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1.
BMC Cardiovasc Disord ; 24(1): 471, 2024 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-39227771

RESUMO

OBJECTIVE: The aim of this study was to investigate the relationship between circulating levels of B cell activating factor (BAFF) and the presence and severity of coronary artery disease (CAD) and acute myocardial infarction (AMI) in humans, as its biological functions in this context remain unclear. METHODS: Serum BAFF levels were measured in a cohort of 723 patients undergoing angiography, including 204 patients without CAD (control group), 220 patients with stable CAD (CAD group), and 299 patients with AMI (AMI group). Logistic regression analyses were used to assess the association between BAFF and CAD or AMI. RESULTS: Significantly elevated levels of BAFF were observed in patients with CAD and AMI compared to the control group. Furthermore, BAFF levels exhibited a positive correlation with the SYNTAX score (r = 0.3002, P < 0.0001) and the GRACE score (r = 0.5684, P < 0.0001). Logistic regression analysis demonstrated that increased BAFF levels were an independent risk factor for CAD (adjusted OR 1.305, 95% CI 1.078-1.580) and AMI (adjusted OR 2.874, 95% CI 1.708-4.838) after adjusting for confounding variables. Additionally, elevated BAFF levels were significantly associated with a high GRACE score (GRACE score 155 to 319, adjusted OR 4.297, 95% CI 1.841-10.030). BAFF exhibited a sensitivity of 75.0% and specificity of 71.4% in differentiating CAD patients with a high SYNTAX score, and a sensitivity of 75.5% and specificity of 72.8% in identifying AMI patients with a high GRACE score. CONCLUSION: Circulating BAFF levels serve as a valuable diagnostic marker for CAD and AMI. Elevated BAFF levels are associated with the presence and severity of these conditions, suggesting its potential as a clinically relevant biomarker in cardiovascular disease.


Assuntos
Fator Ativador de Células B , Biomarcadores , Angiografia Coronária , Doença da Artéria Coronariana , Infarto do Miocárdio , Valor Preditivo dos Testes , Índice de Gravidade de Doença , Regulação para Cima , Humanos , Masculino , Fator Ativador de Células B/sangue , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/diagnóstico , Feminino , Pessoa de Meia-Idade , Biomarcadores/sangue , Idoso , Infarto do Miocárdio/sangue , Infarto do Miocárdio/diagnóstico , Estudos de Casos e Controles , Fatores de Risco , Medição de Risco , Prognóstico
2.
Commun Biol ; 7(1): 1114, 2024 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-39256610

RESUMO

Sarcoidosis and tuberculosis (TB) are two granulomatous diseases that often share overlapping clinical features, including uveitis. We measured 368 inflammation-related proteins in serum in both diseases, with and without uveitis from two distinct geographically separated cohorts: sarcoidosis from the Netherlands and TB from Indonesia. A total of 192 and 102 differentially expressed proteins were found in sarcoidosis and active pulmonary TB compared to their geographical healthy controls, respectively. While substantial overlap exists in the immune-related pathways involved in both diseases, activation of B cell activating factor (BAFF) signaling and proliferation-inducing ligand (APRIL) mediated signaling pathways was specifically associated with sarcoidosis. We identified a B-lymphocyte activation signature consisting of BAFF, TNFRSF13B/TACI, TRAF2, IKBKG, MAPK9, NFATC1, and DAPP1 that was associated with sarcoidosis, regardless of the presence of uveitis. In summary, a difference in B-lymphocyte activation is a key discriminative immunological feature between sarcoidosis/ocular sarcoidosis (OS) and TB/ocular TB (OTB).


