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1.
Nat Commun ; 10(1): 4768, 2019 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-31628339

RESUMO

B-1a cells are long-lived, self-renewing innate-like B cells that predominantly inhabit the peritoneal and pleural cavities. In contrast to conventional B-2 cells, B-1a cells have a receptor repertoire that is biased towards bacterial and self-antigens, promoting a rapid response to infection and clearing of apoptotic cells. Although B-1a cells are known to primarily originate from fetal tissues, the mechanisms by which they arise has been a topic of debate for many years. Here we show that in the fetal liver versus bone marrow environment, reduced IL-7R/STAT5 levels promote immunoglobulin kappa gene recombination at the early pro-B cell stage. As a result, differentiating B cells can directly generate a mature B cell receptor (BCR) and bypass the requirement for a pre-BCR and pairing with surrogate light chain. This 'alternate pathway' of development enables the production of B cells with self-reactive, skewed specificity receptors that are peculiar to the B-1a compartment. Together our findings connect seemingly opposing lineage and selection models of B-1a cell development and explain how these cells acquire their unique properties.


Assuntos
Subpopulações de Linfócitos B/imunologia , Linfócitos B/imunologia , Diferenciação Celular/imunologia , Receptores de Células Precursoras de Linfócitos B/imunologia , Receptores de Antígenos de Linfócitos B/imunologia , Animais , Subpopulações de Linfócitos B/metabolismo , Linfócitos B/metabolismo , Medula Óssea/imunologia , Medula Óssea/metabolismo , Diferenciação Celular/genética , Cadeias Leves Substitutas da Imunoglobulina/genética , Cadeias Leves Substitutas da Imunoglobulina/imunologia , Cadeias Leves Substitutas da Imunoglobulina/metabolismo , Fígado/embriologia , Fígado/imunologia , Fígado/metabolismo , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Células Precursoras de Linfócitos B/genética , Receptores de Células Precursoras de Linfócitos B/metabolismo , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos B/metabolismo , Receptores de Interleucina-7/genética , Receptores de Interleucina-7/imunologia , Receptores de Interleucina-7/metabolismo , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/imunologia , Fator de Transcrição STAT5/metabolismo
2.
Hematol Oncol ; 37(4): 375-382, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31408531

RESUMO

In large B-cell lymphoma (LBCL), MYC translocation and MYC/BCL2 or MYC/BCL6 double hit (DH) are associated with poor prognosis, and there is an unmet need for novel treatment targets in this patient group. Treatments targeting the PD-L1/PD-1 pathway are still poorly elucidated in LBCL. PD-L1 expression might predict response to treatment targeting the PD-L1/PD-1 pathway. We therefore investigated the relationship between PD-L1 protein and mRNA expression levels and MYC and DH translocation in LBCL. We detected MYC, BCL2, and BCL6 translocation by fluorescent in situ hybridization in tissue samples from 130 patients randomly selected from two cohorts of patients with LBCL: 49 patients with MYC translocation of whom 36 had DH and 81 without MYC translocation. PD-L1 protein expression was detected by immunohistochemistry (IHC) in tissue samples from 77 patients and PD-L1 mRNA expression by next-generation RNA sequencing (NGS) in another 77 patients. Twenty-four patients overlapped, ie, were analysed with both IHC and NGS. Nonparametric tests were performed to evaluate intergroup differences. PD-L1 protein expression level was significantly lower in patients with MYC (n = 42, median = 3.3%, interquartile range [IQR] 0.0-10.8) or DH translocations (n = 31, median = 3.3%, IQR 0.0-10.0) compared with patients with no MYC (n = 35, median = 16.7%, IQR 3.3-30.0) or no DH translocations (n = 46, 13.3%, IQR 2.5-30.0), P = .004 and P ≤ .001, respectively. PD-L1 mRNA expression was also significantly lower in patients with MYC or DH translocations, P = .001 and P = .006, respectively. Higher PD-L1 protein and mRNA expression levels were associated with non-germinal centre (GC) type compared with germinal centre B-cell (GCB)-type diffuse LBCL (DLBCL), P = .004 and P = .002, respectively. In conclusion, we report an association between low PD-L1 expression and MYC and DH translocation in patients with LBCL. Our findings may indicate that patients with MYC or DH translocation may benefit less from treatment with PD-L1/PD-1-inhibitors compared with patients without these translocations. This should be evaluated in larger, prospective, consecutive trials.


