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1.
Immunol Rev ; 324(1): 95-103, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38747455

RESUMO

Fat is stored in distinct depots with unique features in both mice and humans and B cells reside in all adipose depots. We have shown that B cells modulate cardiometabolic disease through activities in two of these key adipose depots: visceral adipose tissue (VAT) and perivascular adipose tissue (PVAT). VAT refers to the adipose tissue surrounding organs, within the abdomen and thorax, and is comprised predominantly of white adipocytes. This depot has been implicated in mediating obesity-related dysmetabolism. PVAT refers to adipose tissue surrounding major arteries. It had long been thought to exist to provide protection and insulation for the vessel, yet recent work demonstrates an important role for PVAT in harboring immune cells, promoting their function and regulating the biology of the underlying vessel. The role of B-2 cells and adaptive immunity in adipose tissue biology has been nicely reviewed elsewhere. Given that, the predominance of B-1 cells in adipose tissue at homeostasis, and the emerging role of B-1 cells in a variety of disease states, we will focus this review on how B-1 cells function in VAT and PVAT depots to promote homeostasis and limit inflammation linked to cardiometabolic disease and factors that regulate this function.


Assuntos
Tecido Adiposo , Imunidade Inata , Inflamação , Humanos , Animais , Inflamação/imunologia , Inflamação/metabolismo , Tecido Adiposo/metabolismo , Tecido Adiposo/imunologia , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Obesidade/imunologia , Obesidade/metabolismo , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/imunologia , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Doenças Metabólicas/imunologia , Doenças Metabólicas/metabolismo , Doenças Metabólicas/etiologia , Imunomodulação
2.
Immunol Rev ; 315(1): 11-30, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36929134

RESUMO

It has been over three decades since Drs. Herzenberg and Herzenberg proposed the layered immune system hypothesis, suggesting that different types of stem cells with distinct hematopoietic potential produce specific immune cells. This layering of immune system development is now supported by recent studies showing the presence of fetal-derived immune cells that function in adults. It has been shown that various immune cells arise at different embryonic ages via multiple waves of hematopoiesis from special endothelial cells (ECs), referred to as hemogenic ECs. However, it remains unknown whether these fetal-derived immune cells are produced by hematopoietic stem cells (HSCs) during the fetal to neonatal period. To address this question, many advanced tools have been used, including lineage-tracing mouse models, cellular barcoding techniques, clonal assays, and transplantation assays at the single-cell level. In this review, we will review the history of the search for the origins of HSCs, B-1a progenitors, and mast cells in the mouse embryo. HSCs can produce both B-1a and mast cells within a very limited time window, and this ability declines after embryonic day (E) 14.5. Furthermore, the latest data have revealed that HSC-independent adaptive immune cells exist in adult mice, which implies more complicated developmental pathways of immune cells. We propose revised road maps of immune cell development.


Assuntos
Sistema Imunitário , Sistema Imunitário/citologia , Sistema Imunitário/crescimento & desenvolvimento , Humanos , Animais , Hematopoese , Embrião de Mamíferos/citologia , Células-Tronco Hematopoéticas/citologia , Linfócitos/citologia , Linhagem da Célula
3.
Proc Natl Acad Sci U S A ; 118(47)2021 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-34782464

RESUMO

Regulatory B cells (Breg cells) that secrete IL-10 or IL-35 (i35-Breg) play key roles in regulating immunity in tumor microenvironment or during autoimmune and infectious diseases. Thus, loss of Breg function is implicated in development of autoimmune diseases while aberrant elevation of Breg prevents sterilizing immunity, exacerbates infectious diseases, and promotes cancer metastasis. Breg cells identified thus far are largely antigen-specific and derive mainly from B2-lymphocyte lineage. Here, we describe an innate-like IL-27-producing natural regulatory B-1a cell (i27-Breg) in peritoneal cavity and human umbilical cord blood. i27-Bregs accumulate in CNS and lymphoid tissues during neuroinflammation and confers protection against CNS autoimmune disease. i27-Breg immunotherapy ameliorated encephalomyelitis and uveitis through up-regulation of inhibitory receptors (Lag3, PD-1), suppression of Th17/Th1 responses, and propagating inhibitory signals that convert conventional B cells to regulatory lymphocytes that secrete IL-10 and/or IL-35 in eye, brain, or spinal cord. Furthermore, i27-Breg proliferates in vivo and sustains IL-27 secretion in CNS and lymphoid tissues, a therapeutic advantage over administering biologics (IL-10, IL-35) that are rapidly cleared in vivo. Mutant mice lacking irf4 in B cells exhibit exaggerated increase of i27-Bregs with few i35-Bregs, while mice with loss of irf8 in B cells have abundance of i35-Bregs but defective in generating i27-Bregs, identifying IRF8/BATF and IRF4/BATF axis in skewing B cell differentiation toward i27-Breg and i35-Breg developmental programs, respectively. Consistent with its developmental origin, disease suppression by innate i27-Bregs is neither antigen-specific nor disease-specific, suggesting that i27-Breg would be effective immunotherapy for a wide spectrum of autoimmune diseases.


