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1.
Gene ; 732: 144336, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-31935514

RESUMO

In the present study, we aimed to evaluate effects of autologous mesenchymal stem cells (MSCs) intravenous administration on the response of B cells, BAFF, APRIL, and their receptors on the surface of B cells at 1, 6, and 12 month follow-up periods in refractory rheumatoid arthritis (RA) patients. Thirteen patients with refractory RA received autologous MSCs. Plasma levels of BAFF and APRIL were measured employing ELISA method, followed by estimating B cell population and BAFFRs evaluation by flow cytometry technique. Gene expression of BAFF, APRIL, and their receptors on B cell surface in PBMCs was evaluated by SYBR Green real-time PCR technique. Plasma concentration of BAFF significantly decreased 1 and 6 months after the MSCT (MSCs Transplantation). Plasma concentration of APRIL significantly decreased 1 month after the MSCT. Percentages of CD19 + B cells in the PBMC population significantly decreased 12 months after the MSCT. Percentages of BR3 + CD19 + B cells and BCMA + CD19 + B cells significantly decreased at the 12th month after the MSCT. The gene expression of BAFF in the PBMC population significantly decreased during 6, and 12 months after the MSCT. The gene expression of APRIL significantly decreased on month 6 after the MSCT. The gene expression of BR3 significantly decreased during 1, 6, and 12 months after the MSCT. The MSCT seems to decrease B cells response because of the reduced production of BAFF and APRIL cytokines and decrease the expression of their receptors on the surface of B cells.


Assuntos
Artrite Reumatoide/terapia , Fator Ativador de Células B/metabolismo , Receptor do Fator Ativador de Células B/metabolismo , Regulação para Baixo , Transplante de Células-Tronco Mesenquimais/métodos , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Administração Intravenosa , Adulto , Antígenos CD19/metabolismo , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Fator Ativador de Células B/genética , Receptor do Fator Ativador de Células B/genética , Linfócitos B/imunologia , Feminino , Perfilação da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Resultado do Tratamento , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética
2.
J Immunol Res ; 2019: 8042097, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31240234

RESUMO

B cell activating factor (BAFF), a member of the tumor necrosis factor (TNF) family, plays a critical role in the pathogenesis and progression of rheumatoid arthritis (RA). Chlorogenic acid (CGA) is a phenolic compound and exerts antiarthritic activities in arthritis. However, it is not clear whether the anti-inflammatory property of CGA is associated with the regulation of BAFF expression. In this study, we found that treatment of the collagen-induced arthritis (CIA) mice with CGA significantly attenuated arthritis progression and markedly inhibited BAFF production in serum as well as the production of serum TNF-α. Furthermore, CGA inhibits TNF-α-induced BAFF expression in a dose-dependent manner and apoptosis in MH7A cells. Mechanistically, we found the DNA-binding site for the transcription factor NF-κB in the BAFF promoter region is required for this regulation. Moreover, CGA reduces the DNA-binding activity of NF-κB to the BAFF promoter region and suppresses BAFF expression through the NF-κB pathway in TNF-α-stimulated MH7A cells. These results suggest that CGA may serve as a novel therapeutic agent for the treatment of RA by targeting BAFF.


Assuntos
Fator Ativador de Células B/genética , Ácido Clorogênico/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sinoviócitos/efeitos dos fármacos , Sinoviócitos/metabolismo , Animais , Apoptose/efeitos dos fármacos , Artrite Experimental , Fator Ativador de Células B/metabolismo , Biomarcadores , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Humanos , Imuno-Histoquímica , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Regiões Promotoras Genéticas , Ativação Transcricional , Fator de Necrose Tumoral alfa/metabolismo
3.
BMC Pregnancy Childbirth ; 19(1): 169, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31088412

RESUMO

BACKGROUND: Tubal pregnancy is recognized as one of the most common ectopic pregnancy types. Salpingitis may result in tubal pregnancy by causing fallopian tube occlusion and hydrosalpinx. B cell activation factor (BAFF) is a proinflammatory cytokine that helps regulate both innate and adaptive immune responses. Our previous study firstly showed that BAFF immunostaining appeared on the cellular membrane and in the cytoplasm of tubal epithelial cells, and both BAFF protein and mRNA in human inflamed fallopian tubes had higher expression levels than those in normal fallopian tubes. This study aimed to elucidate the association between the expression of BAFF gene and the inflammation in the human fallopian tube leading to tubal pregnancy. METHODS: We examined 70 patients undergoing salpingectomy for salpingitis (n = 35) and tubal pregnancy (n = 35). Twenty patients with benign uterine diseases undergoing complete hysterectomy and salpingectomy were recruited into control group. BAFF mRNA and protein in tissue samples were detected by qPCR and Western blotting methods. Furthermore, serum levels of BAFF, tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 were measured using ELISA kits. RESULTS: We found statistically significantly elevated expressions of BAFF mRNA or protein in whole tissue samples, and serum levels of BAFF, TNF-α and IL-6 in whole blood samples from patients with salpingitis and tubal pregnancy, in comparison to the control group. CONCLUSION: Based on the results, high expression of BAFF gene might induce inflammation in the human fallopian tube, suggesting its possible role in the tubal pregnancy process.