Assuntos
Antígeno B7-H1/biossíntese , Regulação Neoplásica da Expressão Gênica , Genes myc , Linfoma Difuso de Grandes Células B/metabolismo , Proteínas de Neoplasias/biossíntese , RNA Mensageiro/biossíntese , RNA Neoplásico/biossíntese , Translocação Genética , Adulto , Idoso , Subpopulações de Linfócitos B/metabolismo , Subpopulações de Linfócitos B/patologia , Antígeno B7-H1/genética , Feminino , Perfilação da Expressão Gênica , Genes bcl-2 , Centro Germinativo/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Proteínas Proto-Oncogênicas c-bcl-6/genética , RNA Mensageiro/genética , RNA Neoplásico/genética , Estudos Retrospectivos
3.
Zhonghua Gan Zang Bing Za Zhi ; 27(7): 541-546, 2019 Jul 20.
Artigo em Chinês | MEDLINE | ID: mdl-31357781

RESUMO

Objective: To study the correlation between the level of T-bet expression and liver damage in peripheral plasma cells of patients with autoimmune hepatitis (AIH) in order to provide reference for the study of pathogenesis and development of diseases. Methods: The peripheral venous blood and clinical examination data of 29 cases with AIH and 6 healthy volunteers were collected. The percentage of subpopulations of peripheral blood B cells and the proportion of T-bet(+) cells in each subgroup were detected by flow cytometry. Plasma cells (CD19(+)CD10(-)CD27(hi)CD38(hi)), primary B cells (CD19(+)CD10(-)CD27(-)IgD(+)), transitional B cells (CD19(+)CD10(+)), and memory B cells (CD19(+)CD10(-)CD27(+)IgD(-)) were the included subsets of B cells. Serum immunoglobulin G (IgG) and alanine aminotransferase (ALT) levels, the proportion of B cells in peripheral blood subsets and IgG level, the proportion of T-bet(+) cells in each subset and the proportion of T-bet(+) plasma cells in each subset in B cells, the proportion of T-bet(+) plasma cells and the level of serum ALT were analyzed for correlation analysis. Statistical analysis was performed using two independent sample t-tests and linear regression. Results: The serum IgG level of AIH patients with abnormal ALT (19.47 ± 1.039)g/L was significantly higher than that of normal ALT patients (15.5 ± 1.069)g/L, and the difference was statistically significant (t = 2.65, P < 0.05). The percentage of peripheral plasma cells in B cells of AIH patients (2.80 ± 0.14) % was higher than that of healthy volunteers (0.73 ± 0.09) %, and the difference was statistically significant (P < 0.01). The percentage of T-bet(+) cells in peripheral plasma cells of AIH patients (23.54 ± 1.61) % was higher than that of healthy volunteers (6.59±0.59) % , and the difference was statistically significant (P < 0.01). The correlation analysis showed that the proportion of T-bet(+) cells in peripheral plasma cells of AIH patients was positively correlated with the proportion of plasma cells to B cells (r = 0.224 7, P < 0.01), and the percentage of peripheral plasma cells to B cells was positively correlated with the level of serum IgG (r = 0.299 1, P < 0.01). Serum IgG level was correlated with the level of ALT, reflecting an indicator of liver damage (t = 2.65, P < 0.05). Conclusion: The increase of T-bet expression in the peripheral plasma cells of AIH patients is associated with liver damage, which is a new mechanism of AIH pathogenesis and disease progression.


