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1.
Nat Immunol ; 20(8): 1071-1082, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31263277

RESUMO

Systemic lupus erythematosus (SLE) is characterized by the expansion of extrafollicular pathogenic B cells derived from newly activated naive cells. Although these cells express distinct markers, their epigenetic architecture and how it contributes to SLE remain poorly understood. To address this, we determined the DNA methylomes, chromatin accessibility profiles and transcriptomes from five human B cell subsets, including a newly defined effector B cell subset, from subjects with SLE and healthy controls. Our data define a differentiation hierarchy for the subsets and elucidate the epigenetic and transcriptional differences between effector and memory B cells. Importantly, an SLE molecular signature was already established in resting naive cells and was dominated by enrichment of accessible chromatin in motifs for AP-1 and EGR transcription factors. Together, these factors acted in synergy with T-BET to shape the epigenome of expanded SLE effector B cell subsets. Thus, our data define the molecular foundation of pathogenic B cell dysfunction in SLE.


Assuntos
Subpopulações de Linfócitos B/patologia , Metilação de DNA/genética , Epigênese Genética/genética , Lúpus Eritematoso Sistêmico/genética , Subpopulações de Linfócitos B/imunologia , Montagem e Desmontagem da Cromatina/fisiologia , Fatores de Transcrição de Resposta de Crescimento Precoce/genética , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Fator de Transcrição AP-1/genética , Transcriptoma/genética
3.
Scand J Immunol ; 90(2): e12792, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31141193

RESUMO

Depletion of B cells is beneficial in rheumatoid arthritis (RA) patients with autoantibodies to citrullinated proteins (ACPA) and/or the Fc portion of immunoglobulins (rheumatoid factor [RF]), suggesting a role for B cells in disease pathogenesis. To date, however, the identity of specifically pathogenic B cell subsets has not been discovered. One candidate population is identified by the low expression or absence of complement receptor 2 (CD21-/low B cells). In this study, we sought to determine whether there was any correlation between CD21-/low B cells and clinical outcome in patients with established RA, either ACPA+ /RF+ (n = 27) or ACPA- /RF- (n = 10). Healthy donors (n = 17) were included as controls. The proportion of the CD21-/low CD27- IgD- memory B cell subset in peripheral blood (PB) was significantly increased in ACPA+ /RF+ RA patients compared with healthy donors, and the frequency of this subset correlated with joint destruction (r = 0.57, P < 0.04). The levels of the chemokines CXCL-9 and CXCL-10 were higher in synovial fluid than in plasma, and PB CD21-/low cells expressed the receptor, CXCR3. In synovial fluid, most of the B cells were CD21-/low , approximately 40% of that population was CD27- IgD- , and a third of those expressed the pro-osteoclastogenic factor receptor activator of the nuclear factor κB ligand (RANKL). This subset also secreted RANKL, in addition to other factors such as IL-6, even in the absence of stimulation. We interpret these data as reason to propose the hypothesis that the CD27- IgD- subset of CD21-/low B cells may mediate joint destruction in patients with ACPA+ /RF+ RA.


Assuntos
Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Subpopulações de Linfócitos B/imunologia , Imunoglobulina D/metabolismo , Receptores de Complemento 3d/metabolismo , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo , Adulto , Quimiocina CXCL10/sangue , Quimiocina CXCL10/metabolismo , Quimiocina CXCL9/sangue , Quimiocina CXCL9/metabolismo , Feminino , Humanos , Articulações/imunologia , Articulações/patologia , Masculino , Pessoa de Meia-Idade , Ligante RANK/biossíntese , Receptores CXCR3/biossíntese , Líquido Sinovial/metabolismo
4.
EBioMedicine ; 43: 411-423, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31053557