Assuntos
Linfócitos B , Ativação Linfocitária , Sarcoidose , Humanos , Sarcoidose/imunologia , Sarcoidose/sangue , Sarcoidose/diagnóstico , Linfócitos B/imunologia , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Países Baixos/epidemiologia , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/sangue , Tuberculose Pulmonar/diagnóstico , Uveíte/imunologia , Uveíte/sangue , Uveíte/diagnóstico , Fator Ativador de Células B/sangue , Indonésia , Biomarcadores/sangue , Tuberculose/imunologia , Tuberculose/sangue , Tuberculose/diagnóstico
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.
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
5.
Blood Cancer J ; 14(1): 132, 2024 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-39112445

RESUMO

IMPACT: Immune dysregulation is thought to contribute to chronic lymphocytic leukemia (CLL) risk, but biological mechanisms are unclear. We discovered that increased serum levels of B-cell activating factor (BAFF), an important regulator of B-cell maturation, were associated with a decreased risk of CLL, even >10 years after blood draw. Our findings suggest that BAFF could be a useful biomarker to assess risk among individuals at high risk, such as those with monoclonal b-cell lymphocytosis.


Assuntos
Fator Ativador de Células B , Leucemia Linfocítica Crônica de Células B , Humanos , Leucemia Linfocítica Crônica de Células B/sangue , Fator Ativador de Células B/sangue , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Biomarcadores Tumorais/sangue , Fatores de Risco , Idoso de 80 Anos ou mais
6.
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
7.
Ren Fail ; 46(2): 2391069, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-39143819

RESUMO

OBJECTIVE: High serum levels of B-cell activation factor (BAFF) and a proliferation-inducing ligand (APRIL) have been observed in patients with idiopathic membranous nephropathy (iMN); however, their relationships with disease severity and progression remain unclear. METHODS: Patients with iMN diagnosed via renal biopsy were enrolled in this study. The concentrations of BAFF and APRIL were determined using ELISA kits. Proteinuria remission, including complete remission (CR) and partial remission (PR), and renal function deterioration were defined as clinical events. The Cox proportional hazards method was used to analyze the relationship between cytokine levels and disease progression. RESULTS: Seventy iMN patients were enrolled in this study, with a median follow-up time of 24 months (range 6-72 months). The serum levels of BAFF and APRIL were higher in iMN patients than in healthy controls but lower than those in minimal change disease (MCD) patients. The serum BAFF level was positively correlated with the serum APRIL level, serum anti-phospholipase A2 receptor (anti-PLA2R) antibody level, and 24-h proteinuria and negatively correlated with the serum albumin (ALB) level. However, no significant correlation was observed between the serum APRIL level and clinical parameters. According to the multivariate Cox proportional hazards regression model adjusted for sex, age, systolic blood pressure (SBP), estimated glomerular filtration rate (eGFR), immunosuppressive agent use, 24-h proteinuria, APRIL level, and anti-PLA2R antibody, only the serum BAFF level was identified as an independent predictor of PR (HR, 0.613; 95% CI, 0.405-0.927; p = 0.021) and CR of proteinuria (HR, 0.362; 95% CI, 0.202-0.648; p < 0.001). CONCLUSIONS: A high serum BAFF level is associated with severe clinical manifestations and poor disease progression in patients with iMN.


Assuntos
Fator Ativador de Células B , Progressão da Doença , Glomerulonefrite Membranosa , Proteinúria , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral , Humanos , Glomerulonefrite Membranosa/sangue , Glomerulonefrite Membranosa/diagnóstico , Fator Ativador de Células B/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Prognóstico , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/sangue , Proteinúria/sangue , Proteinúria/etiologia , Modelos de Riscos Proporcionais , Receptores da Fosfolipase A2/imunologia , Receptores da Fosfolipase A2/sangue , Estudos de Casos e Controles , Idoso , Taxa de Filtração Glomerular , Rim/fisiopatologia , Rim/patologia
8.
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
9.
Brain Behav Immun ; 121: 178-188, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39047848

