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1.
Int J Mol Sci ; 25(19)2024 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-39409173

RESUMO

The BAFF-APRIL system is crucial for the pathogenesis of systemic lupus erythematosus (SLE) by promoting B cell survival, differentiation and the maintenance of humoral autoimmunity. Here, we investigated the relationship of BCMA expression on B cell subsets with its ligands BAFF and APRIL, together with soluble BCMA, and with clinical and serologic variables in a cohort of 100 SLE patients (86 under conventional and 14 under belimumab therapy) and 30 healthy controls (HCs) using multicolor flow cytometry and ELISA. We found that BCMA expression in SLE patients was significantly increased on all B cell subsets compared to HCs, with all examined components of the BAFF-APRIL system being upregulated. BCMA expression was significantly increased on switched and unswitched memory B cells compared to naïve B cells, both in HCs and SLE. BCMA expression on B cells correlated with plasmablast frequencies, serum anti-dsDNA antibodies and complement consumption, while soluble BCMA correlated with plasmablast frequency, highlighting its potential as a clinical biomarker. Belimumab treatment significantly reduced BCMA expression on most B cell subsets and soluble TACI and contributed to the inhibition of almost the entire BAFF-APRIL system and restoration of B cell homeostasis. These results provide insights into the complex dysregulation of the BAFF-APRIL system in SLE and highlight the therapeutic potential of targeting its components, particularly BCMA, in addition to its use as a biomarker for disease activity.


Assuntos
Anticorpos Monoclonais Humanizados , Fator Ativador de Células B , Antígeno de Maturação de Linfócitos B , Biomarcadores , Lúpus Eritematoso Sistêmico , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral , Humanos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/metabolismo , Lúpus Eritematoso Sistêmico/sangue , Antígeno de Maturação de Linfócitos B/metabolismo , Antígeno de Maturação de Linfócitos B/imunologia , Biomarcadores/sangue , Feminino , Adulto , Masculino , Fator Ativador de Células B/sangue , Fator Ativador de Células B/metabolismo , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/sangue , Pessoa de Meia-Idade , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Antinucleares/sangue , Anticorpos Antinucleares/imunologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linfócitos B/efeitos dos fármacos , Subpopulações de Linfócitos B/metabolismo , Subpopulações de Linfócitos B/imunologia , Estudos de Casos e Controles
2.
Int J Mol Sci ; 25(15)2024 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-39125769

RESUMO

A T-cell-independent (TI) pathway activated by microbiota results in the generation of low-affinity homeostatic IgA with a critical role in intestinal homeostasis. Moderate aerobic exercise (MAE) provides a beneficial impact on intestinal immunity, but the action of MAE on TI-IgA generation under senescence conditions is unknown. This study aimed to determine the effects of long-term MAE on TI-IgA production in young (3 month old) BALB/c mice exercised until adulthood (6 months) or aging (24 months). Lamina propria (LP) from the small intestine was obtained to determine B cell and plasma cell sub-populations by flow cytometry and molecular factors related to class switch recombination [Thymic Stromal Lymphopoietin (TSLP), A Proliferation-Inducing Ligand (APRIL), B Cell Activating Factor (BAFF), inducible nitric oxide synthase (iNOS), and retinal dehydrogenase (RDH)] and the synthesis of IgA [α-chain, interleukin (IL)-6, IL-21, and Growth Factor-ß (TGF-ß)]; and epithelial cells evaluated IgA transitosis [polymeric immunoglobulin receptor (pIgR), tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), IL-4] by the RT-qPCR technique. The results were compared with data obtained from sedentary age-matched mice. Statistical analysis was computed with ANOVA, and p < 0.05 was considered to be a statistically significant difference. Under senescence conditions, MAE promoted the B cell and IgA+ B cells and APRIL, which may improve the intestinal response and ameliorate the inflammatory environment associated presumably with the downmodulation of pro-inflammatory mediators involved in the upmodulation of pIgR expression. Data suggested that MAE improved IgA and downmodulate the cytokine pro-inflammatory expression favoring homeostatic conditions in aging.