RESUMO

BACKGROUND: Multiple Sclerosis (MS) is a chronic inflammatory disease and a leading cause of progressive neurological disability among young adults. DNA methylation, which intersects genes and environment to control cellular functions on a molecular level, may provide insights into MS pathogenesis. METHODS: We measured DNA methylation in CD4+ T cells (n = 31), CD8+ T cells (n = 28), CD14+ monocytes (n = 35) and CD19+ B cells (n = 27) from relapsing-remitting (RRMS), secondary progressive (SPMS) patients and healthy controls (HC) using Infinium HumanMethylation450 arrays. Monocyte (n = 25) and whole blood (n = 275) cohorts were used for validations. FINDINGS: B cells from MS patients displayed most significant differentially methylated positions (DMPs), followed by monocytes, while only few DMPs were detected in T cells. We implemented a non-parametric combination framework (omicsNPC) to increase discovery power by combining evidence from all four cell types. Identified shared DMPs co-localized at MS risk loci and clustered into distinct groups. Functional exploration of changes discriminating RRMS and SPMS from HC implicated lymphocyte signaling, T cell activation and migration. SPMS-specific changes, on the other hand, implicated myeloid cell functions and metabolism. Interestingly, neuronal and neurodegenerative genes and pathways were also specifically enriched in the SPMS cluster. INTERPRETATION: We utilized a statistical framework (omicsNPC) that combines multiple layers of evidence to identify DNA methylation changes that provide new insights into MS pathogenesis in general, and disease progression, in particular. FUND: This work was supported by the Swedish Research Council, Stockholm County Council, AstraZeneca, European Research Council, Karolinska Institutet and Margaretha af Ugglas Foundation.


Assuntos
Metilação de DNA , Imunidade , Esclerose Múltipla/etiologia , Esclerose Múltipla/metabolismo , Transdução de Sinais , Adulto , Idoso , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Biomarcadores , Ilhas de CpG , Progressão da Doença , Suscetibilidade a Doenças , Feminino , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/patologia , Esclerose Múltipla Crônica Progressiva/diagnóstico , Esclerose Múltipla Crônica Progressiva/etiologia , Esclerose Múltipla Crônica Progressiva/metabolismo , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Esclerose Múltipla Recidivante-Remitente/etiologia , Esclerose Múltipla Recidivante-Remitente/metabolismo , Locos de Características Quantitativas , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
6.
Parasitol Res ; 118(5): 1343-1352, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30941496

RESUMO

The peritoneal cavity has a microenvironment capable of promoting proliferation, differentiation, and activation of the resident cells and recruitment of blood cells through the capillary network involved in the peritoneum. Among the cells found in the peritoneal cavity, B-1 cells are a particular cell type that contains features that are not very well defined. These cells differ from conventional B lymphocytes (B-2) by phenotypic, functional, and molecular characteristics. B-1 cells can produce natural antibodies, migrate to the inflammatory focus, and have the ability to phagocytose pathogens. However, the role of B-1 cells in immunity against parasites is still not completely understood. Several experimental models have demonstrated that B-1 cells can affect the susceptibility or resistance to parasite infections depending on the model and species. Here, we review the literature to provide information on the peculiarities of B-1 lymphocytes as well as their interaction with parasites.


Assuntos
Subpopulações de Linfócitos B/imunologia , Helmintíase/imunologia , Helmintos/imunologia , Imunidade Humoral/imunologia , Parasitos/imunologia , Cavidade Peritoneal/citologia , Infecções por Protozoários/imunologia , Animais , Citocinas/biossíntese , Citocinas/imunologia , Helmintíase/parasitologia , Humanos , Camundongos , Peritônio/citologia , Peritônio/imunologia , Infecções por Protozoários/parasitologia
7.
Scand J Immunol ; 89(6): e12763, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30887554

RESUMO

The clinical consequences of isolated decreased serum immunoglobulin (Ig)M are not sufficiently known. Therefore, it is difficult to determine the clinical policy following such a finding. Only few reported IgM-deficient patients fulfil the European Society for Immunodeficiencies (ESID) diagnostic criteria for selective IgM deficiency (true sIgMdef), or their diagnosis is uncertain due to insufficient laboratory data (possible sIgMdef). Decreased serum IgM is often incidentally found in asymptomatic adults. The objective of our study was to further characterize true sIgMdef and to compare the European data collected through the ESID Registry community (tertiary centres) to our previously published Dutch cohort (secondary centre). Fifteen centres (12 countries) participated with 98 patients. Patients were excluded if serum IgM was only determined once (n = 14), had normalized (n = 8), or if they also had other immunological abnormalities (n = 15). Ten patients (5 adults) completely fulfilled the ESID criteria for true sIgMdef. Age-matched cut-off values varied widely between centres; when using the ESID diagnostic protocol reference values, only six patients (five adults) had true sIgMdef. Because of these small numbers, further analyses were performed in patients with true or possible sIgMdef (13 adults, 48 children). Respiratory infections were commonly reported at presentation (adults 54%, children 60%). Symptomatic adults had lower serum IgM levels (mean 0.27 g/L, 95% CI 0.22-0.31) than those without symptoms (mean 0.33 g/L, 95% CI 0.30-0.36; P = 0.02). To be able to explore the clinical consequences of true sIgMdef, we should fully analyse and accurately describe those patients in whom a decreased serum IgM is found.