RESUMO

Immune dysregulation is an important aspect of schizophrenia (SZ) and bipolar disorders (BD) pathophysiology, including not only inflammatory but also autoimmune process reflective of abnormal humoral immune responses. Given that B cell-activating factor (BAFF) is an integral aspect of B lymphocyte regulation, the current study investigated BAFF in SZ and BD. 255 SZ patients, 407 BD patients and 185 healthy controls (HC) were investigated across three aspects of soluble BAFF (sBAFF) by (i) comparing sBAFF circulatory levels across SZ, BD and HC, (ii) determining potential correlations between the circulating levels of sBAFF and the genotype distribution of a functionally relevant polymorphism, namely the TNFSF13B 3'UTR insertion-deletion polymorphism (GCTGT>A), (iii) analyzing relationships between both sBAFF levels and 3'UTR insertion-deletion genotypes and disease risk, patients clinical characteristics and circulating levels of potent inflammatory molecules. In addition, in subsets of patients, we also searched for possible correlations between sBAFF levels and stigma of past infectious events as well as positivity for circulating systemic autoantibodies or those directed against central nervous system (CNS) structures. Studying blood derived serum and DNA, weobserved that circulating sBAFF levels were significantly higher in SZ and BD patients, versus HC (p = 5.3*10-10and p = 4.4*10-09). Patients experiencing acute episodes, versus stable patients, in between acute episodes, exhibited higher sBAFF levels (p = 0.017).In SZ patients, positive correlations were observed between elevated sBAFF levels and: (i) elevated positive psychotic symptoms (PANSS pos), (ii) history of childhood trauma (physical abuse), and (iii) low scores on global functioning (GAF) (p = 0.024, p = 0.024, and p = 0.041).We also found that the distribution of the BAFF Ins/Del genotypes was significantly correlated with circulating sBAFF levels in SZ and BD patients (p = 0.0004). Elevated sBAFF levels were also correlated with increased levels of pro-inflammatory markers in both SZ and BD cohorts (p < 0.001). Regarding infectious stigma, only patients seropositive, versus seronegative, for herpes simplex virus (HSV)1 immunoglobulin (Ig)G antibodies exhibited a significant association with high sBAFF levels (p = 0.013). In contrast, positivity for systemic or CNS autoantibodies was significantly associated with reduced sBAFF levels, compared to patients without autoantibodies (p = 0.0017). Overall, our findings indicate that BAFF may be a promising trans-nosographic biomarker of inflammation that is likely to offer predictive, diagnostic, and prognostic tools for the management of SZ and BD. The results therefore have practicable clinical utility given the availability of immunotherapeutic treatment options including targeted monoclonal antibodies against BAFF.


Assuntos
Autoimunidade , Fator Ativador de Células B , Biomarcadores , Transtorno Bipolar , Inflamação , Esquizofrenia , Humanos , Fator Ativador de Células B/sangue , Fator Ativador de Células B/genética , Masculino , Feminino , Transtorno Bipolar/imunologia , Transtorno Bipolar/genética , Esquizofrenia/imunologia , Esquizofrenia/sangue , Esquizofrenia/genética , Adulto , Biomarcadores/sangue , Pessoa de Meia-Idade , Inflamação/imunologia , Genótipo , Autoanticorpos/sangue
10.
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
11.
Rev Clin Esp (Barc) ; 224(7): 474-478, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38849075

RESUMO

BACKGROUND: The long-term use of rituximab (RTX) has been gaining ground in the treatment of systemic autoimmune diseases. The adverse events (AEs) associated with its use different to infections are being reported. METHODS: A cohort of patients with SAIDs treated at a high-complexity center in Cali (southwestern Colombia) with follow-up from January 2008 to December 2022 were examined to search for potential AEs associated with prolonged use of RTX. RESULTS: From 178 patients with long-term use of RTX 3 (1.68%) had lymphadenopathies with lymphoid follicular hyperplasia related to BAFF overexpression, 4 (2.24%) with bronchiectasis, and 4 (2.24%) with lymphoplasmacytic cystitis. CONCLUSION: Bronchiectasis, lymphoid follicular hyperplasia related to BAFF overexpression, and lymphoplasmacytic cystitis may be life-threatening long-term AEs in patients with prolonged use of RTX.