Assuntos
Envelhecimento , Homeostase , Imunoglobulina A , Camundongos Endogâmicos BALB C , Condicionamento Físico Animal , Animais , Imunoglobulina A/metabolismo , Imunoglobulina A/imunologia , Camundongos , Envelhecimento/imunologia , Citocinas/metabolismo , Linfócitos B/imunologia , Linfócitos B/metabolismo , Fator Ativador de Células B/metabolismo , Fator Ativador de Células B/genética , Mucosa Intestinal/metabolismo , Mucosa Intestinal/imunologia , Intestino Delgado/imunologia , Intestino Delgado/metabolismo , Masculino , Plasmócitos/imunologia , Plasmócitos/metabolismo , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética
3.
J Autoimmun ; 148: 103291, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39146891

RESUMO

BLyS and APRIL have the capability to bind to B cells within the body, allowing these cells to evade elimination when they should naturally be removed. While BLyS primarily plays a role in B cell development and maturation, APRIL is linked to B cell activation and the secretion of antibodies. Thus, in theory, inhibiting BLyS or APRIL could diminish the population of aberrant B cells that contribute to SLE and reduce disease activity in patients. Telitacicept functions by binding to and neutralizing the activities of both BLyS and APRIL, thus hindering the maturation and survival of plasma cells and fully developed B cells. The design of telitacicept is distinctive; it is not a monoclonal antibody but a TACI-Fc fusion protein generated through recombinant DNA technology. This fusion involves merging gene segments of the TACI protein, which can target BLyS/APRIL simultaneously, with the Fc gene segment of the human IgG protein. The TACI-Fc fusion protein exhibits the combined characteristics of both proteins. Currently utilized for autoimmune disease treatment, telitacicept is undergoing clinical investigations globally to assess its efficacy in managing various autoimmune conditions. This review consolidates information on the mechanistic actions, dosing regimens, pharmacokinetics, efficacy, and safety profile of telitacicept-a dual-targeted biological agent. It integrates findings from prior experiments and pharmacokinetic analyses in the treatment of RA and SLE, striving to offer a comprehensive overview of telitacicept's research advancements.


Assuntos
Autoimunidade , Proteínas Recombinantes de Fusão , Doenças Reumáticas , Humanos , Doenças Reumáticas/imunologia , Doenças Reumáticas/tratamento farmacológico , Proteínas Recombinantes de Fusão/genética , Linfócitos B/imunologia , Linfócitos B/metabolismo , Fator Ativador de Células B/genética , Fator Ativador de Células B/metabolismo , Fator Ativador de Células B/imunologia , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/tratamento farmacológico , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/imunologia
4.
RMD Open ; 10(3)2024 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-39209370

RESUMO

INTRODUCTION: The therapeutic interest of targeting B-cell activating factor (BAFF) in Sjögren's disease (SjD) can be suspected from the results of two phase II clinical trials but has not been evaluated in an animal model of the disease. We aimed to evaluate the therapeutic efficacy of this strategy on dryness and salivary gland (SG) infiltrates in the NOD mouse model of SjD. MATERIAL AND METHODS: Female NOD mice between ages 10 and 18 weeks were treated with a BAFF-blocking monoclonal antibody, Sandy-2 or an isotype control. Dryness was measured by the stimulated salivary flow. Salivary lymphocytic infiltrates were assessed by immunohistochemistry. Blood, SGs, spleen and lymph-node lymphocyte subpopulations were analysed by flow cytometry. SG mRNA expression was analysed by transcriptomic analysis. RESULTS: BAFF inhibition significantly decreased SG lymphocytic infiltrates, which was inversely correlated with salivary flow. The treatment markedly decreased B-cell number in SGs, blood, lymph nodes and spleen and increased Foxp3+ regulatory and CD3+CD4-CD8- double negative T-cell numbers in SGs. CONCLUSION: A monoclonal antibody blocking BAFF and depleting B cells had therapeutic effectiveness in the NOD mouse model of SjD. The increase in regulatory T-lymphocyte populations might underlie the efficacy of this treatment.