Assuntos
Subpopulações de Linfócitos B/imunologia , Imunoglobulina M/sangue , Síndromes de Imunodeficiência/diagnóstico , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/imunologia , Subpopulações de Linfócitos T/imunologia , Adolescente , Adulto , Doenças Assintomáticas/epidemiologia , Subpopulações de Linfócitos B/citologia , Criança , Pré-Escolar , Feminino , Humanos , Síndromes de Imunodeficiência/sangue , Síndromes de Imunodeficiência/imunologia , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Subpopulações de Linfócitos T/citologia , Adulto Jovem
8.
Immunology ; 157(2): 137-150, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30801682

RESUMO

The mechanisms underlying the chronic, progressive airways inflammation, remodelling and alveolar structural damage characteristic of human chronic obstructive pulmonary disease (COPD) remain unclear. In the present study, we address the hypothesis that these changes are at least in part mediated by respiratory epithelial alarmin (IL-33)-induced production of autoantibodies against airways epithelial cells. Mice immunized with homologous, syngeneic lung tissue lysate along with IL-33 administered directly to the respiratory tract or systemically produced IgG autoantibodies binding predominantly to their own alveolar type II epithelial cells, along with increased percentages of Tfh cells and B2 B-cells in their local, mediastinal lymph nodes. Consistent with its specificity for respiratory epithelial cells, this autoimmune inflammation was confined principally to the lung and not other organs such as the liver and kidney. Furthermore, the serum autoantibodies produced by the mice bound not only to murine, but also to human alveolar type II epithelial cells, suggesting specificity for common, cross-species determinants. Finally, concentrations of antibodies against both human and murine alveolar epithelial cells were significantly elevated in the serum of patients with COPD compared with those of control subjects. These data are consistent with the hypothesis that IL-33 contributes to the chronic, progressive airways obstruction, inflammation and alveolar destruction characteristic of phenotypes of COPD/emphysema through induction of autoantibodies against lung tissue, and particularly alveolar type II epithelial cells.


Assuntos
Células Epiteliais Alveolares/imunologia , Autoanticorpos/imunologia , Subpopulações de Linfócitos B/imunologia , Interleucina-33/imunologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Células Epiteliais Alveolares/patologia , Animais , Autoenxertos , Subpopulações de Linfócitos B/patologia , Modelos Animais de Doenças , Humanos , Linfonodos/imunologia , Linfonodos/patologia , Mediastino/patologia , Camundongos , Doença Pulmonar Obstrutiva Crônica/patologia
9.
Clin Exp Rheumatol ; 37 Suppl 119(4): 23-31, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30719970

RESUMO

OBJECTIVES: In systemic sclerosis (SSc), B cell hyperactivation and abnormality are considered to play an important role in the disease pathophysiology. We aimed to clarify if the abnormal activation of B cells involves inhibitory FcγRIIB on B cells in SSc patients. METHODS: Blood samples were collected from 76 SSc patients (38 limited cutaneous SSc and 38 diffuse cutaneous SSc) and 59 healthy controls. We evaluated the expression levels of FcγRIIB on different B cell subsets. B cells were classified into five subsets based on their surface phenotype as measured by flow cytometry: naïve B cells (CD19+IgD+CD27-), pre-switched memory B cells (CD19+IgD+CD27+), double-negative (DN) memory B cells (CD19+IgD-CD27-), switched memory B cells (CD19+IgD-CD27mid), and plasmablasts (CD19+IgD-CD27high). The expression levels of the activation markers CD80, CD86, and CD95 were also examined. RESULTS: The expression levels of FcγRIIB on SSc naïve and DN memory B cells were significantly increased compared to healthy controls (p<0.05 and p<0.001, respectively). CD80, CD86, and CD95 expression levels were significantly higher in all five B cell subsets, except for CD80 in switched memory B cells and plasmablasts. Increased FcγRIIB expression levels on DN memory B cells were associated with disease activity as assessed by the European Scleroderma Study Group Activity Index, presence of interstitial lung disease (ILD), and reduced lung function. Intravenous cyclophosphamide pulse therapy decreased FcγRIIB expression levels on memory B cell subsets. CONCLUSIONS: SSc B cells may exhibit compensatory elevation in the expression levels of FcγRIIB in order to suppress the abnormal activation of B cells. In addition, FcγRIIB expression levels may serve as a marker of severe complications, such as ILD, in SSc.