Assuntos
Hepatite Autoimune/patologia , Plasmócitos/metabolismo , Proteínas com Domínio T/metabolismo , Subpopulações de Linfócitos B/metabolismo , Citometria de Fluxo , Humanos
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
5.
Life Sci Alliance ; 2(3)2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31097471

RESUMO

A fast antibody response can be critical to contain rapidly dividing pathogens. This can be achieved by the expansion of antigen-specific B cells in response to T-cell help followed by differentiation into plasmablasts. MicroRNA-155 (miR-155) is required for optimal T-cell-dependent extrafollicular responses via regulation of PU.1, although the cellular processes underlying this defect are largely unknown. Here, we show that miR-155 regulates the early expansion of B-blasts and later on the survival and proliferation of plasmablasts in a B-cell-intrinsic manner, by tracking antigen-specific B cells in vivo since the onset of antigen stimulation. In agreement, comparative analysis of the transcriptome of miR-155-sufficient and miR-155-deficient plasmablasts at the peak of the response showed that the main processes regulated by miR-155 were DNA metabolic process, DNA replication, and cell cycle. Thus, miR-155 controls the extent of the extrafollicular response by regulating the survival and proliferation of B-blasts, plasmablasts and, consequently, antibody production.


Assuntos
Subpopulações de Linfócitos B/metabolismo , MicroRNAs/genética , Plasmócitos/metabolismo , Animais , Formação de Anticorpos/genética , Formação de Anticorpos/imunologia , Subpopulações de Linfócitos B/imunologia , Biomarcadores , Proliferação de Células , Sobrevivência Celular/genética , Imunofenotipagem , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Camundongos , Camundongos Knockout , Plasmócitos/imunologia
6.
Breast Cancer Res Treat ; 177(1): 17-27, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31134489

RESUMO

PURPOSE: Ductal carcinoma in situ (DCIS) of the breast is often regarded as a non-obligate precursor to invasive breast carcinoma but current diagnostic tools are unable to accurately predict the invasive potential of DCIS. Infiltration of immune cells into the tumour and its microenvironment is often an early event at the site of tumourigenesis. These immune infiltrates may be potential predictive and/or prognostic biomarkers for DCIS. This review aims to discuss recent findings pertaining to the potential prognostic significance of immune infiltrates as well as their evaluation in DCIS. METHODS: A literature search on PubMed was conducted up to 28th January 2019. Search terms used were "DCIS", "ductal carcinoma in situ", "immune", "immunology", "TIL", "TIL assessment", and "tumour-infiltrating lymphocyte". Search filters for "Most Recent" and "English" were applied. Information from published papers related to the research topic were synthesised and summarised for this review. RESULTS: Studies have revealed that immune infiltrates play a role in the biology and microenvironment of DCIS, as well as treatment response. There is currently no consensus on the evaluation of TILs in DCIS for clinical application. CONCLUSIONS: This review highlights the recent findings on the potential influence and prognostic value of immunological processes on DCIS progression, as well as the evaluation of TILs in DCIS. Further characterisation of the immune milieu of DCIS is recommended to better understand the immune response in DCIS progression and recurrence.


Assuntos
Neoplasias da Mama/imunologia , Neoplasias da Mama/mortalidade , Carcinoma Ductal de Mama/imunologia , Carcinoma Ductal de Mama/mortalidade , Carcinoma Intraductal não Infiltrante/imunologia , Carcinoma Intraductal não Infiltrante/mortalidade , Linfócitos do Interstício Tumoral/imunologia , Microambiente Tumoral/imunologia , Animais , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Subpopulações de Linfócitos B/patologia , Biomarcadores , Biomarcadores Tumorais , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Carcinoma Intraductal não Infiltrante/patologia , Citotoxicidade Imunológica , Progressão da Doença , Estrogênios/metabolismo , Feminino , Humanos , Imunofenotipagem , Contagem de Linfócitos , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Prognóstico , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologia
8.
Blood ; 133(24): 2610-2614, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-30992267