Assuntos
Fator Ativador de Células B , Linfócitos B , Modelos Animais de Doenças , Camundongos Endogâmicos NOD , Síndrome de Sjogren , Animais , Fator Ativador de Células B/antagonistas & inibidores , Fator Ativador de Células B/metabolismo , Síndrome de Sjogren/imunologia , Camundongos , Feminino , Linfócitos B/imunologia , Linfócitos B/metabolismo , Glândulas Salivares/patologia , Glândulas Salivares/metabolismo , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/farmacologia , Depleção Linfocítica
5.
Front Immunol ; 15: 1436900, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39185417

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 Doenças
6.
Immunol Cell Biol ; 102(9): 801-816, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39009814

RESUMO

Chronic viral infections cause thymic involution yet the potential for broader, longer-term impact on thymic composition remains unexplored. Here we show that chronic, but not acute, lymphocytic choriomeningitis virus infection promotes a unique population of immature B cells in the thymus. We show that chronic viral infection promotes signals within the thymus, including the expression of B-cell activating factor (BAFF), that favor the maturation of this population as these cells acquire expression of CD19 and immunoglobulin M. Mechanistically, type I interferon (IFN-I), predominantly IFNß, signals to thymic hematopoietic cells, strongly delaying T-cell development at the earliest precursor stage. Furthermore, IFN-I signaling to the nonhematopoietic compartment provides a second signal essential to favor B-cell differentiation and maturation within the thymus. Importantly, chronic infection yields changes in the B-cell population for at least 50 days following infection, long after thymic atrophy has subsided. Thus, the inflammatory milieu induced by chronic viral infection has a profound, and long-lasting, effect on thymic composition leading to the generation of a novel population of thymic B cells.


Assuntos
Linfócitos B , Diferenciação Celular , Interferon Tipo I , Coriomeningite Linfocítica , Vírus da Coriomeningite Linfocítica , Timo , Timo/imunologia , Timo/virologia , Animais , Linfócitos B/imunologia , Linfócitos B/virologia , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/virologia , Interferon Tipo I/metabolismo , Vírus da Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/fisiologia , Camundongos Endogâmicos C57BL , Camundongos , Transdução de Sinais , Doença Crônica , Fator Ativador de Células B/metabolismo , Infecção Persistente/imunologia , Infecção Persistente/virologia
7.
Proc Natl Acad Sci U S A ; 121(29): e2404309121, 2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-38990948

RESUMO

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 C57BL
8.
Cell Signal ; 120: 111201, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38714287

RESUMO

Cytokines from the Tumour Necrosis Factor (TNF) family are important regulators of both physiological and pathological processes. The discovery of novel TNF ligands and receptors, BAFF and APRIL, have opened up new possibilities for scientists to explore the effect of these cytokines on the human immune system. The role of BAFF/APRIL system in B lymphocytes is particularly important for survival and maintenance of homeostasis. Aberrant expression of the system is associated with various immunological disorders. Hence, this study provides a comprehensive overview of the past and present BAFF/APRIL system research development in a bibliometric perspective. To our best knowledge, this is the first ever bibliometric analysis conducted focusing on the BAFF/APRIL system. A total of 1055 relevant documents were retrieved from WoSCC. Microsoft Excel, VOSviewer, and Biblioshiny of R studio were bibliometric tools used to analyse the scientific literature. From 1999, the annual publications showed an upward trend, with Journal of Immunology being the most productive journal. USA leads the race for BAFF/APRIL system research developments. Pascal Schneider, a senior researcher affiliated with University of Lausanne, Switzerland was recognised as the most productive author and institution in the BAFF/APRIL system research field. The research focus transitioned from focusing on the role of the system in B cell biology, to immunological disorders and finally to development of BAFF/APRIL targeting drugs. Despite several studies elucidating briefly the pathway mechanism of BAFF/APRIL system in B-cell selection, substantial research on the mechanism of action in disease models and T cell activation and development of immunomodulating drugs from natural origins remains largely unexplored. Therefore, future research focusing on these areas are crucial for the deeper understanding of the system in disease manifestations and progression allowing a better treatment management for various immunological disorders.


Assuntos
Fator Ativador de Células B , Bibliometria , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral , Humanos , Fator Ativador de Células B/metabolismo , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo
9.
Am J Physiol Cell Physiol ; 327(1): C1-C10, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38708521

RESUMO

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 , Feminino
10.
Int J Mol Sci ; 25(10)2024 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-38791453

RESUMO

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.


