. Despite a uniform expression pattern of BAFFR in peripheral mature B cells, depletion of BAFF with neutralizing antibodies in patients with systemic lupus erythematosus does not affect the survival of switched memory B cells. These findings imply a distinct dependency of mature B cell subsets on BAFF/BAFFR interaction and highlight the contribution of BAFFR-derived signals in peripheral B cell development and homeostasis.
Assuntos
Receptor do Fator Ativador de Células B/genética , Polimorfismo Genético/genética , Fator Ativador de Células B/imunologia , Receptor do Fator Ativador de Células B/deficiência , Receptor do Fator Ativador de Células B/imunologia , Linfócitos B/imunologia , Homeostase/imunologia , HumanosRESUMO
Polymorphisms in TACI, a BAFF family cytokine receptor, are linked to diverse human immune disorders including common variable immunodeficiency (CVID) and systemic lupus erythematosus (SLE). Functional studies of individual variants show modest impacts on surface TACI expression and/or downstream signal transduction, indicating that relatively subtle variation in TACI activity can impact human B-cell biology. However, significant complexity underlies TACI biology, including both positive and negative regulation of physiologic and pathogenic B-cell responses. To model these contradictory events, we compared the functional impact of TACI deletion on separate models of murine SLE driven by T cell-independent and -dependent breaks in B-cell tolerance. First, we studied whether reduced surface TACI expression was sufficient to protect against progressive BAFF-mediated systemic autoimmunity. Strikingly, despite a relatively modest impact on surface TACI levels, TACI haploinsufficiency markedly reduced pathogenic RNA-associated autoantibody titers and conferred long-term protection from BAFF-driven lupus nephritis. In contrast, B cell-intrinsic TACI deletion exerted a limited impact of autoantibody generation in murine lupus characterized by spontaneous germinal center formation and T cell-dependent humoral autoimmunity. Together, these combined data provide new insights into TACI biology and highlight how TACI signals must be tightly regulated during protective and pathogenic B-cell responses.
Assuntos
Autoimunidade/genética , Fator Ativador de Células B/imunologia , Nefrite Lúpica/genética , Nefrite Lúpica/imunologia , Proteína Transmembrana Ativadora e Interagente do CAML/genética , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Autoimunidade/imunologia , Fator Ativador de Células B/antagonistas & inibidores , Fator Ativador de Células B/genética , Receptor do Fator Ativador de Células B/genética , Linfócitos B/imunologia , Quimera , Feminino , Haploinsuficiência/genética , Imunossupressores/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Proteína Transmembrana Ativadora e Interagente do CAML/imunologiaRESUMO
BAFF, APRIL and BAFF-R are key proteins involved in the development of B-lymphocytes and autoimmunity. Additionally, BAFF, APRIL and BAFFR polymorphisms were associated with immune-mediated conditions, being BAFF GCTGT>A a shared insertion-deletion genetic variant for several autoimmune diseases. Accordingly, we assessed whether BAFF, APRIL and BAFFR represent novel genetic risk factors for Immunoglobulin-A vasculitis (IgAV), a predominantly B-lymphocyte inflammatory condition. BAFF rs374039502, which colocalizes with BAFF GCTGT>A, and two tag variants within APRIL (rs11552708 and rs6608) and BAFFR (rs7290134 and rs77874543) were genotyped in 386 Caucasian IgAV patients and 806 matched healthy controls. No genotypes or alleles differences were observed between IgAV patients and controls when BAFF, APRIL and BAFFR variants were analysed independently. Likewise, no statistically significant differences were found in the genotype and allele frequencies of BAFF, APRIL or BAFFR when IgAV patients were stratified according to the age at disease onset or to the presence/absence of gastrointestinal (GI) or renal manifestations. Similar results were disclosed when APRIL and BAFFR haplotypes were compared between IgAV patients and controls and between IgAV patients stratified according to the clinical characteristics mentioned above. Our results suggest that BAFF, APRIL and BAFFR do not contribute to the genetic network underlying IgAV.
Assuntos
Doenças Autoimunes , Fator Ativador de Células B/genética , Receptor do Fator Ativador de Células B/genética , Imunoglobulina A/imunologia , Polimorfismo de Nucleotídeo Único , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Vasculite , Adulto , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Fator Ativador de Células B/imunologia , Receptor do Fator Ativador de Células B/imunologia , Feminino , Humanos , Masculino , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/imunologia , Vasculite/genética , Vasculite/imunologiaRESUMO
B cell activating factor (BAFF or BLyS), an important cytokine for B cell survival and humoral immune responses, is targeted in the clinic for the treatment of systemic lupus erythematosus. This review focuses on the structure, function and inhibition profiles of membrane-bound BAFF, soluble BAFF 3-mer and soluble BAFF 60-mer, all of which have distinct properties. BAFF contains a loop region not required for receptor binding but essential for receptor activation via promotion of BAFF-to-BAFF contacts. This loop region additionally allows formation of BAFF 60-mer, in which epitopes of the BAFF inhibitor belimumab are inaccessible. If 60-mer forms in humans, it is predicted to be short-lived and to act locally because adult serum contains a BAFF 60-mer dissociating activity. Cord blood contains elevated levels of BAFF, part of which displays attributes of 60-mer, suggesting a role for this form of BAFF in the development of foetal or neonate B cells.