Assuntos
Fator Ativador de Células B/genética , Fator Ativador de Células B/metabolismo , Gravidez Tubária/metabolismo , Salpingite/genética , Salpingite/metabolismo , Adulto , Fator Ativador de Células B/sangue , Estudos de Casos e Controles , Tubas Uterinas , Feminino , Expressão Gênica , Humanos , Interleucina-6/sangue , Gravidez , Gravidez Tubária/sangue , Gravidez Tubária/etiologia , RNA Mensageiro/metabolismo , Salpingite/complicações , Fator de Necrose Tumoral alfa/sangue
4.
Eur J Clin Invest ; 49(7): e13122, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31034586

RESUMO

BACKGROUND: Osteopontin (OPN) is recognized as a potent immunoregulator of autoimmune disease. In the study, we tried to explore the association of serum OPN levels with autoimmune thyroid disease, including Graves' disease (GD) and Hashimoto's thyroiditis (HT), in an ethnic Chinese population. MATERIALS AND METHODS: We enrolled 131 patients with GD, 33 patients with HT and 123 healthy controls. Serum OPN, B cell-activating factor (BAFF) and interferon (IFN)-α levels were quantified. Graves' disease patients with high thyroid function at the time of sample collection were defined as having active GD, while the other patients were defined as having inactive GD. RESULTS: Serum OPN levels were higher in active GD than in inactive GD and the control groups (P = 0.001 and P = 0.018, respectively). In GD, significant associations of OPN levels with thyroid-stimulating hormone receptor antibody (TSHRAb) levels were observed in women (r = -0.344, P = 0.002, and r = 0.440, P = 0.004, respectively) but not in men. Osteopontin levels were associated with BAFF levels only in women with GD or HT (r = 0.506, P < 0.001 and r = 0.430, P = 0.025, respectively), but not in men with GD or HT. CONCLUSIONS: Serum OPN levels were upregulated in active GD, and serum OPN levels were associated with thyroid function and TSHRAb levels in GD. Additionally, OPN levels were correlated with BAFF levels in GD and HT. The associations of OPN levels with clinical phenotypes of GD and BAFF levels showed a dimorphic pattern.


Assuntos
Fator Ativador de Células B/metabolismo , Doença de Graves/sangue , Doença de Hashimoto/sangue , Osteopontina/metabolismo , Adulto , Autoanticorpos/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Interferon-alfa/metabolismo , Masculino , Caracteres Sexuais , Glândula Tireoide/imunologia , Tireotropina/metabolismo , Tiroxina/metabolismo , Regulação para Cima/fisiologia
5.
Hum Immunol ; 80(6): 393-399, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30849450

RESUMO

Allogeneic hematopoietic stem cell transplantation (alloHCT) is the definitive therapy for numerous otherwise incurable hematologic malignancies and non-malignant diseases. The genetic disparity between donor and recipient both underpins therapeutic effects and confers donor immune system-mediated damage in the recipient, called graft-versus-host disease (GVHD). Chronic GVHD (cGVHD) is a major cause of late post-transplant morbidity and mortality. B cells have a substantiated role in cGVHD pathogenesis, as first demonstrated by clinical response to the anti-CD20 monoclonal antibody, rituximab. Initiation of CD20 blockade is met at times with limited therapeutic success that has been associated with altered peripheral B cell homeostasis and excess B Cell Activating Factor of the TNF family (BAFF). Increased BAFF to B cell ratios are associated with the presence of circulating, constitutively activated B cells in patients with cGVHD. These cGVHD patient B cells have increased survival capacity and signal through both BAFF-associated and B Cell Receptor (BCR) signaling pathways. Proximal BCR signaling molecules, Syk and BTK, appear to be hyper-activated in cGVHD B cells and can be targeted with small molecule inhibitors. Murine studies have confirmed roles for Syk and BTK in development of cGVHD. Emerging evidence has prompted investigation of several small molecule inhibitors in an attempt to restore B cell homeostasis and potentially target rare, pathologic B cell populations.