Assuntos
Subpopulações de Linfócitos B , Ativação Linfocitária , Escleroderma Sistêmico , Subpopulações de Linfócitos B/imunologia , Linfócitos B/imunologia , Estudos de Casos e Controles , Separação Celular/métodos , Humanos , Memória Imunológica , Contagem de Linfócitos , Plasmócitos , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/imunologia
10.
PLoS One ; 14(2): e0212525, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30794605

RESUMO

The bone marrow (BM) is, in addition to being the site of B cell development, a tissue that harbors long-lived plasma cells (PC), the cells that protect the body against foreign antigens by continuous production of antibodies. Nothing is known about the long-term stability and functionality of both B cells and PC in the BM at the individual donor level since repeated sampling possibilities outside of oncology are scarce. Here, we had the opportunity to obtain BM samples from a patient undergoing bilateral total hip arthroplasty half a year apart. We observed that the frequencies of the analyzed B cell and PC subsets were similar despite a time of six months in between and sampling on left and right side of the body. Additionally, B cell receptor stimulation led to comparable results. Our data suggest that composition and functionality of B cells are stable in the BM of adults at the individual donor level.


Assuntos
Subpopulações de Linfócitos B/citologia , Células da Medula Óssea/citologia , Artroplastia de Quadril , Subpopulações de Linfócitos B/imunologia , Células da Medula Óssea/imunologia , Feminino , Fêmur/citologia , Humanos , Pessoa de Meia-Idade , Osteoartrite do Quadril/cirurgia , Plasmócitos/citologia , Plasmócitos/imunologia , Fatores de Tempo
11.
Tuberculosis (Edinb) ; 114: 1-8, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30711147

RESUMO

The role of B cells and antibodies in tuberculosis (TB) immunity, protection and pathogenesis remain contradictory. The presence of organized B cell follicles close to active TB lesions in the lung tissue raises the question about the role of these cells in local host-pathogen interactions. In this short review, we summarize the state of our knowledge concerning phenotypes of B cells populating tuberculous lungs, their secretory activity, interactions with other immune cells and possible involvement in protective vs. pathogenic TB immunity.


Assuntos
Subpopulações de Linfócitos B/imunologia , Tuberculose Pulmonar/imunologia , Animais , Anticorpos Antibacterianos/biossíntese , Citocinas/imunologia , Interações Hospedeiro-Patógeno , Humanos , Imunidade Celular , Imunização Passiva/métodos , Imunofenotipagem , Mycobacterium tuberculosis/imunologia , Tuberculose Pulmonar/prevenção & controle
12.
J Immunol ; 202(5): 1465-1478, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30674575