Assuntos
Doenças Autoimunes , Fator Ativador de Células B , Bronquiectasia , Cistite , Doenças Reumáticas , Rituximab , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antirreumáticos/efeitos adversos , Antirreumáticos/administração & dosagem , Doenças Autoimunes/induzido quimicamente , Doenças Autoimunes/tratamento farmacológico , Bronquiectasia/tratamento farmacológico , Cistite/induzido quimicamente , Linfadenopatia/induzido quimicamente , Estudos Retrospectivos , Doenças Reumáticas/tratamento farmacológico , Rituximab/efeitos adversos , Rituximab/administração & dosagem
12.
Sci Rep ; 14(1): 14356, 2024 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-38906917

RESUMO

Humoral primary immunodeficiencies are the most prevalent form of primary immunodeficiency (PID). Currently, there is no convenient method to quantify newly formed B cells. The aim of this proof-of-concept study was to quantitate the ratio of coding joints (CJs) to Kappa-deleting recombination excision circles (KRECs) and serum B cell activating factor (BAFF) in patients with humoral primary immunodeficiency and assess if they correlate with disease severity. This IRB-approved study was conducted at one academic children's hospital. Patients with humoral PIDs and healthy controls were included. CJ and KREC levels were measured via qPCR. Serum BAFF levels were measured using Mesoscale. 16 patients with humoral PID and 5 healthy controls were included. The mean CJ:KREC ratio in the CVID, antibody deficiency syndromes, and controls groups, respectively were 13.04 ± 9.5, 5.25 ± 4.1, and 4.38 ± 2.5 (p = 0.059). The mean serum BAFF levels in CVID, antibody deficiency syndromes and controls were 216.3 ± 290 pg/mL, 107.9 ± 94 pg/mL and 50.9 ± 12 pg/mL, respectively (p = 0.271). When the CVID patients were subdivided into CVID with or without lymphoproliferative features, the BAFF level was substantially higher in the CVID with lymphoproliferation cohort (mean 372.4 ± 361 pg/mL, p = 0.031). Elevated CJ:KREC ratio was observed in CVID, although statistical significance was not achieved, likely due to the small sample size. Serum BAFF levels were significantly higher in CVID patients with lymphoproliferative features. We speculate that the CJ:KREC ratio and serum BAFF levels can be utilized in patients with humoral PID, once more extensive studies confirm this exploratory investigation.


Assuntos
Fator Ativador de Células B , Humanos , Fator Ativador de Células B/sangue , Feminino , Masculino , Criança , Pré-Escolar , Adolescente , Estudo de Prova de Conceito , Linfócitos B/metabolismo , Linfócitos B/imunologia , Lactente , Doenças da Imunodeficiência Primária/sangue , Imunidade Humoral , Estudos de Casos e Controles , Síndromes de Imunodeficiência/sangue
13.
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
14.
Sci Rep ; 14(1): 11840, 2024 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-38782988

RESUMO

The treatment of HCV and its sequelae are used to be predominantly based on Interferon (IFN). However, this was associated with significant adverse events as a result of its immunostimulant capabilities. Since their introduction, the directly acting antiviral drugs (DAAs), have become the standard of care to treat of HCV and its complications including mixed cryoglobulinemic vasculitis (MCV). In spite of achieving sustained viral response (SVR), there appeared many reports describing unwelcome complications such as hepatocellular and hematological malignancies as well as relapses. Prolonged inflammation induced by a multitude of factors, can lead to DNA damage and affects BAFF and APRIL, which serve as markers of B-cell proliferation. We compared, head-to-head, three antiviral protocols for HCV-MCV treatment As regards the treatment response and relapse, levels of BAFF and APRIL among pegylated interferon α-based and free regimens (Sofosbuvir + Ribavirin; SOF-RIBA, Sofosbuvir + Daclatasvir; SOF-DACLA). Regarding clinical response HCV-MCV and SVR; no significant differences could be identified among the 3 different treatment protocols, and this was also independent form using IFN. We found no significant differences between IFN-based and free regimens DNA damage, markers of DNA repair, or levels of BAFF and APRIL. However, individualized drug-to-drug comparisons showed many differences. Those who were treated with IFN-based protocol showed decreased levels of DNA damage, while the other two IFN-free groups showed increased DNA damage, being the worst in SOF-DACLA group. There were increased levels of BAFF through follow-up periods in the 3 protocols being the best in SOF-DACLA group (decreased at 24 weeks). In SOF-RIBA, CGs relapsed significantly during the follow-up period. None of our patients who were treated with IFN-based protocol had significant clinico-laboratory relapse. Those who received IFN-free DAAs showed a statistically significant relapse of constitutional manifestations. Our findings suggest that IFN-based protocols are effective in treating HCV-MCV similar to IFN-free protocols. They showed lower levels of DNA damage and repair. We believe that our findings may offer an explanation for the process of lymphoproliferation, occurrence of malignancies, and relapses by shedding light on such possible mechanisms.