Assuntos
Doenças Autoimunes/imunologia , Doenças do Sistema Nervoso Central/imunologia , Interleucina-27/metabolismo , Doenças Neuroinflamatórias/imunologia , Animais , Linfócitos B Reguladores/imunologia , Diferenciação Celular , Encefalite , Fatores Reguladores de Interferon , Interleucina-10 , Camundongos , Uveíte/imunologia
4.
Curr Issues Mol Biol ; 45(8): 6272-6282, 2023 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-37623214

RESUMO

Avermectins are a group of macrocyclic lactones that are commonly used as pesticides to treat pests and parasitic worms. Some members of the avermectin family, such as ivermectin, have been found to exhibit anti-proliferative activity toward cancer cells. This study aimed to investigate the potential anti-cancer activities of avermectin B1a using the HCT-116 colon cancer cell line. The MTT assay was used to calculate the IC50 by incubating cells with increasing doses of avermectin B1a for 24, 48, and 72 h. Flow cytometry was used to evaluate apoptosis following the 24 h incubation of cells. The migration capacity of the HCT-116 cells in the absence or presence of avermectin B1a was also investigated. Finally, tubulin polymerization in the presence of avermectin B1a was evaluated. Avermectin B1a presented anti-proliferative activity with an IC50 value of 30 µM. Avermectin B1a was found to promote tubulin polymerization at 30 µM. In addition, avermectin B1a induced apoptosis in HCT-116 cells and substantially diminished their ability to migrate. Avermectin B1a exhibits significant anti-cancer activity and enhances tubulin polymerization, suggesting that it can be used as a promising microtubule-targeting agent for the development of future anticancer drugs.

5.
Development ; 146(15)2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31371526

RESUMO

The current paradigm that a single long-term hematopoietic stem cell can regenerate all components of the mammalian immune system has been challenged by recent findings in mice. These findings show that adult tissue-resident macrophages and innate-like lymphocytes develop early in fetal hematopoiesis from progenitors that emerge prior to, and apparently independently of, conventional long-term hematopoietic stem cells. Here, we discuss these recent findings, which show that an early and distinct wave of hematopoiesis occurs for all major hematopoietic lineages. These data provide evidence that fetal hematopoietic progenitors not derived from the bona fide long-term hematopoietic stem cells give rise to tissue-resident immune cells that persist throughout adulthood. We also discuss recent insights into B lymphocyte development and attempt to synthesize seemingly contradictory recent findings on the origins of innate-like B-1a lymphocytes during fetal hematopoiesis.


Assuntos
Subpopulações de Linfócitos B/citologia , Hematopoese/fisiologia , Células-Tronco Hematopoéticas/citologia , Macrófagos/citologia , Animais , Linhagem da Célula , Embrião de Mamíferos/embriologia , Camundongos
6.
Appl Microbiol Biotechnol ; 106(5-6): 2191-2205, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35258669

RESUMO

Avermectins (AVEs) are economically potent anthelmintic agents produced by Streptomyces avermitilis. Among eight AVE components, B1a exhibits the highest insecticidal activity. The purpose of this study was to enhance B1a production, particularly in the high-yielding industrial strain A229, by a combination strategy involving the following steps. (i) aveC gene was engineered to increase B1a:B2a ratio. Three aveC variants (aveC2m, aveC5m, and aveC8m, respectively encoding two, five, and eight amino acid mutations) were synthesized by fusion PCR. B1a:B2a ratio in A229 derivative having kasOp*-controlled aveC8m reached 1.33 (B1a and B2a titers were 8120 and 6124 µg/mL). Corresponding values in A229 were 0.99 and 6447 and 6480 µg/mL. (ii) ß-oxidation pathway genes fadD and fadAB were overexpressed in wild-type (WT) strain and A229 to increase supply of acyl-CoA precursors for AVE production. The resulting strains all showed increased B1a titer. Co-overexpression of pkn5p-driven fadD and fadAB in A229 led to B1a titer of 8537 µg/mL. (iii) Genes bicA and ecaA involved in cyanobacterial CO2-concentrating mechanism (CCM) were introduced into WT and A229 to enhance carboxylation velocity of acetyl-CoA and propionyl-CoA carboxylases, leading to increased supply of malonyl- and methylmalonyl-CoA precursors and increased B1a titer. Co-expression of bicA and ecaA in A229 led to B1a titer of 8083 µg/mL. (iv) aveC8m, fadD-fadAB, and bicA-ecaA were co-overexpressed in A229, resulting in maximal B1a titer (9613 µg/mL; 49.1% increase relative to A229). Our findings demonstrate that the combination strategy we provided here is an efficient approach for improving B1a production in industrial strains.Key points• aveC mutation increased avermectin B1a:B2a ratio and B1a titer.• Higher levels of acyl-CoA precursors contributed to enhanced B1a production.• B1a titer in an industrial strain was increased by 49.1% via a combination strategy.