RESUMO

Infections during pregnancy can expose the fetus to microbial Ags, leading to inflammation that affects B cell development. Prenatal fetal immune priming may have an important role in infant acquisition of pathogen-specific immunity. We examined plasma proinflammatory biomarkers, the proportions of various B cell subsets, and fetal priming to tetanus vaccination in cord blood from human United States and Kenyan neonates. United States neonates had no identified prenatal infectious exposures, whereas Kenyan neonates examined had congenital CMV or mothers with prenatal HIV or Plasmodium falciparum or no identified infectious exposures. Kenyan neonates had higher levels of IP-10, TNF-α, CRP, sCD14, and BAFF than United States neonates. Among the Kenyan groups, neonates with prenatal infections/infectious exposures had higher levels of cord blood IFN-γ, IL-7, sTNFR1, and sTNFR2 compared with neonates with no infectious exposures. Kenyan neonates had greater proportions of activated memory B cells (MBC) compared with United States neonates. Among the Kenyan groups, HIV-exposed neonates had greater proportions of atypical MBC compared with the other groups. Although HIV-exposed neonates had altered MBC subset distributions, detection of tetanus-specific MBC from cord blood, indicative of fetal priming with tetanus vaccine given to pregnant women, was comparable in HIV-exposed and non-HIV-exposed neonates. These results indicate that the presence of infections during pregnancy induces fetal immune activation with inflammation and increased activated MBC frequencies in neonates. The immunologic significance and long-term health consequences of these differences warrant further investigation.


Assuntos
Subpopulações de Linfócitos B/imunologia , Citomegalovirus/imunologia , HIV/imunologia , Inflamação/imunologia , Malária/imunologia , Adulto , Feminino , Humanos , Lactente , Recém-Nascido , Quênia , Masculino , Gravidez , Adulto Jovem
13.
Nat Commun ; 10(1): 190, 2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-30643147

RESUMO

A number of different B cell subsets have been shown to exhibit regulatory activity using a variety of mechanisms to attenuate inflammatory diseases. Here we show, using anti-CD20-mediated partial B cell depletion in mice, that a population of mature B cells distinguishable by IgDlow/- expression maintains tolerance by, at least in part, promoting CD4+Foxp3+ regulatory T cell homeostatic expansion via glucocorticoid-induced tumor necrosis factor receptor ligand, or GITRL. Cell surface phenotyping, transcriptome analysis and developmental study data show that B cells expressing IgD at a low level (BDL) are a novel population of mature B cells that emerge in the spleen from the transitional-2 stage paralleling the differentiation of follicular B cells. The cell surface phenotype and regulatory function of BDL are highly suggestive that they are a new B cell subset. Human splenic and peripheral blood IgDlow/- B cells also exhibit BDL regulatory activity, rendering them of therapeutic interest.


Assuntos
Subpopulações de Linfócitos B/imunologia , Dermatite de Contato/imunologia , Regulação da Expressão Gênica no Desenvolvimento/imunologia , Tolerância Imunológica , Linfócitos T Reguladores/imunologia , Animais , Subpopulações de Linfócitos B/metabolismo , Separação Celular/métodos , Células Cultivadas , Técnicas de Cocultura , Modelos Animais de Doenças , Citometria de Fluxo/métodos , Perfilação da Expressão Gênica , Voluntários Saudáveis , Humanos , Imunoglobulina D/metabolismo , Leucócitos Mononucleares , Camundongos , Camundongos Endogâmicos C57BL , Oxazolona/imunologia , Baço/citologia , Baço/crescimento & desenvolvimento , Baço/imunologia , Linfócitos T Reguladores/metabolismo , Fatores de Necrose Tumoral/imunologia , Fatores de Necrose Tumoral/metabolismo
14.
Retrovirology ; 16(1): 1, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30602379

RESUMO

BACKGROUND: The pathogenesis of immunological tolerance caused by avian leukosis virus subgroup J (ALV-J), an oncogenic retrovirus, is largely unknown. RESULTS: In this study, the development, differentiation, and immunological capability of B cells and their progenitors infected with ALV-J were studied both morphologically and functionally by using a model of ALV-J congenital infection. Compared with posthatch infection, congenital infection of ALV-J resulted in severe immunological tolerance, which was identified as the absence of detectable specific antivirus antibodies. In congenitally infected chickens, immune organs, particularly the bursa of Fabricius, were poorly developed. Moreover, IgM-and IgG-positive cells and total immunoglobulin levels were significantly decreased in these chickens. Large numbers of bursa follicles with no differentiation into cortex and medulla indicated that B cell development was arrested at the early stage. Flow cytometry analysis further confirmed that ALV-J blocked the differentiation of CD117+chB6+ B cell progenitors in the bursa of Fabricius. Furthermore, both the humoral immunity and the immunological capability of B cells and their progenitors were significantly suppressed, as assessed by (a) the antibody titres against sheep red blood cells and the Marek's disease virus attenuated serotype 1 vaccine; (b) the proliferative response of B cells against thymus-independent antigen lipopolysaccharide (LPS) in the spleen germinal centres; and (c) the capacities for proliferation, differentiation and immunoglobulin gene class-switch recombination of B cell progenitors in response to LPS and interleukin-4(IL-4) in vitro. CONCLUSIONS: These findings suggested that the anergy of B cells in congenitally infected chickens is caused by the developmental arrest and dysfunction of B cell progenitors, which is an important factor for the immunological tolerance induced by ALV-J.