Assuntos
Antivirais , Crioglobulinemia , Vasculite , Humanos , Crioglobulinemia/tratamento farmacológico , Crioglobulinemia/etiologia , Antivirais/uso terapêutico , Masculino , Vasculite/tratamento farmacológico , Vasculite/virologia , Pessoa de Meia-Idade , Feminino , Idoso , Hepacivirus/efeitos dos fármacos , Ribavirina/uso terapêutico , Sofosbuvir/uso terapêutico , Imidazóis/uso terapêutico , Valina/análogos & derivados , Valina/uso terapêutico , Pirrolidinas/uso terapêutico , Fator Ativador de Células B , Interferon-alfa/uso terapêutico , Quimioterapia Combinada , Hepatite C/tratamento farmacológico , Hepatite C/complicações , Hepatite C/virologia , Resultado do Tratamento , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/complicações , Hepatite C Crônica/virologia , Carbamatos
15.
Neurol Res ; 46(6): 495-504, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38697017

RESUMO

OBJECTIVES: Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease. Patients with relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS) differ in their responses to treatment; therefore, the correct diagnosis of the particular type of MS is crucial, and biomarkers that can differentiate between the forms of MS need to be identified. The aim of this study was to compare the levels of inflammatory parameters in serum samples from patients with RRMS and SPMS. METHODS: The study group consisted of 60 patients with diagnosed MS. The patients were divided into RRMS and SPMS groups. In the RRMS patients, the usage of disease-modifying treatment was included in our analysis. The serum levels of inflammatory parameters were evaluated. RESULTS: The serum levels of BAFF, gp130 and osteopontin were significantly higher in SPMS patients than in RRMS patients. The serum levels of BAFF correlated with age in both RRMS and SPMS patients. The serum levels of MMP-2 were significantly higher in RRMS patients than in SPMS patients and correlated with the number of past relapses. The serum levels of IL-32 were significantly higher in RRMS treatment-naïve patients than in RRMS patients treated with disease-modifying therapy. DISCUSSION: Significant differences were found in BAFF, gp130, MMP-2 and osteopontin levels between RRMS and SPMS patients. Serum IL-32 levels were statistically lower in RRMS patients treated with disease-modifying therapy than in treatment-naïve patients.


Assuntos
Biomarcadores , Esclerose Múltipla Crônica Progressiva , Esclerose Múltipla Recidivante-Remitente , Humanos , Feminino , Masculino , Adulto , Esclerose Múltipla Recidivante-Remitente/sangue , Pessoa de Meia-Idade , Esclerose Múltipla Crônica Progressiva/sangue , Esclerose Múltipla Crônica Progressiva/diagnóstico , Biomarcadores/sangue , Osteopontina/sangue , Fator Ativador de Células B/sangue , Metaloproteinase 2 da Matriz/sangue , Receptor gp130 de Citocina/sangue , Adulto Jovem
16.
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
17.
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
18.
J Neurol Sci ; 461: 123046, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38761670