RESUMO

Approximately 10% of NUP98-PHF23 (NP23) mice develop an aggressive acute lymphoblastic leukemia of B-1 lymphocyte progenitor origin (pro-B1 ALL), accompanied by somatic frameshift mutations of the BCL6 interacting corepressor (Bcor) gene, most commonly within a 9-bp "hotspot" in Bcor exon 8. To determine whether experimentally engineered Bcor mutations would lead to pro-B1 ALL, we used clustered, regularly interspaced, short palindromic repeats-associated protein 9 to introduce a Bcor frameshift mutation into NP23 hematopoietic stem and progenitor cells through the use of Bcor small guide RNAs (Bcor sgRNAs). Recipient mice transplanted with NP23 bone marrow or fetal liver cells that had been transduced with a Bcor sgRNA developed pro-B1 ALL, characterized by a B-1 progenitor immunophenotype, clonal Igh gene rearrangement, and Bcor indel mutation, whereas control recipients did not. Similar to a subset of human B-cell precursor ALL, the murine pro-B1 ALL had acquired somatic mutations in Jak kinase genes. JAK inhibitors (ruxolitinib and tofacitinib) inhibited the growth of pro-B1 ALL cell lines established from Bcor sgRNA/NP23 recipients at clinically achievable concentrations (100 nM). Our results demonstrate that Bcor mutations collaborate with NP23 to induce pro-B1 ALL, and that JAK inhibitors are potential therapies for pro-B1 ALL.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas Repressoras/genética , Animais , Subpopulações de Linfócitos B/metabolismo , Subpopulações de Linfócitos B/patologia , Mutação da Fase de Leitura , Inibidores de Janus Quinases/farmacologia , Janus Quinases/antagonistas & inibidores , Janus Quinases/genética , Camundongos , Camundongos Transgênicos , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Proteínas de Fusão Oncogênica/genética , Células Precursoras de Linfócitos B/metabolismo , Células Precursoras de Linfócitos B/patologia
9.
PLoS One ; 14(3): e0213744, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30917149

RESUMO

This study examines the relationship between regulatory B (Breg) and T (Treg) compartments, which play crucial roles in the maintenance of immune homeostasis in the context of HIV. Using flow cytometry, the phenotypes of different Breg and Treg subsets from HIV-infected and healthy individuals were analyzed, along with the suppressive capacity of Breg. Peripheral blood samples of thirteen HIV+ treatment-naïve individuals, fourteen treated-HIV+ individuals with undetectable viral load and twelve healthy individuals were analyzed. The absolute counts of Breg and Treg subsets were decreased in HIV+ treatment-naïve individuals in comparison to treated-HIV+ and healthy individuals. Interestingly, correlations between Breg subsets (CD24hiCD27+ and PD-L1+ B cells) and IL-10-producing Breg observed in healthy individuals were lost in HIV+ treatment-naïve individuals. However, a correlation between frequencies of CD24hiCD38hi or TIM-1+-Breg subsets and Treg was observed in HIV+ treatment-naïve individuals and not in healthy individuals. Therefore, we hypothesized that various Breg subsets might have different functions during B and T-cell homeostasis during HIV-1 infection. In parallel, stimulated Breg from HIV-infected treatment-naïve individuals presented a decreased ability to suppress CD4+ T-cell proliferation in comparison to the stimulated Breg from treated-HIV+ or healthy individuals. We demonstrate a dysregulation between Breg and Treg subsets in HIV-infected individuals, which might participate in the hyper-activation and exhaustion of the immune system that occurs in such patients.