Assuntos
Fator Ativador de Células B , Receptor do Fator Ativador de Células B , Nefrite , Transcriptoma , Animais , Masculino , Camundongos , Fator Ativador de Células B/genética , Fator Ativador de Células B/metabolismo , Receptor do Fator Ativador de Células B/metabolismo , Receptor do Fator Ativador de Células B/genética , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nefrite/metabolismo , Nefrite/genética , Nefrite/patologia , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/patologia , Transdução de Sinais
11.
Nat Immunol ; 25(5): 820-833, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38600356

RESUMO

Human bone marrow permanently harbors high numbers of neutrophils, and a tumor-supportive bias of these cells could significantly impact bone marrow-confined malignancies. In individuals with multiple myeloma, the bone marrow is characterized by inflammatory stromal cells with the potential to influence neutrophils. We investigated myeloma-associated alterations in human marrow neutrophils and the impact of stromal inflammation on neutrophil function. Mature neutrophils in myeloma marrow are activated and tumor supportive and transcribe increased levels of IL1B and myeloma cell survival factor TNFSF13B (BAFF). Interactions with inflammatory stromal cells induce neutrophil activation, including BAFF secretion, in a STAT3-dependent manner, and once activated, neutrophils gain the ability to reciprocally induce stromal activation. After first-line myeloid-depleting antimyeloma treatment, human bone marrow retains residual stromal inflammation, and newly formed neutrophils are reactivated. Combined, we identify a neutrophil-stromal cell feed-forward loop driving tumor-supportive inflammation that persists after treatment and warrants novel strategies to target both stromal and immune microenvironments in multiple myeloma.


Assuntos
Fator Ativador de Células B , Interleucina-1beta , Mieloma Múltiplo , Neutrófilos , Células Estromais , Microambiente Tumoral , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/patologia , Humanos , Microambiente Tumoral/imunologia , Neutrófilos/imunologia , Neutrófilos/metabolismo , Células Estromais/metabolismo , Células Estromais/imunologia , Fator Ativador de Células B/metabolismo , Interleucina-1beta/metabolismo , Ativação de Neutrófilo , Fator de Transcrição STAT3/metabolismo , Medula Óssea/imunologia , Medula Óssea/patologia
12.
Zhongguo Dang Dai Er Ke Za Zhi ; 26(3): 315-320, 2024 Mar 15.
Artigo em Chinês | MEDLINE | ID: mdl-38557386

RESUMO

B-cell activating factor (BAFF), a critical regulator of B cells, is involved in various autoimmune diseases. Inflammatory bowel disease (IBD) is a group of chronic and recurrent intestinal inflammatory disorders with unclear etiology, and its global incidence has been increasing in recent years. Abnormal immune responses triggered by multiple factors are closely related to the pathogenesis of IBD. Previous studies have confirmed the association of B-cell abnormal activation and increased production of autoantibodies with the development of ulcerative colitis. However, the involvement of BAFF in the mechanisms of IBD remains unclear. This review summarizes the potential role of BAFF in the pathogenesis of IBD and provides an overview of targeted therapies on BAFF in IBD, aiming to contribute insights for targeted treatments of IBD.


Assuntos
Fator Ativador de Células B , Colite Ulcerativa , Doenças Inflamatórias Intestinais , Humanos , Fator Ativador de Células B/metabolismo , Linfócitos B , Colite Ulcerativa/complicações , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/etiologia
13.
Am J Physiol Cell Physiol ; 326(5): C1494-C1504, 2024 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-38406824

RESUMO

Primary Sjögren's syndrome (pSS) is characterized by its autoimmune nature. This study investigates the role of the IFNγ SNP rs2069705 in modulating the susceptibility to pSS. Differential expression of IFNγ and BAFF was analyzed using the GEO database's mRNA microarray GSE84844. Genotyping of the IFNγ SNP rs2069705 was conducted via the dbSNP website. The JASPAR tool was used for predicting transcription factor bindings. Techniques such as dual-luciferase reporter assays, Chromatin immunoprecipitation, and analysis of a pSS mouse model were applied to study gene and protein interactions. A notable increase in the mutation frequency of IFNγ SNP rs2069705 was observed in MNCs from the exocrine glands of pSS mouse models. Bioinformatics analysis revealed elevated levels of IFNγ and BAFF in pSS samples. The model exhibited an increase in both CD20+ B cells and cells expressing IFNγ and BAFF. Knocking down IFNγ resulted in lowered BAFF expression and less lymphocyte infiltration, with BAFF overexpression reversing this suppression. Activation of the Janus kinase (JAK)/STAT1 pathway was found to enhance transcription in the BAFF promoter region, highlighting IFNγ's involvement in pSS. In addition, rs2069705 was shown to boost IFNγ transcription by promoting interaction between its promoter and STAT4. SNP rs2069705 in the IFNγ gene emerges as a pivotal element in pSS susceptibility, primarily by augmenting IFNγ transcription, activating the JAK/STAT1 pathway, and leading to B-lymphocyte infiltration in the exocrine glands.NEW & NOTEWORTHY The research employed a combination of bioinformatics analysis, genotyping, and experimental models, providing a multifaceted approach to understanding the complex interactions in pSS. We have uncovered that the rs2069705 SNP significantly affects the transcription of IFNγ, leading to altered immune responses and B-lymphocyte activity in pSS.