Assuntos
Vírus da Leucose Aviária/imunologia , Leucose Aviária/congênito , Subpopulações de Linfócitos B/patologia , Anergia Clonal , Doenças das Aves Domésticas/congênito , Células-Tronco/patologia , Animais , Anticorpos Antivirais/sangue , Leucose Aviária/patologia , Vírus da Leucose Aviária/patogenicidade , Subpopulações de Linfócitos B/química , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/virologia , Bolsa de Fabricius/patologia , Diferenciação Celular , Proliferação de Células , Galinhas , Citometria de Fluxo , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Doenças das Aves Domésticas/patologia , Proteínas Proto-Oncogênicas c-kit/análise , Células-Tronco/química , Células-Tronco/imunologia , Células-Tronco/virologia
15.
Microb Pathog ; 127: 225-232, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30528250

RESUMO

Along with robust immunogenicity, an ideal vaccine candidate should be able to produce a long lasting protection. In this regard, the frequency of memory B-cells is possibly an important factor in memory B-cell persistency and duration of immunological memory. On this basis, binding domains of tetanus toxin (HcT), botulinum type A1 toxin (HcA), and heat-labile toxin (LTB) were selected as antigen models that induced long-term, midterm and short-term immune memory, respectively. In the present study, the frequency of total memory B-cells after immunization with HcT, HcA and LTB antigens after 90 and 180 days, and also after one booster, in 190 days, was evaluated. The results showed a significant correlation between frequency of total memory B-cells and duration of humoral immunity. Compared to other antigens, the HcT antibody titers and HcT total memory B-cell populations were greater and persistent even after 6 months. At 6 months after the final immunization, all HcT- and HcA-immunized mice survived against tetanus and botulinum toxins, and also LT toxin binding to GM1 ganglioside was blocked in LTB-immunized mice. We conclude the frequency of memory B-cells and their duration are likely a key factor for vaccine memory duration.


Assuntos
Antígenos de Bactérias/imunologia , Subpopulações de Linfócitos B/imunologia , Toxinas Bacterianas/imunologia , Toxinas Botulínicas/imunologia , Enterotoxinas/imunologia , Proteínas de Escherichia coli/imunologia , Memória Imunológica , Toxina Tetânica/imunologia , Animais , Antígenos de Bactérias/administração & dosagem , Toxinas Bacterianas/administração & dosagem , Toxinas Botulínicas/administração & dosagem , Enterotoxinas/administração & dosagem , Proteínas de Escherichia coli/administração & dosagem , Camundongos , Toxina Tetânica/administração & dosagem , Fatores de Tempo
16.
Eur J Haematol ; 102(3): 203-209, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30578738

RESUMO

The molecular pathogenesis of deletion 5q (del(5q)) myelodysplastic syndrome (MDS) has recently been realized as a result of major advances in our understanding of the mechanisms responsible for clinical phenotype. Identification of commonly deleted genes such as RPS14, miRNA-145, HSPA9, CD78, and CSNK1a1 have elucidated the precise biological changes responsible for the anemia, leukopenia, and thrombocytosis that characterizes del(5q) MDS and highlighted the importance of allelic haploinsufficiency in the hematological phenotype. Recent elegant investigations have also identified a critical role of innate immune signaling in del(5q) pathogenesis. TP53 and Wnt/ß-catenin pathways have also been found to be involved in clonal expansion and progression of the disease as well as resistance and poor outcomes to available therapy. Understanding the molecular pathogenesis of the disease has provided a critical foundation in identifying the biological targets of lenalidomide in del(5q) MDS, which has led to the development of novel therapeutic agents in hematologic malignancies as well as potential alternative targets to exploit in patients who have failed lenalidomide treatment.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 5 , Síndromes Mielodisplásicas/etiologia , Anemia/diagnóstico , Anemia/genética , Anemia/metabolismo , Animais , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Biomarcadores , Calgranulina A/genética , Calgranulina A/metabolismo , Calgranulina B/genética , Calgranulina B/metabolismo , Evolução Clonal/genética , Evolução Clonal/imunologia , Progressão da Doença , Haploinsuficiência/genética , Humanos , Imunidade Inata/genética , MicroRNAs/genética , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/metabolismo , Síndromes Mielodisplásicas/terapia , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Proteínas Ribossômicas/genética , Transdução de Sinais , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Via de Sinalização Wnt
17.
EBioMedicine ; 40: 517-527, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30593436