Assuntos
Linfócitos B Reguladores/metabolismo , Infecções por HIV/patologia , Linfócitos T Reguladores/metabolismo , Adulto , Subpopulações de Linfócitos B/citologia , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Linfócitos B Reguladores/citologia , Linfócitos B Reguladores/imunologia , Estudos de Casos e Controles , Proliferação de Células , Feminino , HIV/isolamento & purificação , HIV/fisiologia , Infecções por HIV/imunologia , Humanos , Interleucina-10/metabolismo , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Fenótipo , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Carga Viral
10.
Clin Lab Med ; 39(1): 15-29, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30709503

RESUMO

B cells shape the alloimmune response through polarized subsets. These cells inhibit or promote immune responses by expressing suppressive or proinflammatory cytokines. Their summed activity dictates the influence of B cells on the alloimmune response. We review the evidence for regulatory B cells and effector B cells in mice and humans, discuss current limitations in their phenotypic identification, and discuss regulatory B cells as a signature for clinical renal allograft tolerance and predictive markers for allograft outcomes. We discuss the effects of therapeutic agents on regulatory B cells and potential approaches to augment their numbers as a therapeutic tool.


Assuntos
Subpopulações de Linfócitos B/fisiologia , Linfócitos B Reguladores/fisiologia , Tolerância ao Transplante , Animais , Subpopulações de Linfócitos B/metabolismo , Linfócitos B Reguladores/metabolismo , Biomarcadores/metabolismo , Humanos , Camundongos , Resultado do Tratamento , Fator de Necrose Tumoral alfa/metabolismo
11.
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
12.
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
13.
J Dermatol Sci ; 93(1): 2-7, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30514664

RESUMO

B cells have moved to the center stage in many autoimmune diseases including autoantibody-mediated diseases and T cell-mediated autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. B cells play an important role for immune response beyond antibody production through mechanisms like antigen presentation and cytokine production. However, not all B cells positively regulate immune responses. Regulatory B cells negatively regulate immune responses by production of anti-inflammatory cytokines such as IL-10, IL-35, and TGF-ß. Regulatory B cells have been found to be decreased and/or functionally impaired in various autoimmune diseases. In contrast, B cells also produce pro-inflammatory cytokines, such as IL-6, IFN-γ and GM - CSF. These effector B cells contribute to the pathogenesis of autoimmune diseases. Regulatory and effector B cell balance regulates immune response through the release of cytokines. Furthermore, a protocol that selectively depletes effector B cells while sparing regulatory B cells would represent a potent therapy for autoimmune diseases rather than pan-B cell depletion using anti-CD20 mAb.


Assuntos
Subpopulações de Linfócitos B/imunologia , Linfócitos B Reguladores/imunologia , Imunidade Celular , Lúpus Eritematoso Sistêmico/imunologia , Escleroderma Sistêmico/imunologia , Subpopulações de Linfócitos B/metabolismo , Linfócitos B Reguladores/metabolismo , Citocinas/metabolismo , Humanos , Imunoterapia/métodos , Mediadores da Inflamação/metabolismo , Lúpus Eritematoso Sistêmico/terapia , Escleroderma Sistêmico/terapia
14.
Cancer Res ; 79(1): 159-170, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30224373

RESUMO

Metastatic cancer involving spread to the peritoneal cavity is referred to as peritoneal carcinomatosis and has a very poor prognosis. Activating the antitumor immune response in the characteristically immune-suppressive peritoneal environment presents a potential strategy to treat this disease. In this study, we show that a toll-like receptor (TLR) and C-type lectin receptor (CLR) agonist pairing of monophosphoryl lipid A (MPL) and trehalose-6,6'-dicorynomycolate (TDCM) effectively inhibits tumor growth and ascites development in a mouse model of aggressive mammary cancer-induced peritoneal carcinomatosis. MPL/TDCM treatment similarly inhibited peritoneal EL4 tumor growth and ascites development. These effects were not observed in mice lacking B cells or mice lacking CD19, which are deficient in B-1a cells, an innate-like B-cell population enriched in the peritoneal cavity. Remarkably, adoptive transfer of B-1a cells, but not splenic B cells from WT mice, restored MPL/TDCM-induced protection in mice with B-cell defects. Treatment induced B-1 cells to rapidly produce high levels of natural IgM reactive against tumor-associated carbohydrate antigens. Consistent with this, we found significant deposition of IgM and C3 on peritoneal tumor cells as early as 5 days post-treatment. Mice unable to secrete IgM or complement component C4 were not protected by MPL/TDCM treatment, indicating tumor killing was mediated by activation of the classical complement pathway. Collectively, our findings reveal an unsuspected role for B-1 cell-produced natural IgM in providing protection against tumor growth in the peritoneal cavity, thereby highlighting potential opportunities to develop novel therapeutic strategies for the prevention and treatment of peritoneal metastases. SIGNIFICANCE: This work identifies a critical antitumor role for innate-like B cells localized within the peritoneal cavity and demonstrates a novel strategy to activate their tumor-killing potential.See related commentary by Tripodo, p. 5.