Assuntos
Linfócitos B , Interferon gama , Polimorfismo de Nucleotídeo Único , Síndrome de Sjogren , Ativação Transcricional , Animais , Feminino , Humanos , Camundongos , Fator Ativador de Células B/genética , Fator Ativador de Células B/metabolismo , Linfócitos B/imunologia , Linfócitos B/metabolismo , Modelos Animais de Doenças , Predisposição Genética para Doença , Interferon gama/genética , Interferon gama/metabolismo , Janus Quinases/metabolismo , Janus Quinases/genética , Polimorfismo de Nucleotídeo Único/genética , Transdução de Sinais , Síndrome de Sjogren/genética , Síndrome de Sjogren/imunologia , Síndrome de Sjogren/metabolismo , Síndrome de Sjogren/patologia , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT4/genética , Fator de Transcrição STAT4/metabolismo
14.
J Exp Med ; 221(4)2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38417019

RESUMO

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with a clear genetic component. While most SLE patients carry rare gene variants in lupus risk genes, little is known about their contribution to disease pathogenesis. Amongst them, SH2B3-a negative regulator of cytokine and growth factor receptor signaling-harbors rare coding variants in over 5% of SLE patients. Here, we show that unlike the variant found exclusively in healthy controls, SH2B3 rare variants found in lupus patients are predominantly hypomorphic alleles, failing to suppress IFNGR signaling via JAK2-STAT1. The generation of two mouse lines carrying patients' variants revealed that SH2B3 is important in limiting the number of immature and transitional B cells. Furthermore, hypomorphic SH2B3 was shown to impair the negative selection of immature/transitional self-reactive B cells and accelerate autoimmunity in sensitized mice, at least in part due to increased IL-4R signaling and BAFF-R expression. This work identifies a previously unappreciated role for SH2B3 in human B cell tolerance and lupus risk.


Assuntos
Autoimunidade , Lúpus Eritematoso Sistêmico , Animais , Humanos , Camundongos , Autoimunidade/genética , Fator Ativador de Células B/metabolismo , Linfócitos B , Lúpus Eritematoso Sistêmico/genética , Células Precursoras de Linfócitos B
15.
Int Immunopharmacol ; 126: 111287, 2024 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-38041956

RESUMO

Loss of retinal ganglion cells (RGCs) is a primary cause of visual impairment in glaucoma, the pathological process is closely related to neuroinflammation and apoptosis. B-cell activating factor (BAFF) is a fundamental survival factor mainly expressed in the B cell lineage. Evidence suggests its neuroprotective effect, but the expression and role in the retina have not yet been investigated. In this study, we adopt optic nerve crush (ONC) as an in vivo model and oxygen-glucose deprivation/reoxygenation (OGD/R) of RGCs as an in vitro model to investigate the expression and function of BAFF. We found that BAFF and its receptors were abundantly expressed in the retina and BAFF inhibition exacerbated the caspase 3-mediated RGCs apoptosis, glial cell activation and pro-inflammatory cytokines expression, which may be caused by the activation of the NF-κB pathway in vivo. In addition, we found that BAFF treatment could alleviate RGCs apoptosis, pro-inflammatory cytokines expression and NF-κB pathway activation, which could be reversed the effect by blockade of the NF-κB pathway in vitro. Meanwhile, we found that microglia induced to overexpress BAFF in the inflammatory microenvironment in a time-dependent manner. Taken together, our results indicated that BAFF deficiency promoted RGCs apoptosis and neuroinflammation through activation of NF-κB pathway in ONC retinas, suggesting that BAFF may serve as a promising therapeutic target for the treatment of glaucoma.