Assuntos
Linfócitos B/imunologia , Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas , Imunoterapia/métodos , Tirosina Quinase da Agamaglobulinemia/metabolismo , Animais , Fator Ativador de Células B/metabolismo , Doença Crônica , Doença Enxerto-Hospedeiro/tratamento farmacológico , Homeostase , Humanos , Camundongos , Receptores de Antígenos de Linfócitos B/metabolismo , Rituximab/uso terapêutico , Transdução de Sinais , Quinase Syk/metabolismo
6.
J Immunol Res ; 2019: 7627384, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30766889

RESUMO

Despite the overall success of using R-CHOP for the care for non-Hodgkin's lymphoma patients, it is clear that the disease is quite complex and new insight is needed to further stratify the patient for a better personized treatment. In current study, based on previous studies from animal model, new panels combining well-established cytokine (BAFF) and autoantibodies (anti-SSA/Ro) with newly identified cytokine (IL14) and autoantibodies (TSA) were used to evaluate the association between B cell growth factor and Sjögren's related autoantibodies in NHL patients. The result clearly indicates that there was a unique difference between BAFF and IL14 in association with autoantibodies. While serum BAFF was negatively associated with the presence of both traditional anti-SSA/Ro and novel TSA antibodies in GI lymphoma patient, IL14 was positively associated with the presence of both traditional anti-SSA/Ro and novel TSA antibodies in non-GI lymphoma patient. Long-term follow-ups on these patients and evaluation of their response to the R-CHOP treatment and recurrence rate will be very interesting. Our result provides a solid evidence to support using novel diagnostic panel to better stratify the NHL patients.


Assuntos
Fator Ativador de Células B/metabolismo , Linfócitos B/imunologia , Interleucina-4/metabolismo , Linfoma não Hodgkin/diagnóstico , Síndrome de Sjogren/imunologia , Proteínas de Transporte Vesicular/metabolismo , Adulto , Anticorpos Antinucleares/sangue , Autoanticorpos/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
7.
Ann Neurol ; 85(3): 406-420, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30635946

RESUMO

OBJECTIVE: The two related tumor necrosis factor members a proliferation-inducing ligand (APRIL) and B-cell activation factor (BAFF) are currently targeted in autoimmune diseases as B-cell regulators. In multiple sclerosis (MS), combined APRIL/BAFF blockade led to unexpected exacerbated inflammation in the central nervous system (CNS) of patients. Here, we investigate the role of the APRIL/BAFF axis in the CNS. METHODS: APRIL expression was analyzed in MS lesions by immunohistochemistry. The in vivo role of APRIL was assessed in the murine MS model, experimental autoimmune encephalitis (EAE). Functional in vitro studies were performed with human and mouse astrocytes. RESULTS: APRIL was expressed in lesions from EAE. In its absence, the disease was worst. Lesions from MS patients also showed APRIL expression upon infiltration of macrophages. Notably, all the APRIL secreted by these macrophages specifically targeted astrocytes. The upregulation of chondroitin sulfate proteoglycan, sometimes bearing chondroitin sulfate of type E sugar moieties, binding APRIL, in reactive astrocytes explained the latter selectivity. Astrocytes responded to APRIL by producing a sufficient amount of IL-10 to dampen antigen-specific T-cell proliferation and pathogenic cytokine secretion. Finally, an intraspinal delivery of recombinant APRIL before disease onset, shortly reduced EAE symptoms. Repeated intravenous injections of recombinant APRIL before and even at disease onset also had an effect. INTERPRETATION: Our data show that APRIL mediates an anti-inflammatory response from astrocytes in MS lesions. This protective activity is not shared with BAFF. ANN NEUROL 2019;85:406-420.


Assuntos
Astrócitos/metabolismo , Fator Ativador de Células B/metabolismo , Encefalomielite Autoimune Experimental/metabolismo , Esclerose Múltipla/metabolismo , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Adulto , Idoso , Animais , Astrócitos/imunologia , Astrócitos/patologia , Proliferação de Células , Proteoglicanas de Sulfatos de Condroitina/metabolismo , Sulfatos de Condroitina/metabolismo , Citocinas/imunologia , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Feminino , Humanos , Imuno-Histoquímica , Interleucina-10/imunologia , Macrófagos/patologia , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Linfócitos T/imunologia , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/farmacologia
8.
Int Immunopharmacol ; 67: 473-482, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30597293