Assuntos
Subpopulações de Linfócitos B/imunologia , Imunidade Inata/imunologia , Imunoglobulina M/imunologia , Ativação Linfocitária/imunologia , Neoplasias Mamárias Animais/imunologia , Cavidade Peritoneal/patologia , Neoplasias Peritoneais/imunologia , Animais , Subpopulações de Linfócitos B/efeitos dos fármacos , Subpopulações de Linfócitos B/metabolismo , Subpopulações de Linfócitos B/patologia , Fatores Corda/farmacologia , Feminino , Imunidade Inata/efeitos dos fármacos , Imunoglobulina M/efeitos dos fármacos , Lectinas Tipo C/agonistas , Lipídeo A/análogos & derivados , Lipídeo A/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Masculino , Neoplasias Mamárias Animais/tratamento farmacológico , Neoplasias Mamárias Animais/metabolismo , Neoplasias Mamárias Animais/patologia , Camundongos , Camundongos Endogâmicos A , Camundongos Endogâmicos C57BL , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/metabolismo , Neoplasias Peritoneais/secundário , Receptores Toll-Like/agonistas
15.
Nat Rev Cardiol ; 16(3): 180-196, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30410107

RESUMO

The cardiovascular system is subject to hyperlipidaemic, inflammatory, and pro-oxidant stressors. Over time, these factors drive prevalent chronic diseases, of which atherosclerosis is most prominent and accounts for the majority of deaths globally. Antibody-producing B cells perform a unique role in responses to stress, injury, and infection. The power, inducibility, and adaptability of the antibody repertoire require an equally complex range of control measures. Defects and chronic perturbations in these checkpoints lead to inappropriate antibody responses, which might have important roles in shaping the development and outcome of atherosclerotic disease. A unique aspect related to atherosclerosis is the prominent role of natural antibodies, specifically those binding to the oxidized epitopes that are abundant on modified lipoproteins and cellular debris. B cells control cellular immune responses through cell-cell contact, antigen presentation, and cytokine production, and thereby participate in systemic and local immune responses in atherosclerotic arteries. To date, both proatherogenic and antiatherogenic properties have been assigned to B cells, depending on subsets and how they are functionally targeted. For these reasons, a deeper understanding of how B cells influence atherosclerotic plaque development is being pursued with the hope of providing novel B cell-targeted interventions to prevent inflammation-driven cardiovascular events.


Assuntos
Aterosclerose/metabolismo , Subpopulações de Linfócitos B/metabolismo , Dislipidemias/metabolismo , Placa Aterosclerótica , Animais , Aterosclerose/imunologia , Aterosclerose/patologia , Aterosclerose/terapia , Autoimunidade , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/patologia , Dislipidemias/imunologia , Dislipidemias/terapia , Humanos , Imunoterapia , Fenótipo , Receptores de Antígenos de Linfócitos B/imunologia , Receptores de Antígenos de Linfócitos B/metabolismo , Transdução de Sinais
16.
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
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.
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
19.
Int J Mol Sci ; 19(10)2018 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-30314337