Assuntos
Glaucoma , Células Ganglionares da Retina , Humanos , Células Ganglionares da Retina/metabolismo , NF-kappa B/metabolismo , Fator Ativador de Células B/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , Doenças Neuroinflamatórias , Nervo Óptico/patologia , Apoptose
16.
Adv Biol Regul ; 92: 101011, 2024 05.
Artigo em Inglês | MEDLINE | ID: mdl-38151421

RESUMO

iRhom2 is a crucial cofactor involved in upregulation of TNF receptors (TNFRs) and the pro-inflammatory cytokine tumor necrosis factor (TNF-) from the cell surface by ADAM17. Tumor necrosis factor- α converting enzyme (TACE) is another name given to ADAM17. Many membrane attached biologically active molecules are cleaved by this enzyme which includes TNFRs and the pro-inflammatory cytokine tumor necrosis factor- α. The TNF receptors are of two types TNFR1 and TNFR2. iRhom2 belongs to the pseudo-protease class of rhomboid family, its abundance is observed in the immune cells. Biological activity of ADAM17 is affected in multiple levels by the iRhom2. ADAM17 is trafficked into the Golgi apparatus by the action of iRhom2, where it gets matured proteolytically and is stimulated to perform its function on the cell surface. This process of activation of ADAM17 results in the protection of the organism from the cascade of inflammatory reactions, as this activation blocks the TNF- α mediated secretion responsible for inflammatory responses produced. Present paper illustrates about the iRhom2-TNF-α-BAFF signaling pathway and its correlation with several autoimmune disorders such as Rheumatoid Arthritis, Systemic Lupus Erythematosus, Hemophilia Arthropathy, Alzheimer's disease and Tylosis with esophageal cancer etc.


Assuntos
Proteína ADAM17 , Doenças Autoimunes , Fator Ativador de Células B , Transdução de Sinais , Fator de Necrose Tumoral alfa , Humanos , Proteína ADAM17/metabolismo , Proteína ADAM17/genética , Doenças Autoimunes/genética , Doenças Autoimunes/metabolismo , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator Ativador de Células B/genética , Fator Ativador de Células B/metabolismo , Animais , Proteínas de Transporte/metabolismo , Proteínas de Transporte/genética , Peptídeos e Proteínas de Sinalização Intracelular
17.
Cell Transplant ; 32: 9636897231204075, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37798940

RESUMO

Breakdown of tolerance and abnormal activation in B cells is an important mechanism in the pathogenesis of Graves' disease (GD) and high levels of thyroid hormones (THs) can drive the progression of GD. However, the interactions between THs and abnormal activation of B cells in the context of GD are not well understood. The aim of this study was to investigate B cell-activating factor (BAFF) mediating the cross talk between THs and B cells and the possible underlying mechanisms. A high-level triiodothyronine (T3) mouse model was used to verify T3-mediated induction of overexpression of BAFF and B cell abnormal differentiation. The possible promotion of BAFF overexpression in the mice spleen macrophages during polarization to M1 by T3 was also studied. We showed that high levels of T3 can induce BAFF overexpression and lead to abnormal differentiation of B cells in the mice. While the overexpression of BAFF was observed across many tissue types in the mice, high levels of T3 could induce M1 macrophages polarization by IFN (interferon-gamma)-γ in the spleen of the mice, which in turn generated BAFF overexpression. Our findings provide a novel insight into the interactions between the endocrine and immune systems, as well as provide insight into the role of TH in the pathogenesis of GD.


Assuntos
Doença de Graves , Tri-Iodotironina , Animais , Camundongos , Tri-Iodotironina/metabolismo , Doença de Graves/metabolismo , Fator Ativador de Células B/metabolismo , Interleucina-4/metabolismo , Linfócitos B/metabolismo , Diferenciação Celular
18.
J Immunol ; 211(2): 199-208, 2023 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-37272840