RESUMO

Activated B cells targeted to autoantigens proliferate and differentiate into antibody-secreting cells. Overproduced autoantibodies will give rise to autoimmune diseases. In this study, we investigated the inhibitory effects of GYF-21, an epoxide 2­(2­phenethyl)­chromone derivative extracted from Chinese agarwood, on the survival, activation, proliferation, and differentiation of B cells for revealing its potential to treat autoimmune diseases related to B cell dysfunction. The results showed that GYF-21 slightly inhibited the survival, activation and proliferation of B cells stimulated by combination of anti-IgM, anti-CD40 and IL-4 while weakly up-regulated differentiation of B cells induced by combination of anti-CD40 and IL-4. In addition, GYF-21 intensively suppressed survival, activation, proliferation, and differentiation of B cells stimulated by B-cell activating factor (BAFF) which plays extremely important roles in autoantibody production and pathogenesis of autoimmune diseases. The mechanism study revealed that GYF-21 slightly down-regulated phosphorylation of NF-κB p65, Akt, STAT3, but up-regulated phosphorylation of Erk1/2 in B cells activated by anti-IgM, anti-CD40, IL-4 or their combinations. However, GYF-21 not only moderately down-regulated phosphorylation of NF-κB p65 and MAPK p38, but also intensively inhibited phosphorylation of Erk1/2 and Akt induced by BAFF. These data suggest the inhibitory effects of GYF-21 on the survival, activation, proliferation, and differentiation of B cells mainly via blocking BAFF activated signaling pathways, and its potential to be developed into therapeutic drug for autoimmune diseases, especially systemic lupus erythematosus (SLE).


Assuntos
Fator Ativador de Células B/metabolismo , Linfócitos B/efeitos dos fármacos , Cromonas/farmacologia , Animais , Anticorpos , Fator Ativador de Células B/genética , Antígenos CD40/imunologia , Proliferação de Células/efeitos dos fármacos , Cromonas/química , Imunoglobulina M/imunologia , Interleucina-4/imunologia , Masculino , Camundongos , Transdução de Sinais/efeitos dos fármacos
9.
Acta Pharmacol Sin ; 40(6): 801-813, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30446734

RESUMO

Paeoniflorin-6'-O-benzene sulfonate (CP-25) is a new ester derivative of paeoniflorin with improved lipid solubility and oral bioavailability, as well as better anti-inflammatory activity than its parent compound. In this study we explored whether CP-25 exerted therapeutic effects in collagen-induced arthritis (CIA) mice through regulating B-cell activating factor (BAFF)-BAFF receptors-mediated signaling pathways. CIA mice were given CP-25 or injected with biological agents rituximab or etanercept for 40 days. In CIA mice, we found that T cells and B cells exhibited abnormal proliferation; the percentages of CD19+ total B cells, CD19+CD27+-activated B cells, CD19+BAFFR+ and CD19+TACI+ cells were significantly increased in PBMCs and spleen lymphocytes. CP-25 suppressed the indicators of arthritis, alleviated histopathology, accompanied by reduced BAFF and BAFF receptors expressions, inhibited serum immunoglobulin levels, decreased the B-cell subsets percentages, and prevented the expressions of key molecules in NF-κB signaling. Furthermore, we showed that treatment with CP-25 reduced CD19+TRAF2+ cell expressions stimulated by BAFF and decreased TRAF2 overexpression in HEK293 cells in vitro. Thus, CP-25 restored the abnormal T cells proliferation and B-cell percentages to the normal levels, and normalized the elevated levels of IgA, IgG2a and key proteins in NF-κB signaling. In comparison, rituximab and etanercept displayed stronger anti-inflammatory activities than CP-25; they suppressed the elevated inflammatory indexes to below the normal levels in CIA mice. In summary, our results provide evidence that CP-25 alleviates CIA and regulates the functions of B cells through BAFF-TRAF2-NF-κB signaling. CP-25 would be a soft immunomodulatory drug with anti-inflammatory effect.


Assuntos
Anti-Inflamatórios/uso terapêutico , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Regulação para Baixo/efeitos dos fármacos , Glucosídeos/uso terapêutico , Monoterpenos/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Animais , Artrite Experimental/induzido quimicamente , Artrite Reumatoide/induzido quimicamente , Fator Ativador de Células B/metabolismo , Linfócitos B/metabolismo , Proliferação de Células/efeitos dos fármacos , Colágeno , Etanercepte/uso terapêutico , Células HEK293 , Humanos , Articulações/patologia , Ativação Linfocitária/efeitos dos fármacos , Masculino , Camundongos Endogâmicos DBA , Subunidade p50 de NF-kappa B/metabolismo , Rituximab/uso terapêutico , Baço/patologia , Linfócitos T/metabolismo , Fator 2 Associado a Receptor de TNF/metabolismo
10.
Scand J Rheumatol ; 48(2): 149-156, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30270699