RESUMO

BACKGROUND: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease, which exhibits multiple B cell abnormalities including expanded populations of memory B cells and elevated levels of autoantibodies. Belimumab is a monoclonal antibody targeting the B cell cytokine BAFF (a.k.a. BLyS), approved for the treatment of SLE. METHODS: In this prospective cohort study, B cells from peripheral blood of 23 SLE patients initiating belimumab treatment and followed longitudinally for up to three years, were assessed using mass cytometry. FINDINGS: B cells decreased during the study period, with a rapid decrease of both naïve and CD11c+CD21- B cells at the first follow-up visit, followed by a continuous reduction at subsequent follow-ups. In contrast, plasma cells and switched memory B cells remained stable throughout the study. The observed immunological changes correlated with early, but not late, clinical improvements. Moreover, high baseline B cell counts were predictive of failure to attain low disease activity. In summary, our data unveiled both rapid and gradual later therapy-associated alterations of both known and unforeseen B cell phenotypes. INTERPRETATION: Our results suggest that evaluation of B cell counts might prove useful prior to initiation of belimumab treatment and that early treatment evaluation and discontinuation might underestimate delayed clinical improvements resultant of late B cell changes.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Fator Ativador de Células B/antagonistas & inibidores , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/metabolismo , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/imunologia , Adulto , Anticorpos Monoclonais Humanizados/farmacologia , Subpopulações de Linfócitos B/efeitos dos fármacos , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Biomarcadores , Feminino , Humanos , Imunossupressores/farmacologia , Lúpus Eritematoso Sistêmico/diagnóstico , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Resultado do Tratamento
18.
Methods Mol Biol ; 1904: 53-81, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30539466

RESUMO

Antibodies are vital components of the adaptive immune system for the recognition and response to foreign antigens. However, some antibodies recognize self-antigens in healthy individuals. These autoreactive antibodies may modulate innate immune functions. IgM natural autoantibodies (IgM-NAAs) are a class of primarily polyreactive immunoglobulins encoded by germline V-gene segments which exhibit low affinity but broad specificity to both foreign and self-antigens. Historically, these autoantibodies were closely associated with autoimmune disease. Nevertheless, not all human autoantibodies are pathogenic and compelling evidence indicates that IgM-NAAs may exert a spectrum of effects from injurious to protective depending upon cellular and molecular context. In this chapter, we review the current state of knowledge regarding the potential physiological and therapeutic roles of IgM-NAAs in different disease conditions such as atherosclerosis, cancer, and autoimmune disease. We also describe the discovery of two reparative IgM-NAAs by our laboratory and delineate their proposed mechanisms of action in central nervous system (CNS) disease.


Assuntos
Autoanticorpos/imunologia , Autoanticorpos/uso terapêutico , Imunoglobulina M/imunologia , Imunoglobulina M/uso terapêutico , Animais , Afinidade de Anticorpos/imunologia , Formação de Anticorpos , Especificidade de Anticorpos/imunologia , Antígenos/imunologia , Autoanticorpos/metabolismo , Autoanticorpos/farmacologia , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Humanos , Imunoglobulina M/metabolismo , Imunoglobulina M/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/imunologia , Neurônios/metabolismo , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/imunologia , Oligodendroglia/metabolismo , Ligação Proteica/imunologia , Resultado do Tratamento
19.
Transplant Proc ; 50(10): 3900-3905, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30577284