RESUMO

The BAFF/APRIL-system with the two cytokines BAFF and APRIL and their three receptors, transmembrane activator and CAML interactor (TACI), BAFF receptor, and B-cell maturation Ag, is important for B cell maintenance. The BAFF/APRIL system is a therapeutic target in B cell-derived malignancies and autoimmune diseases. However, unexpected outcomes of clinical trials with atacicept (TACI-Fc) underline our incomplete understanding of this system. Shedding of the three receptors is one important regulatory element. In humans, TACI exists in two isoforms generated through alternative splicing in their extracellular portion: TACI-long (l) has two cysteine-rich domains, whereas TACI-short (s) lacks the first low-affinity one. In this study, we discriminated soluble (s) forms of TACI-l and TACI-s with newly generated mAbs and found that both were spontaneously released from activated human B cells, with a predominance of sTACI-l. Furthermore, sTACI-l was also the dominant isoform in human serum. Vaccination with the mRNA vaccine from BioNTech does not significantly affect the serum levels of sTACI-l. Both TACI-s and TACI-l were shed by a disintegrin and metalloproteinase domain-containing protein 10. TACI-l and TACI-s formed homo- and hetero-oligomers in soluble and membrane-bound forms. Both sTACI-l and sTACI-s acted as decoy receptors for BAFF, but only sTACI-l also efficiently inhibited APRIL. Dimerization of sTACI-l enhanced its decoy functions only slightly. Together, we extend our knowledge of the complexity of the BAFF/APRIL system by identifying and characterizing the two soluble isoforms of TACI.


Assuntos
Linfócitos B , Proteína Transmembrana Ativadora e Interagente do CAML , Humanos , Processamento Alternativo , Fator Ativador de Células B/metabolismo , Receptor do Fator Ativador de Células B/genética , Citocinas/genética , Isoformas de Proteínas/genética , Proteína Transmembrana Ativadora e Interagente do CAML/genética , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo
19.
Front Immunol ; 14: 1169084, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37342346

RESUMO

B cells and the humoral immunity are important players in the pathogenesis of autoimmune diseases. BAFF (also known as BLYS) and a proliferation-inducing ligand APRIL are required for the maintenance of the B-cell pool and humoral immunity. BAFF and APRIL can promote B-cell differentiation, maturation, and plasma cell antibody secretion. BAFF/APRIL overexpression has been identified in several autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, IgA nephropathy, etc. Telitacicept, a novel fully human TACI-Fc fusion protein that binds both BAFF and APRIL, was approved in China in March 2021 for the treatment of systemic lupus erythematosus at a recommended dose of 160 mg/w subcutaneously and is in clinical trials for the treatment of multiple indications in other autoimmune diseases. In this review, we explored telitacicept's mechanism of action and clinical data. In addition, the immune features of autoimmune nephropathy were discussed, emphasizing lupus nephritis, IgA nephropathy, and membranous nephropathy.


Assuntos
Glomerulonefrite por IGA , Lúpus Eritematoso Sistêmico , Nefrite Lúpica , Humanos , Glomerulonefrite por IGA/tratamento farmacológico , Fator Ativador de Células B/metabolismo , Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/patologia , Autoanticorpos
20.
Elife ; 122023 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-37083495

RESUMO

Senescent cells release a variety of cytokines, proteases, and growth factors collectively known as the senescence-associated secretory phenotype (SASP). Sustained SASP contributes to a pattern of chronic inflammation associated with aging and implicated in many age-related diseases. Here, we investigated the expression and function of the immunomodulatory cytokine BAFF (B-cell activating factor; encoded by the TNFSF13B gene), a SASP protein, in multiple senescence models. We first characterized BAFF production across different senescence paradigms, including senescent human diploid fibroblasts (WI-38, IMR-90) and monocytic leukemia cells (THP-1), and tissues of mice induced to undergo senescence. We then identified IRF1 (interferon regulatory factor 1) as a transcription factor required for promoting TNFSF13B mRNA transcription in senescence. We discovered that suppressing BAFF production decreased the senescent phenotype of both fibroblasts and monocyte-like cells, reducing IL6 secretion and SA-ß-Gal staining. Importantly, however, the influence of BAFF on the senescence program was cell type-specific: in monocytes, BAFF promoted the early activation of NF-κB and general SASP secretion, while in fibroblasts, BAFF contributed to the production and function of TP53 (p53). We propose that BAFF is elevated across senescence models and is a potential target for senotherapy.


Assuntos
Fator Ativador de Células B , Senescência Celular , Humanos , Animais , Camundongos , Senescência Celular/genética , Fator Ativador de Células B/genética , Fator Ativador de Células B/metabolismo , Fator Ativador de Células B/farmacologia , Secretoma , Envelhecimento/genética , Citocinas/metabolismo
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