Assuntos
Anti-Helmínticos , Inseticidas , Streptomyces , Anti-Helmínticos/química , Inseticidas/metabolismo , Ivermectina/análogos & derivados , Streptomyces/genética , Streptomyces/metabolismo
7.
Pflugers Arch ; 473(4): 659-671, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33586023

RESUMO

Innate-like CD5+ B1a cells localized in serous cavities are activated by innate stimuli, such as lipopolysaccharide (LPS), leading to T cell-independent antibody responses. Although ion channels play crucial roles in the homeostasis and activation of immune cells, the electrophysiological properties of B1a cells have not been investigated to date. Previously, in the mouse B cell lymphoma cells, we found that the voltage-independent two-pore-domain potassium (K2P) channels generate a negative membrane potential and drive Ca2+ influx. Here, we newly compared the expression and activities of K2P channels in mouse splenic follicular B (FoB), marginal zone B (MZB), and peritoneal B1a cells. Next-generation sequencing analysis showed higher levels of transcripts for TREK-2 and TWIK-2 in B1a cells than those in FoB or MZB cells. Electrophysiological analysis, using patch clamp technique, revealed higher activity of TREK-2 with the characteristic large unitary conductance (~ 250 pS) in B1a than that in FoB or MZB cells. TREK-2 activity was further increased by LPS treatment (>2 h), which was more prominent in B1a than that in MZB or FoB cells. The cytosolic Ca2+ concentration of B cells was decreased by high-K+-induced depolarization (ΔRKCl (%)), suggesting the basal Ca2+ influx to be driven by negative membrane potential. The LPS treatment significantly increased the ΔRKCl (%) in B1a, though not in FoB and MZB cells. Our study was the first to compare the K2P channels in mouse primary B cell subsets, elucidating the functional upregulation of TREK-2 and augmentation of Ca2+ influx by the stimulation of Toll-like receptor 4 in B1a cells.


Assuntos
Potenciais de Ação , Linfócitos B/metabolismo , Canais de Potássio de Domínios Poros em Tandem/metabolismo , Baço/citologia , Animais , Linfócitos B/efeitos dos fármacos , Linfócitos B/fisiologia , Antígenos CD5/genética , Antígenos CD5/metabolismo , Cálcio/metabolismo , Células Cultivadas , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Peritônio/citologia , Canais de Potássio de Domínios Poros em Tandem/genética , Regulação para Cima
8.
Mol Med ; 27(1): 55, 2021 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-34058975

RESUMO

BACKGROUND: Sepsis is a life-threatening disease syndrome caused by a dysregulated host response to infection and injury. Extracellular cold-inducible RNA-binding protein (eCIRP) acts as a damage-associated molecular pattern. Peritoneal cavity (PerC) B-1a cells attenuate inflammation and tissue injury by spontaneous releasing natural IgM and IL-10. Sialic acid-binding immunoglobulin-type lectin-G (Siglec-G) is a CD33-related receptor highly expressed in B-1a cells to serve critical immunoregulatory functions. In sepsis, B-1a cell numbers in PerC are decreased. We hypothesized that eCIRP causes the reduction of PerC B-1a cells and alters their function during sepsis. METHODS: Sepsis was induced in WT and CIRP-/- mice by cecal ligation and puncture (CLP). PerC washout cells were collected and B-1a cells and Siglec-G were assessed by flow cytometry. Mice were i.p. injected with recombinant murine (rm) CIRP and after 20 h, Siglec-G expression in PerC B-1a cells were assessed. PerC B-1a cells were treated with rmCIRP for 4 h and Siglec-G expression was assessed. PerC B-1a cells were pre-treated with anti-Siglec-G Ab and then after stimulated with rmCIRP for 24 h, IL-6 levels in the culture supernatants were assessed. RESULTS: eCIRP levels in the PerC were elevated in septic mice. In WT mice, the frequencies and numbers of total and Siglec-G+ B-1a cells in the PerC were significantly decreased in the CLP group compared to sham group, whereas in CIRP-/- mice, their frequencies and numbers in sepsis were significantly rescued compared to WT septic mice. Mice injected with rmCIRP showed decreased frequencies and numbers of total and Siglec-G+ PerC B-1a cells compared to PBS-injected mice. In vitro treatment of PerC B-1a cells with rmCIRP demonstrated significant reduction in Siglec-G mRNA and protein compared to PBS group. PerC B-1a cells treated with anti-Siglec-G Ab had significantly higher production of IL-6 in response to rmCIRP compared to IgG control. Anti-Siglec-G Ab treated B-1a cells co-cultured with macrophages produced significantly higher levels of IL-6, and TNF-α, and lower levels of IL-10 compared to IgG-treated B-1a cells and macrophage co-cultures stimulated with rmCIRP. CONCLUSION: eCIRP reduces PerC B-1a cell pool and skews them to a pro-inflammatory phenotype by downregulating Siglec-G expression. Targeting eCIRP will retain Siglec-G expressing B-1a cells in the PerC and preserve their anti-inflammatory function in sepsis.