RESUMO

BACKGROUND: Our previous study demonstrated that regulatory B cells (Bregs) play an indispensable role in dual anti-CD45RB/anti-TIM-1 antibody-induced transplantation tolerance through an IL-10-dependent pathway. However, the potentially specific subsets of Bregs have not been clearly demonstrated. In this study, we aimed to detect the subsets of the Bregs possessing the ability to produce IL-10 in the early stage and tolerance maintenance stage of allogeneic islet transplantation treated by dual anti-CD45RB/anti-TIM-1. METHODS: Isolated Balb/C islets were transplanted under the kidney capsule of C57BL/6J diabetic mice. The recipients were treated with anti-CD45RB and anti-TIM-1. Two major IL-10-producing Breg subsets of CD19+CD5+CD1d+ B10 cells and CD19+TIM-1+B cells, and the T cells of CD4+CD25+ (Tregs), CD4+IFN-γ+ Th1 cells, and CD4+IL-4+ Th2 cells in splenocytes of grafted recipients were detected by flow cytometry after 1 week, 2 weeks, and more than 100 days posttransplantation. RESULTS: On day 14 after islet transplantation, the frequency of CD19+CD5+CD1d+ B10 cells in recipient mice increased significantly, compared with day 0 and 7 (P = .001, P < .001, respectively), while it dropped to normal level in the recipients with long-term graft survival. In contrast, there was significant increase of CD19+TIM-1+B cells on day 14 (P = .003) and day 100 after transplant (P = .009). CD4+CD25+ Treg cells have similar increasing tendency with CD19+TIM-1+B cells, as they increased from normal 10% to almost 20% both on day 14 and day 90 after transplantation. Conversely, the expression of CD4+IFN-γ+ Th1 cells decreased significantly on day 14 (P = .004) and on day 100 after transplant (P = .002). As another kind of helper T cells, CD4+IL-4+ Th2 cells increased only on day 14 after transplant (P < .001). CONCLUSIONS: CD19+CD5+CD1d+ B10 cells may play an important role only in the early stage of transplantation tolerance induction by dual anti-CD45RB/anti-TIM-1 antibody treatment, whereas CD19+TIM-1+B cells may play crucial parts in the whole process of tolerance induction and maintenance.


Assuntos
Subpopulações de Linfócitos B/imunologia , Linfócitos B Reguladores/imunologia , Interleucina-10/biossíntese , Transplante das Ilhotas Pancreáticas/imunologia , Tolerância ao Transplante/imunologia , Aloenxertos , Animais , Diabetes Mellitus Experimental , Interleucina-10/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL
20.
PLoS One ; 13(12): e0208187, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30540814

RESUMO

Differentiation of B cells is a stringently controlled multi-step process, which is still incompletely understood. Here we identify and characterize a rare population of human B cells, which surprisingly carry CD8AB on their surface. Existence of such cells was demonstrated both in tonsils and in human apheresis material. Gene expression profiling and real time PCR detected however no CD8A or CD8B message in these cells. Instead, we found that surface CD8 was hijacked from activated CD8+ T cells by a transfer process that required direct cell-to-cell contact. A focused transcriptome analysis at single cell level allowed the dissection of the CD8 positive B cell population. We found that the affected cells are characteristically of the CD27+CD200- phenotype, and consist of two discrete late-stage subpopulations that carry signatures of activated memory B like cells, and early plasmablasts. Thus, there is only a restricted time window in the differentiation process during which B cells can intimately interact with CD8+ T cells. The findings point to a novel link between the T and B arms of the adaptive immune system, and suggest that CD8+ T cells have the capability to directly shape the global antibody repertoire.


Assuntos
Subpopulações de Linfócitos B/imunologia , Antígenos CD8/metabolismo , Linfócitos T CD8-Positivos/microbiologia , Comunicação Celular/imunologia , Memória Imunológica , Antígenos CD/genética , Antígenos CD/metabolismo , Subpopulações de Linfócitos B/metabolismo , Antígenos CD8/genética , Antígenos CD8/imunologia , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular/imunologia , Separação Celular , Células Cultivadas , Citometria de Fluxo , Perfilação da Expressão Gênica , Voluntários Saudáveis , Humanos , Cultura Primária de Células , RNA Mensageiro/análise , Análise de Célula Única , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo
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