RESUMO

The risk of developing lymphoma in patients with Sjögren's syndrome (SS) is 44 times higher than in the normal population with the most common lymphomas derived from marginal zone B (MZB) cells. Current understanding of the role of MZB cells in SS is primarily based on salivary gland pathology, while their contextual association with lacrimal glands and ocular manifestations largely remains unknown. We examined this possibility using a SS mouse model (thrombospondin-1 deficient (TSP1-/-)) with well-characterized ocular disease. We determined the frequency, localization, and cytokine profiles of MZB cells and their association with an antibody response in TSP1-/- mice treated with a TSP-derived peptide. A significantly increased frequency of MZB cells was detected in the spleens and lacrimal glands of TSP1-/- mice in comparison to wild-type tissues as detected by immunostaining. An altered cytokine profile of TSP1-/- MZB cells was supportive of T helper 17 (Th17)-related pathogenesis. A significantly reduced antibody response and the splenic MZB compartment against an eye-derived antigen were noted in TSP-derived peptide-treated mice. These changes correspond with the previously reported ability of the peptide to ameliorate SS-related ocular manifestations. Collectively, our results demonstrate dysregulation of MZB cells in TSP1-/- mice and highlight their role in the context of SS-related chronic ocular surface disease.


Assuntos
Subpopulações de Linfócitos B/imunologia , Endoftalmite/etiologia , Síndrome de Sjogren/etiologia , Animais , Autoanticorpos/imunologia , Subpopulações de Linfócitos B/metabolismo , Citocinas/biossíntese , Modelos Animais de Doenças , Endoftalmite/metabolismo , Endoftalmite/patologia , Imunidade Inata , Mediadores da Inflamação/metabolismo , Aparelho Lacrimal/imunologia , Aparelho Lacrimal/metabolismo , Aparelho Lacrimal/patologia , Contagem de Linfócitos , Tecido Linfoide/imunologia , Tecido Linfoide/metabolismo , Tecido Linfoide/patologia , Masculino , Camundongos , Camundongos Knockout , Glândulas Salivares/imunologia , Glândulas Salivares/metabolismo , Glândulas Salivares/patologia , Síndrome de Sjogren/metabolismo , Síndrome de Sjogren/patologia , Baço/imunologia , Baço/metabolismo , Trombospondina 1/genética , Trombospondina 1/imunologia , Trombospondina 1/metabolismo
20.
Immunity ; 49(4): 725-739.e6, 2018 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-30314758

RESUMO

Systemic Lupus Erythematosus (SLE) is characterized by B cells lacking IgD and CD27 (double negative; DN). We show that DN cell expansions reflected a subset of CXCR5- CD11c+ cells (DN2) representing pre-plasma cells (PC). DN2 cells predominated in African-American patients with active disease and nephritis, anti-Smith and anti-RNA autoantibodies. They expressed a T-bet transcriptional network; increased Toll-like receptor-7 (TLR7); lacked the negative TLR regulator TRAF5; and were hyper-responsive to TLR7. DN2 cells shared with activated naive cells (aNAV), phenotypic and functional features, and similar transcriptomes. Their PC differentiation and autoantibody production was driven by TLR7 in an interleukin-21 (IL-21)-mediated fashion. An in vivo developmental link between aNAV, DN2 cells, and PC was demonstrated by clonal sharing. This study defines a distinct differentiation fate of autoreactive naive B cells into PC precursors with hyper-responsiveness to innate stimuli, as well as establishes prominence of extra-follicular B cell activation in SLE, and identifies therapeutic targets.


Assuntos
Subpopulações de Linfócitos B/imunologia , Linfócitos B/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Receptor 7 Toll-Like/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Subpopulações de Linfócitos B/metabolismo , Linfócitos B/metabolismo , Feminino , Redes Reguladoras de Genes/genética , Redes Reguladoras de Genes/imunologia , Humanos , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/metabolismo , Masculino , Pessoa de Meia-Idade , Plasmócitos/imunologia , Plasmócitos/metabolismo , Receptor 7 Toll-Like/genética , Receptor 7 Toll-Like/metabolismo , Transcriptoma/genética , Transcriptoma/imunologia , Adulto Jovem
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