Assuntos
Regulação da Expressão Gênica , Fenótipo , Proteínas de Ligação a RNA/metabolismo , Receptores de Antígenos de Linfócitos B/genética , Sepse/metabolismo , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/genética , Animais , Líquido Ascítico/metabolismo , Biomarcadores , Citocinas/sangue , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Espaço Extracelular/metabolismo , Imunofenotipagem , Mediadores da Inflamação/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Knockout , Proteínas de Ligação a RNA/genética , Receptores de Antígenos de Linfócitos B/metabolismo , Sepse/diagnóstico , Sepse/etiologia , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/metabolismo , Receptor 4 Toll-Like/metabolismo
9.
Int Immunol ; 32(1): 17-26, 2020 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-31412363

RESUMO

B-cell novel protein 1 (BCNP1) has recently been identified as a new B-cell receptor (BCR) signaling molecule but its physiological function remains unknown. Here, we demonstrate that mice deficient in BCNP1 exhibit impaired B-cell maturation and a reduction of B-1a cells. BCNP1-deficient spleen B cells show enhanced survival, proliferation and Ca2+ influx in response to BCR cross-linking as compared with wild-type spleen B cells. Consistently, mutant B cells show elevated phosphorylation of SYK, B-cell linker protein (BLNK) and PLCγ2 upon BCR cross-linking. In vivo, BCNP1-deficient mice exhibit enhanced humoral immune responses to T-independent and T-dependent antigens. Moreover, aged mutant mice contain elevated levels of serum IgM and IgG3 antibodies and exhibit polyclonal and monoclonal B-cell expansion in lymphoid organs. These results reveal distinct roles for BCNP1 in B-cell development, activation and homeostasis.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/imunologia , Linfócitos B/imunologia , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Animais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
10.
J Surg Res ; 268: 326-336, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34399355

RESUMO

BACKGROUND: Acute mesenteric ischemia is a common surgical emergency. Restoration of blood flow is a critical objective of treating this pathology. However, many patients suffer from ischemia-reperfusion (I/R) injuries at the time of revascularization, requiring prolonged hospitalizations. B-1a cells are a subtype of B lymphocytes with roles in regulating inflammation and tissue injury by spontaneous release of natural IgM and IL-10. We hypothesized that treatment with B-1a cells protects mice from intestinal I/R. METHODS: Mesenteric ischemia was induced in mice by placing a vascular clip on the superior mesenteric artery for 60 minutes. At the time of reperfusion, B-1a cells or PBS control were instilled into the peritoneal cavity (PerC) of mice. PerC lavage, blood, intestine, and lungs were collected 4 h after reperfusion. Serum organ injury and inflammatory markers such as ALT, AST, LDH, lactate, IL-6, as well as lung and gut histology and myeloperoxidase (MPO) were assessed. RESULTS: In intestinal I/R, B-1a cell frequency and number in the PerC were significantly decreased compared to sham-operated mice. There was an increase in the serum levels of ALT, AST, LDH, lactate, and IL-6 when comparing the vehicle group with the sham group. These increases were significantly reduced in the B-1a cell treated group. B-1a cell treatment significantly decreased the intestine and lung injury scores as well as MPO content, compared to vehicle treated mice. B-1a cell treatment resulted in a reduction of apoptotic cells in these tissues. Serum IgM levels were decreased in intestinal I/R, while treatment with B-1a cells significantly increased their levels towards normal levels. CONCLUSIONS: B-1a cell treatment at the time of mesenteric reperfusion ameliorates end organ damage and reduces systemic inflammation through the improvement of serum IgM levels. Preserving B-1a cells pool could serve as a novel therapeutic avenue in intestinal I/R injury.