RESUMO

INTRODUCTION: Progressive multifocal leukoencephalopathy (PML) is a potentially life-threatening complication among Multiple Sclerosis (MS) patients under natalizumab treatment, with serum anti-JCV antibody titers being used for stratification risk. Given the critical role of interferon (IFN)/B-cell activating factor (BAFF) axis in humoral immune responses against viruses, we explored whether it is involved in the generation of serum anti-JCV antibodies among these patients. METHODS: 162 consecutive patients with relapsing-remitting MS under natalizumab treatment were included. Serum anti-JCV antibodies were measured at baseline, as well as 12 and 24 months after treatment initiation. Type I and II IFN-inducible genes and BAFF expression were quantitated in peripheral blood by qRT-PCR. Moreover, BAFF rs9514828, rs1041569, and rs9514827 gene variants were assessed by RFLP-PCR. RESULTS: While type I and II IFN inducible gene expression were not associated with anti-JCV serum titers, the latter were significantly correlated with BAFF gene expression. Of interest, the TTT haplotype of the studied BAFF variants was more frequently detected in male, but not female anti-JCV (+) MS patients compared to anti-JCV (-) counterparts at baseline, as well as at 12 months and 24 months of natalizumab treatment. Measures of clinical validity/utility for the BAFF TTT haplotype showed 88% specificity, 45%, positive predictive value, and sensitivity of 70% for the discrimination of anti-JCV (+) male MS patients after 24 months of treatment. CONCLUSIONS: Our study suggests an implication of the BAFF axis in the production of serum anti-JCV antibodies. Additionally, the BAFF TTT haplotype derived from the rs9514828, rs1041569, and rs9514827 variants may represent a novel risk factor for anti-JCV seropositivity and indirectly for PML development among male MS patients treated with natalizumab.


Assuntos
Fator Ativador de Células B , Fatores Imunológicos , Vírus JC , Leucoencefalopatia Multifocal Progressiva , Natalizumab , Humanos , Natalizumab/uso terapêutico , Fator Ativador de Células B/sangue , Fator Ativador de Células B/genética , Masculino , Leucoencefalopatia Multifocal Progressiva/sangue , Leucoencefalopatia Multifocal Progressiva/genética , Adulto , Feminino , Fatores Imunológicos/uso terapêutico , Vírus JC/imunologia , Vírus JC/genética , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/sangue , Esclerose Múltipla Recidivante-Remitente/genética , Esclerose Múltipla Recidivante-Remitente/imunologia , Pessoa de Meia-Idade , Anticorpos Antivirais/sangue , Polimorfismo de Nucleotídeo Único
19.
Mol Biol Rep ; 51(1): 629, 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38717637

RESUMO

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/terapia
20.
Diabetes Metab Syndr ; 18(4): 103019, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38653036

RESUMO

BACKGROUND: Gestational diabetes mellitus (GDM) is a prevalent condition with an unclear pathogenesis. B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) are potential key players in GDM. PARTICIPANTS, MATERIALS, AND METHODS: In a longitudinal observational study, we monitored women from the first trimester through 24-28 weeks of gestation, focusing on the development of GDM. Serum levels of BAFF and APRIL, as well as their mRNA expression, were evaluated in both the first and third trimesters. Furthermore, we assessed cytokines, adipokines, and placental hormones in the serum. RESULTS: In the first trimester, participants who later developed GDM exhibited elevated serum BAFF and reduced serum APRIL levels, although the mRNA expression of these molecules was similar to controls. Serum BAFF exhibited significant positive correlations with metabolic markers and placental hormones. Conversely, serum APRIL was negatively correlated with insulin resistance and inflammatory markers but positively correlated with adiponectin. In the early third trimester, GDM participants continued to display higher serum BAFF levels and lower serum APRIL levels than controls. There was no significant difference in mRNA expression of BAFF between GDM and control groups. Conversely, APRIL mRNA expression was significantly lower in the GDM group. The predictive potential of first-trimester BAFF and APRIL levels for future GDM development was explored, with both molecules demonstrating strong predictive capability. DISCUSSION AND CONCLUSION: This study suggests that elevated serum BAFF and reduced serum APRIL levels during pregnancy may be associated with the development of GDM. These biomarkers can serve as potential early predictors for GDM.


Assuntos
Fator Ativador de Células B , Biomarcadores , Diabetes Gestacional , Primeiro Trimestre da Gravidez , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral , Humanos , Fator Ativador de Células B/sangue , Feminino , Gravidez , Diabetes Gestacional/sangue , Diabetes Gestacional/diagnóstico , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/sangue , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Adulto , Primeiro Trimestre da Gravidez/sangue , Biomarcadores/sangue , Estudos Longitudinais , Prognóstico , Seguimentos , Estudos de Casos e Controles
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