RESUMO

OBJECTIVE: Small airway disease and chronic obstructive pulmonary disease are common in primary Sjögren's syndrome (pSS). However, the underlying inflammatory mechanisms behind pSS-associated airway disease have not been studied in detail. We therefore wanted to study cytokine and leucocyte levels in induced sputum in never-smoking patients with pSS. METHOD: Induced sputum cytokines and leucocytes were assessed in 20 never-smoking patients with pSS and 19 age- and gender-matched population-based controls. In addition, pulmonary function, disease activity, respiratory symptoms, and inflammatory and serological features of pSS were assessed. RESULTS: B-cell activating factor (BAFF), interleukin-6 (IL-6) and IL-8 were significantly increased in induced sputum in pSS patients compared to population-based controls, while IL-1ß, interferon-α, and tumour necrosis factor-α levels and leucocytes were not. The proportion of lymphocytes and BAFF levels in induced sputum correlated significantly in pSS patients. However, cytokine levels in induced sputum were not associated with pulmonary function tests, disease activity, respiratory symptoms, or serological features of pSS. CONCLUSION: The increase in BAFF, IL-6, and IL-8 in induced sputum suggests a specific ongoing inflammatory disease process in the airways in pSS patients. Its association with pSS-associated airway disease needs to be further examined in future larger studies.


Assuntos
Fator Ativador de Células B/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Síndrome de Sjogren/metabolismo , Escarro/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Leucócitos , Masculino , Pessoa de Meia-Idade , Escarro/citologia
11.
Fish Shellfish Immunol ; 85: 9-17, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28989090

RESUMO

In teleost fish, IgM+ B cells are one of the main responders against inflammatory stimuli in the peritoneal cavity, as IgM+ B cells dominate the peritoneum after intraperitoneal stimulation, also increasing the levels of secreted IgM. BAFF, a cytokine known to play a major role in B cell biology, has been shown to be up-regulated along with its receptors in the peritoneum of rainbow trout upon antigenic exposure, however, the regulatory mechanisms underneath this response remain unclear. In this study, we have identified two different IgM+ B cell types residing in the peritoneal cavity of previously vaccinated rainbow trout (Oncorhynchus mykiss): IgD+IgMhiMHCIIhi cells, resembling naïve B cells, and IgD-IgMloMHCIIlo cells, resembling antibody-secreting cells. Based on their membrane IgM levels, these cell types were named IgMhi and IgMlo B cells, respectively. As each of these B cell populations showed a distinct expression pattern for the different BAFF receptors, we studied the effect of BAFF individually on each cell subset. Recombinant BAFF promoted the survival of IgMlo but not IgMhi B cells in vitro, resulting in increased levels of IgM-secreting cells. In contrast, BAFF increased the levels of membrane MHC II only on IgMhi B cells, suggesting different functions on these B cell subsets. Moreover, we also showed that peritoneal IgMhi B cells expressed BAFF at levels comparable to those seen on myeloid cells. These results point to BAFF as a main regulator of B cell homeostasis in the peritoneal cavity, suggesting that this cytokine can trigger different signals on different peritoneal B cell subsets in a specific manner.


Assuntos
Fator Ativador de Células B/genética , Linfócitos B/imunologia , Proteínas de Peixes/genética , Imunoglobulina M/metabolismo , Oncorhynchus mykiss/genética , Oncorhynchus mykiss/imunologia , Animais , Fator Ativador de Células B/metabolismo , Proteínas de Peixes/metabolismo , Cavidade Peritoneal/fisiologia , Vacinação/veterinária
12.
J Leukoc Biol ; 105(3): 507-518, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30576006

RESUMO

B cell development is regulated by stromal cells (SCs) that form a supportive microenvironment. These SCs along with other cell types produce cytokines, chemokines, and adhesion molecules that guide B cell commitment and differentiation. BM, spleen (Sp), and the gut lamina propria (LP) constitute distinctive anatomical compartments that support B cell differentiation. In order to characterize and compare the signals necessary to generate IgA+ B cells, we developed an in vitro system to co-culture gut LP, BM, or Sp-derived SCs with B lineage cells. Using this co-culture system, we found that gut LP SCs promote IgA+ B cell accumulation through the production of soluble stimulatory factors. In contrast to gut LP SCs, BM and splenic SCs were found to impair IgA+ B cell accumulation in vitro. Taken together, these observations provide new insights into how SCs derived from different anatomical locations shape IgA+ B cell responses.