Assuntos
Lesão Pulmonar Aguda , Isquemia Mesentérica , Traumatismo por Reperfusão , Lesão Pulmonar Aguda/patologia , Animais , Linfócitos B/patologia , Humanos , Intestinos/irrigação sanguínea , Isquemia Mesentérica/patologia , Camundongos , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/prevenção & controle
11.
Cell Immunol ; 352: 104100, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32305130

RESUMO

B-1a cells represent a distinct B cell population with unique phenotype, self-renewing capacity and restricted Igµ repertoire. They primarily locate in body cavity and also exist in spleen. The different subpopulations of B-1a cells are heavily affected by local environment. Our previous studies revealed that MARVEL-domain-containing membrane protein, CMTM7, was involved in B-1a cell development. Here, we focused its influence on peritoneal and splenic B-1a cells. Unlike peritoneal B-1a cells, we found that splenic Cmtm7-/- B-1a cells expressed higher level of CD5, CD80 and CD86 compared with WT counterparts. They also exhibited an enhanced tonic BCR signals in steady state. Though the cell viability was unaffected in vitro, Cmtm7 knockout markedly promoted splenic B-1a cell apoptosis in situ, which was likely associated with down-regulation of Il-5rα. With regard to Igµ repertoire, peritoneal and splenic Cmtm7-/- B-1a cells exhibit similar changes exemplified by the loss of VH11 and gain of VH12, whereas an increase in VH1 usage and skewed J segments from JH1 to JH2 and JH4 families could only be detected within splenic Cmtm7-/- B-1a cells. Overall, these data indicate that Cmtm7 functions differently in peritoneal and splenic B-1a cells and plays a more important role in splenic cells.


Assuntos
Subpopulações de Linfócitos B/metabolismo , Quimiocinas/metabolismo , Proteínas com Domínio MARVEL/metabolismo , Receptores de Antígenos de Linfócitos B/metabolismo , Animais , Apoptose/imunologia , Subpopulações de Linfócitos B/imunologia , Diferenciação Celular/imunologia , Membrana Celular/metabolismo , Proliferação de Células , Quimiocinas/imunologia , Feminino , Proteínas com Domínio MARVEL/genética , Proteínas com Domínio MARVEL/imunologia , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fenótipo , Receptores de Antígenos de Linfócitos B/imunologia , Transdução de Sinais/imunologia , Baço/imunologia , Baço/patologia
12.
Cell Immunol ; 346: 103993, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31679751

RESUMO

RasGRP1 is a key molecule that mediates antigen-initiated signaling for activation of the RAS-MAPK pathway in lymphocytes. Patients with aberrant RasGRP1 expression experience lymphocyte dysfunction and are afflicted with recurrent microbial infections. Yet, the underlying mechanism that accounts for microbial infection remains unknown. We previously reported that B1a cells are heterogeneous with respect to PD-L2 expression and that RasGRP1 deficiency preferentially impairs PD-L2+ B1a cell development. In the present study, we show that PD-L2+ B1a cells exhibit increased capacity for differentiation to CD138+ plasma cells that secrete natural IgM antibody, as well as IL-10 and GM-CSF, in response to TLR stimulation. In keeping with this, we show here that RasGRP1-deficent mice are much more susceptible to septic infection triggered by cecalligation and puncture than wild type mice, and that reconstitution of RasGRP1-deficient mice with wild type PD-L2+ B1a cells greatly rescues RasGRP1-deficient mice from sepsis. Thus, this study indicates a mechanism for the association of RasGRP1 deficiency with predispostion to infection in the loss of a particular B1a subpopulation.


Assuntos
Linfócitos B/imunologia , Infecções Bacterianas/imunologia , Fatores de Troca do Nucleotídeo Guanina/genética , Sepse/imunologia , Animais , Ceco/cirurgia , Diferenciação Celular/imunologia , Proliferação de Células , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Imunoglobulina M/imunologia , Interleucina-10/imunologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 2 Ligante de Morte Celular Programada 1/metabolismo , Sepse/patologia , Transdução de Sinais/imunologia , Sindecana-1/metabolismo
13.
Mol Med ; 24(1): 26, 2018 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-30134811

RESUMO

BACKGROUND: Sepsis morbidity and mortality are aggravated by acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). Mouse B-1a cells are a phenotypically and functionally unique sub-population of B cells, providing immediate protection against infection by releasing natural antibodies and immunomodulatory molecules. We hypothesize that B-1a cells ameliorate sepsis-induced ALI. METHODS: Sepsis was induced in C57BL/6 mice by cecal ligation and puncture (CLP). PBS or B-1a cells were adoptively transferred into the septic mice intraperitoneally. After 20 h of CLP, lungs were harvested and assessed by PCR and ELISA for pro-inflammatory cytokines (IL-6, IL-1ß) and chemokine (MIP-2) expression, by histology for injury, by TUNEL and cleaved caspase-3 for apoptosis, and by myeloperoxidase (MPO) assay for neutrophil infiltration. RESULTS: We found that septic mice adoptively transferred with B-1a cells significantly decreased the mRNA and protein levels of IL-6, IL-1ß and MIP-2 in the lungs compared to PBS-treated mice. Mice treated with B-1a cells showed dramatic improvement in lung injury compared to PBS-treated mice after sepsis. We found apoptosis in the lungs was significantly inhibited in B-1a cell injected mice compared to PBS-treated mice after sepsis. B-1a cell treatment significantly down-regulated MPO levels in the lungs compared to PBS-treated mice in sepsis. The protective outcomes of B-1a cells in ALI was further confirmed by using B-1a cell deficient CD19-/- mice, which showed significant increase in the lung injury scores following sepsis as compared to WT mice. CONCLUSIONS: Our results demonstrate a novel therapeutic potential of B-1a cells to treat sepsis-induced ALI.