Assuntos
Linfócitos B/metabolismo , Imunoglobulina A/metabolismo , Células Estromais/metabolismo , Animais , Fator Ativador de Células B/metabolismo , Diferenciação Celular , Linhagem Celular , Feminino , Mucosa Intestinal/citologia , Camundongos Endogâmicos C57BL , Solubilidade , Células Estromais/citologia
13.
Front Immunol ; 9: 2871, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30574145

RESUMO

Breaking tolerance is a key event leading to autoimmunity, but the exact mechanisms responsible for this remain uncertain. Here we show that the alarmin IL-33 is able to drive the generation of autoantibodies through induction of the B cell survival factor BAFF. A temporary, short-term increase in IL-33 results in a primary (IgM) response to self-antigens. This transient DNA-specific autoantibody response was dependent on the induction of BAFF. Notably, radiation resistant cells and not myeloid cells, such as neutrophils or dendritic cells were the major source of BAFF and were critical in driving the autoantibody response. Chronic exposure to IL-33 elicited dramatic increases in BAFF levels and resulted in elevated numbers of B and T follicular helper cells as well as germinal center formation. We also observed class-switching from an IgM to an IgG DNA-specific autoantibody response. Collectively, the results provide novel insights into a potential mechanism for breaking immune-tolerance via IL-33-mediated induction of BAFF.


Assuntos
Autoanticorpos/imunologia , Autoantígenos/imunologia , Doenças Autoimunes/imunologia , Fator Ativador de Células B/metabolismo , Tolerância Imunológica , Interleucina-33/imunologia , Animais , Autoantígenos/administração & dosagem , Fator Ativador de Células B/genética , Fator Ativador de Células B/imunologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Células Cultivadas , Células Dendríticas , Modelos Animais de Doenças , Humanos , Imunoglobulina M/imunologia , Interleucina-33/administração & dosagem , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos , Cultura Primária de Células , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/imunologia
14.
Nucleic Acids Res ; 46(22): 12040-12051, 2018 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-30272251

RESUMO

Polymorphisms in untranslated regions (UTRs) of disease-associated mRNAs can alter protein production. We recently identified a genetic variant in the 3'UTR of the TNFSF13B gene, encoding the cytokine BAFF (B-cell-activating factor), that generates an alternative polyadenylation site yielding a shorter, more actively translated variant, BAFF-var mRNA. Accordingly, individuals bearing the TNFSF13B variant had higher circulating BAFF and elevated risk of developing autoimmune diseases. Here, we investigated the molecular mechanisms controlling the enhanced translation of BAFF-var mRNA. We identified nuclear factor 90 (NF90, also known as ILF3) as an RNA-binding protein that bound preferentially the wild-type (BAFF-WT mRNA) but not BAFF-var mRNA in human monocytic leukemia THP-1 cells. NF90 selectively suppressed BAFF translation by recruiting miR-15a to the 3'UTR of BAFF-WT mRNA. Our results uncover a paradigm whereby an autoimmunity-causing BAFF polymorphism prevents NF90-mediated recruitment of microRNAs to suppress BAFF translation, raising the levels of disease-associated BAFF.


Assuntos
Regiões 3' não Traduzidas/genética , Fator Ativador de Células B/genética , Fator Ativador de Células B/metabolismo , MicroRNAs/fisiologia , Proteínas do Fator Nuclear 90/fisiologia , Polimorfismo Genético , Doenças Autoimunes/genética , Doenças Autoimunes/metabolismo , Regulação para Baixo/genética , Células HeLa , Humanos , Proteínas do Fator Nuclear 90/metabolismo , Polimorfismo Genético/fisiologia , Ligação Proteica , Biossíntese de Proteínas/genética , RNA Mensageiro/metabolismo , Células THP-1
15.
J Immunol ; 201(11): 3258-3268, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30373855

RESUMO

The B cell survival cytokine BAFF has been linked with the pathogenesis of systemic lupus erythematosus (SLE). BAFF binds distinct BAFF-family surface receptors, including the BAFF-R and transmembrane activator and CAML interactor (TACI). Although originally characterized as a negative regulator of B cell activation, TACI signals are critical for class-switched autoantibody (autoAb) production in BAFF transgenic mice. Consistent with this finding, a subset of transitional splenic B cells upregulate surface TACI expression and contribute to BAFF-driven autoAb. In the current study, we interrogated the B cell signals required for transitional B cell TACI expression and Ab production. Surprisingly, despite established roles for dual BCR and TLR signals in autoAb production in SLE, signals downstream of these receptors exerted distinct impacts on transitional B cell TACI expression and autoAb titers. Whereas loss of BCR signals prevented transitional B cell TACI expression and resulted in loss of serum autoAb across all Ig isotypes, lack of TLR signals exerted a more limited impact restricted to autoAb class-switch recombination without altering transitional B cell TACI expression. Finally, in parallel with the protective effect of TACI deletion, loss of BAFF-R signaling also protected against BAFF-driven autoimmunity. Together, these findings highlight how multiple signaling pathways integrate to promote class-switched autoAb production by transitional B cells, events that likely impact the pathogenesis of SLE and other BAFF-dependent autoimmune diseases.


Assuntos
Autoanticorpos/metabolismo , Glomerulonefrite por IGA/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Glicoproteínas de Membrana/metabolismo , Células Precursoras de Linfócitos B/fisiologia , Receptores de Antígenos de Linfócitos B/metabolismo , Receptor 7 Toll-Like/metabolismo , Animais , Fator Ativador de Células B/genética , Fator Ativador de Células B/metabolismo , Receptor do Fator Ativador de Células B/genética , Modelos Animais de Doenças , Humanos , Switching de Imunoglobulina , Ativação Linfocitária , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Receptor Cross-Talk , Receptores de Antígenos de Linfócitos B/genética , Transdução de Sinais , Receptor 7 Toll-Like/genética , Proteína Transmembrana Ativadora e Interagente do CAML/genética , Proteína Transmembrana Ativadora e Interagente do CAML/metabolismo
16.
Front Immunol ; 9: 2285, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30349534

RESUMO

The BAFF-receptor (BAFFR) is encoded by the TNFRSF13C gene and is one of the main pro-survival receptors in B cells. Its function is impressively documented in humans by a homozygous deletion within exon 2, which leads to an almost complete block of B cell development at the stage of immature/transitional B cells. The resulting immunodeficiency is characterized by B-lymphopenia, agammaglobulinemia, and impaired humoral immune responses. However, different from mutations affecting pathway components coupled to B cell antigen receptor (BCR) signaling, BAFFR-deficient B cells can still develop into IgA-secreting plasma cells. Therefore, BAFFR deficiency in humans is characterized by very few circulating B cells, very low IgM and IgG serum concentrations but normal or high IgA levels.


Assuntos
Fator Ativador de Células B/metabolismo , Receptor do Fator Ativador de Células B/metabolismo , Linfócitos B/citologia , Animais , Autoimunidade , Receptor do Fator Ativador de Células B/deficiência , Linfócitos B/metabolismo , Sobrevivência Celular/genética , Regulação da Expressão Gênica , Humanos , Linfopoese/genética , Camundongos , Transdução de Sinais
17.
Front Immunol ; 9: 1880, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30150995

RESUMO

Tumor necrosis factor ligand superfamily members such as B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) have been identified in mammals as key regulators of B cell homeostasis and activation. However, the immune functions of APRIL are not as well defined as those of BAFF. Furthermore, while BAFF is present in all vertebrates, APRIL is missing in some animal groups, suggesting that BAFF has compensated the functions of APRIL in these species. In this context, we thought of great interest to explore the effects of APRIL on teleost B cells, given that APRIL appears for the first time in evolution in bony fish. Thus, in this study, we have performed an extensive analysis of the effect of APRIL on B cells using rainbow trout (Oncorhynchus mykiss) as a model species. Our results demonstrate that APRIL induces a specific proliferation of IgM+ B cells by itself and increases IgM secretion without promoting a terminal differentiation to plasma cells. APRIL also increased the levels of surface MHC II and augmented the capacity of these cells to process antigen, effects that were exclusively exerted on IgM+ B cells. Although our results point to a highly conserved role of APRIL on B cell homeostasis and activation throughout evolution, some specific differential effects have been observed in fish in comparison to the effects of APRIL previously described in mammals. Finally, the effects that APRIL induces on rainbow trout IgM+ B cells described in this paper have been compared with those previously reported in response to BAFF.


Assuntos
Linfócitos B/imunologia , Proteínas de Peixes/metabolismo , Mamíferos/imunologia , Oncorhynchus mykiss/imunologia , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Animais , Fator Ativador de Células B/metabolismo , Evolução Biológica , Diferenciação Celular , Proliferação de Células , Autorrenovação Celular , Proteínas de Peixes/genética , Homeostase , Imunoglobulina M/metabolismo , Ativação Linfocitária , Filogenia , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética
18.
EBioMedicine ; 35: 106-113, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30139628

RESUMO

Mixed Cryoglobulinemic Vasculitis (MCV) is a prominent extra-hepatic manifestation of Hepatitis C virus (HCV) infection. HCV has been reported to cause B-cell disorders and genomic instability. Here, we investigated B-cell activation and genome stability in HCV-MCV patients receiving the direct antiviral agent, Sofosbuvir, at multiple centers in Egypt. Clinical manifestations in HCV-MCV patients were improved at the end of treatment (EOT), such as purpura (100%), articular manifestations (75%) and neuropathy (68%). Eighteen patients (56%) showed vasculitis relapse after EOT. BAFF and APRIL were higher at EOT and continued to increase one year following treatment onset. Chromosomal breaks were elevated at EOT compared to baseline levels and were sustained at 3 and 6 months post treatment. We report increased expression of DNA genome stability transcripts such as topoisomerase 1 and TDP1 in HCV-MCV patients after treatment, which continued to increase at 12 months from treatment onset. This data suggest that B-cell activation and DNA damage are important determinants of HCV-MCV treatment outcomes.