Assuntos
Lesão Pulmonar Aguda/terapia , Linfócitos B/transplante , Sepse/terapia , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/patologia , Transferência Adotiva , Animais , Citocinas/imunologia , Pulmão/imunologia , Pulmão/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Peroxidase/imunologia , Sepse/complicações , Sepse/imunologia , Sepse/patologia
14.
Dig Dis ; 36(3): 194-201, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29421816

RESUMO

BACKGROUND/AIMS: B1a cells (CD19+CD5+) are considered elements of the innate immune system. The aim of this study was to evaluate the frequency of B1a cells in the peripheral blood of patients with Crohn's disease (CD) and its relation with disease severity. METHODS: In this prospective study, a total of 128 subjects (64 CD patients and 64 healthy controls) were studied. B1a cells in peripheral blood, CD Activity Index, and Simple Endoscopic Score of B1a cells were studied. RESULTS: A significant decrease of B1a cells in peripheral blood was observed in patients with CD versus controls (p = 0.002), especially in perforating or penetrating patterns (p = 0.017). A lower frequency of B1a cells is related to increased endoscopic severity (Spearman's Rho: -0.559, p = 0.004). The mean frequency of B1a cells in patients with pre- and post-study surgery was significantly lower than that in patients who did not undergo surgery (p = 0.050 and p = 0.026, respectively). CONCLUSIONS: The B1a cell count in peripheral blood is lower in CD patients. This decrease is directly related to the severity of the disease (penetrating or perforating, Simple Endoscopy Score and surgery complication). These results pointed to the fact that B1a cells play an important role in immune protection in CD.


Assuntos
Antígenos CD19/metabolismo , Antígenos CD5/metabolismo , Doença de Crohn/imunologia , Linfócitos/patologia , Índice de Gravidade de Doença , Adulto , Doença de Crohn/sangue , Doença de Crohn/diagnóstico por imagem , Feminino , Hospitalização , Humanos , Mucosa Intestinal/patologia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Cicatrização
15.
Proc Natl Acad Sci U S A ; 112(49): 15016-23, 2015 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-26621719

RESUMO

Amyloid fibrils composed of peptides as short as six amino acids are therapeutic in experimental autoimmune encephalomyelitis (EAE), reducing paralysis and inflammation, while inducing several pathways of immune suppression. Intraperitoneal injection of fibrils selectively activates B-1a lymphocytes and two populations of resident macrophages (MΦs), increasing IL-10 production, and triggering their exodus from the peritoneum. The importance of IL-10-producing B-1a cells in this effective therapy was established in loss-of-function experiments where neither B-cell-deficient (µMT) nor IL10(-/-) mice with EAE responded to the fibrils. In gain-of-function experiments, B-1a cells, adoptively transferred to µMT mice with EAE, restored their therapeutic efficacy when Amylin 28-33 was administered. Stimulation of adoptively transferred bioluminescent MΦs and B-1a cells by amyloid fibrils resulted in rapid (within 60 min of injection) trafficking of both cell types to draining lymph nodes. Analysis of gene expression indicated that the fibrils activated the CD40/B-cell receptor pathway in B-1a cells and induced a set of immune-suppressive cell-surface proteins, including BTLA, IRF4, and Siglec G. Collectively, these data indicate that the fibrils activate B-1a cells and F4/80(+) MΦs, resulting in their migration to the lymph nodes, where IL-10 and cell-surface receptors associated with immune-suppression limit antigen presentation and T-cell activation. These mechanisms culminate in reduction of paralytic signs of EAE.


Assuntos
Amiloide/farmacologia , Linfócitos B/imunologia , Encefalomielite Autoimune Experimental/tratamento farmacológico , Ativação Linfocitária/efeitos dos fármacos , Transferência Adotiva , Amiloide/metabolismo , Amiloide/uso terapêutico , Animais , Encefalomielite Autoimune Experimental/imunologia , Endocitose , Feminino , Interleucina-10/fisiologia , Polipeptídeo Amiloide das Ilhotas Pancreáticas/farmacologia , Camundongos , Camundongos Endogâmicos C57BL
16.
Cytokine ; 95: 43-50, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28235675

RESUMO

Interleukin (IL)-15, a key manipulator of T-cell function also modulates B-1a cell activity by augmenting activation markers, turning them towards type 1 polarization and immunoglobulin (Ig) expression which is significant in the context of gut immunity. Here we show, for the first time, IL-15 mediated up-regulation of the activation receptor NKG2D and its adaptor DAP10 in B-1a cells indicating their essential coupling with IL-15 receptor signaling pathway. Our results demonstrate IL-15 treatment increases phosphorylation of STAT5 and p38 leading to translocation of NF-κB onto the nucleus, an attribute that delineates activation of B-1a cells and its role in inflammation. In parallel, increase of anti-apoptotic Bcl-xL suggests its role in long term survival of B-1a cells in culture by IL-15. The cytokine induced overexpression of the plasma cell differentiation transcription factor BLIMP-1 while reducing PAX-5a that could be responsible for the spontaneous Ig secretion by B-1a cells. Up-regulation of IgM transcripts in presence of IL-15 validates mucosal response of the cells through natural Abs to counter pathogens.


Assuntos
Subpopulações de Linfócitos B/imunologia , Imunoglobulina M/biossíntese , Interleucina-15/fisiologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/biossíntese , Animais , Subpopulações de Linfócitos B/metabolismo , Células Cultivadas , Feminino , Regulação da Expressão Gênica , Imunoglobulina M/genética , Masculino , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Subfamília K de Receptores Semelhantes a Lectina de Células NK/genética , Fator 1 de Ligação ao Domínio I Regulador Positivo/metabolismo , RNA Mensageiro/metabolismo , Receptores Imunológicos/biossíntese , Receptores Imunológicos/genética , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais , Regulação para Cima , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
17.
Immunology ; 147(1): 97-113, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26456931

RESUMO

We describe a protective early acquired immune response to pneumococcal pneumonia that is mediated by a subset of B1a cells. Mice deficient in B1 cells (xid), or activation-induced cytidine deaminase (AID(-/-) ), or invariant natural killer T (iNKT) cells (Jα18(-/-) ), or interleukin-13 (IL-13(-/-) ) had impaired early clearance of pneumococci in the lung, compared with wild-type mice. In contrast, AID(-/-) mice adoptively transferred with AID(+/+) B1a cells, significantly cleared bacteria from the lungs as early as 3 days post infection. We show that this early bacterial clearance corresponds to an allergic contact sensitivity-like cutaneous response, probably due to a subpopulation of initiating B1a cells. In the pneumonia model, these B1a cells were found to secrete higher affinity antigen-specific IgM. In addition, as in contact sensitivity, iNKT cells were required for the anti-pneumococcal B1a cell initiating response, probably through early production of IL-13, given that IL-13(-/-) mice also failed to clear infection. Our study is the first to demonstrate the importance of AID in generating an appropriate B1a cell response to pathogenic bacteria. Given the antibody affinity and pneumonia resistance data, natural IgM produced by conventional B1a cells are not responsible for pneumonia clearance compared with the AID-dependent subset.


Assuntos
Imunidade Adaptativa , Linfócitos B/enzimologia , Citidina Desaminase/metabolismo , Pulmão/enzimologia , Fagocitose , Pneumonia Pneumocócica/enzimologia , Streptococcus pneumoniae/imunologia , Transferência Adotiva , Tirosina Quinase da Agamaglobulinemia , Animais , Antígenos de Bactérias/imunologia , Linfócitos B/imunologia , Linfócitos B/microbiologia , Linfócitos B/transplante , Ativação do Complemento , Citidina Desaminase/deficiência , Citidina Desaminase/genética , Citidina Desaminase/imunologia , Citocinas/imunologia , Citocinas/metabolismo , Dermatite de Contato/enzimologia , Dermatite de Contato/imunologia , Dermatite de Contato/microbiologia , Modelos Animais de Doenças , Genótipo , Imunoglobulina M/imunologia , Imunoglobulina M/metabolismo , Interleucina-13/deficiência , Interleucina-13/genética , Pulmão/imunologia , Pulmão/microbiologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Knockout , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/microbiologia , Fenótipo , Pneumonia Pneumocócica/imunologia , Pneumonia Pneumocócica/microbiologia , Proteínas Tirosina Quinases/imunologia , Proteínas Tirosina Quinases/metabolismo , Baço/enzimologia , Baço/imunologia , Baço/microbiologia , Streptococcus pneumoniae/patogenicidade , Fatores de Tempo
18.
Eur J Immunol ; 45(11): 2978-84, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26339791