Assuntos
Antivirais/farmacologia , Instabilidade Genômica/efeitos dos fármacos , Hepacivirus/efeitos dos fármacos , Antivirais/uso terapêutico , Fator Ativador de Células B/metabolismo , Linfócitos B/efeitos dos fármacos , Crioglobulinemia/tratamento farmacológico , Crioglobulinemia/patologia , Crioglobulinemia/virologia , Crioglobulinas/metabolismo , Dano ao DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Sofosbuvir/farmacologia , Sofosbuvir/uso terapêutico , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Vasculite/tratamento farmacológico , Vasculite/patologia , Vasculite/virologia
19.
Parasite Immunol ; 40(10): e12580, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30102786

RESUMO

B cell-mediated humoral responses are essential for controlling malarial infection. Studies have addressed the effects of Plasmodium falciparum infection on peripheral B-cell subsets but not much is known for P. vivax infection. Furthermore, majority of the studies investigate changes during acute infection, but not after parasite clearance. In this prospective study, we analysed peripheral B-cell profiles and antibody responses during acute P. vivax infection and upon recovery (30 days post-treatment) in a low-transmission area in India. Dengue patients were included as febrile-condition controls. Both dengue and malaria patients showed a transient increase in atypical memory B cells during acute infection. However, transient B cell-activating factor (BAFF)-independent increase in the percentage of total and activated immature B cells was observed in malaria patients. Naïve B cells from malaria patients also showed increased TLR4 expression. Total IgM levels remained unchanged during acute infection but increased significantly at recovery. Serum antibody profiling showed a parasite-specific IgM response that persisted at recovery. A persistent IgM autoantibody response was also observed in malaria but not dengue patients. Our data suggest that in hypoendemic regions acute P. vivax infection skews peripheral B-cell subsets and results in a persistent parasite-specific and autoreactive IgM response.


Assuntos
Anticorpos Antiprotozoários/sangue , Subpopulações de Linfócitos B/imunologia , Imunoglobulina M/sangue , Malária Vivax/imunologia , Plasmodium vivax/imunologia , Adulto , Anticorpos Antiprotozoários/imunologia , Formação de Anticorpos , Fator Ativador de Células B/metabolismo , Feminino , Humanos , Imunoglobulina M/imunologia , Índia , Malária Vivax/parasitologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Receptor 4 Toll-Like/biossíntese
20.
Clin Immunol ; 197: 19-26, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30056130

RESUMO

B-cell activating factor (BAFF) has been proposed to play a crucial role in the pathogenesis of chronic rhinosinusitis with nasal polyp (CRSwNP). The aim of this study was to evaluate the role of toll-like receptor (TLR) 9-mediated BAFF activation on the pathogenesis of CRSwNP. NP and uncinate tissue (UT) were obtained from patients with CRSwNP or CRS without NP, and control subjects. The expression of TLR9, high mobility group box-1 protein (HMGB1), type I interferon (IFN), BAFF, and anti-double stranded DNA (dsDNA) antibody were examined in the tissues and the cultured dispersed NP cells (DNPCs). The expression of TLR9, HMGB1, type I IFN, BAFF, and anti-dsDNA antibody were elevated in NP tissue compared to the UTs. Exposure to TLR9 agonist increased the type I IFN expression in vitro, which further increased BAFF production. In conclusion, we provided a novel therapeutic potential of TLR9 agonist in CRSwNP.


Assuntos
Fator Ativador de Células B/genética , Proteína HMGB1/genética , Pólipos Nasais/metabolismo , Rinite/metabolismo , Sinusite/metabolismo , Receptor Toll-Like 9/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Fator Ativador de Células B/efeitos dos fármacos , Fator Ativador de Células B/metabolismo , Doença Crônica , Feminino , Seio Frontal/metabolismo , Proteína HMGB1/metabolismo , Humanos , Técnicas In Vitro , Interferon-alfa/efeitos dos fármacos , Interferon-alfa/genética , Interferon-alfa/metabolismo , Interferon beta/efeitos dos fármacos , Interferon beta/genética , Interferon beta/metabolismo , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo , Receptor Toll-Like 9/agonistas
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