RESUMO

CD5(+) B-cell origins and their predisposition to lymphoma are long-standing issues. Transfer of fetal and adult liver BM Pro-B cells generates B cells with distinct phenotypes: fetal cells generate IgM(high) IgD(low) CD5(+) , whereas adult cells IgM(low) IgD(high) CD5(-) . This suggests a developmental switch in B lymphopoiesis, similar to the switch in erythropoiesis. Comparison of mRNA and miRNA expression in fetal and adult Pro-B cells revealed differential expression of Lin28b mRNA and Let-7 miRNA, providing evidence that this regulatory axis functions in the switch. Recent work has shown that Arid3a is a key transcription factor mediating fetal-type B-cell development. Lin28b-promoted fetal development generates CD5(+) B cells as a consequence of positively selected self-reactivity. CD5(+) B cells play important roles in clearance of apoptotic cells and in protective immune responses, but also pose a risk of progression to leukemia/lymphoma. Differential Lin28b expression in fetal and adult human B-cell precursors showed that human B-cell development may resemble mouse, with self-reactive "innate-like" B cells generated early in life. It remains to be determined whether such human B cells have a higher propensity to leukemic progression. This review describes our recent research with CD5(+) B cells and presents our perspective on their role in disease.


Assuntos
Subpopulações de Linfócitos B/imunologia , Linfócitos B/imunologia , Antígenos CD5/imunologia , Linfopoese/imunologia , Células Precursoras de Linfócitos B/imunologia , Animais , Feto , Humanos , Leucemia de Células B/imunologia
19.
Int Immunol ; 27(10): 537-41, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25957266

RESUMO

Innate response activator (IRA) B cells are a subset of B-1a derived B cells that produce the growth factors granulocyte macrophage colony stimulating factor and IL-3. In mouse models of sepsis and pneumonia, B-1a B cells residing in serosal sites recognize bacteria, migrate to the spleen or lung, and differentiate to IRA B cells that then contribute to the host response by amplifying inflammation and producing polyreactive IgM. In atherosclerosis, IRA B cells accumulate in the spleen, where they promote extramedullary hematopoiesis and activate classical dendritic cells. In this review, we focus on the ontogeny and function of IRA B cells in acute and chronic inflammation.


Assuntos
Aterosclerose/imunologia , Subpopulações de Linfócitos B/imunologia , Linhagem da Célula/imunologia , Imunidade Inata , Pneumonia/imunologia , Sepse/imunologia , Animais , Aterosclerose/genética , Aterosclerose/patologia , Subpopulações de Linfócitos B/microbiologia , Subpopulações de Linfócitos B/patologia , Modelos Animais de Doenças , Regulação da Expressão Gênica/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Imunoglobulina M/biossíntese , Imunoglobulina M/genética , Interleucina-3/genética , Interleucina-3/imunologia , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/patologia , Camundongos , Pneumonia/genética , Pneumonia/microbiologia , Pneumonia/patologia , Sepse/genética , Sepse/microbiologia , Sepse/patologia , Transdução de Sinais , Baço/imunologia , Baço/microbiologia , Baço/patologia
20.
Folia Morphol (Warsz) ; 75(2): 257-263, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26711647

RESUMO

BACKGROUND: Interferon beta (IFNb) was the first proven drug for the treatment of multiple sclerosis (MS). The diagnosis of MS frequently occurs in women at childbearing age (especially in twenties and thirties). Therefore, the pregnancy process is major concern for many women with MS. Data on women exposed to IFNb during pregnancy are limited. The aim of our study was to investigate the teratogenic potential of IFNb on embryonic development via embryo culture technique. Recently, this technique has been often used for determining teratogenic effect of pharmacologic drugs and potential teratogens on embryonic development. MATERIALS AND METHODS: In this study, IFNb was applied to the culture medium and after 48 h of culture effects of IFNbs (1000 IU/IFNb-1a and 1000 IU/IFNb-1b) on embryonic development were morphologically investigated. RESULTS: According to morphologic scoring system, total morphologic score, somite number and protein contents were similar between control group and two experimental groups (p > 0.05). On the other hand, yolk sac diameter, crown- -rump length and head length were significantly decreased in two experimental groups compared with control group (p < 0.05). CONCLUSIONS: Consequently, IFNb-1a and IFNb-1b, applied to the culture medium, have no macroscopic teratogenic effect on embryonic development. However, in respect of morphometric measurements, IFNb-1a and IFNb-1b have caused growth retardation in embryo. This research related to interferon was the first study using vitro embryo culture technique; thus, in our point of view, future studies which will be performed by using different doses of IFN will contribute to the literature.


Assuntos
Interferon beta-1a/farmacologia , Interferon beta-1b/farmacologia , Feminino , Humanos , Esclerose Múltipla
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