Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 650
Filtrar
1.
Hematol Oncol ; 37(4): 352-359, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31385336

RESUMO

Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who are unfit for or relapsed postautologous stem-cell transplantation have poor outcomes. Historically, mTORC1 inhibitors have produced responses in approximately 30% of patients in this setting. mTORC1 inhibitor efficacy may be limited by resistance mechanisms including AKT activation by mTORC2. To date, dual mTORC1/2 inhibitors targeting both the TORC1 and TORC2 complexes have not been investigated in DLBCL. This phase II trial investigated the oral dual mTORC1/2 inhibitor vistusertib in an intermittent dosing schedule of 125 mg b.d. for 2 days per week. Thirty patients received vistusertib and six received vistusertib-rituximab for up to six cycles (28-day cycles). Two partial responses were achieved on monotherapy. Durations of response were 57 and 62 days, respectively, for these patients. 19% had stable disease within six cycles. In the monotherapy arm, the median progression-free survival was1.69 (95% confidence interval [CI] 1.61-2.14) months and median overall survival was 6.58 (95% CI 3.81-not reached) months, respectively. The median duration of response or stable disease across the trial duration was 153 days (95% CI 112-not reached). Tumour responses according to positron emission tomography/computed tomography versus computed tomography were concordant. There were no differences noted in tumour volume response according to cell of origin by either gene expression profiling or immunohistochemistry. Vistusertib ± rituximab was well tolerated; across 36 patients 86% of adverse events were grade (G) 1-2. Common vistusertib-related adverse events were similar to those described with mTORC1 inhibitors: nausea (47% G1-2), diarrhoea (27% G1-2, 6% G3), fatigue (30% G1-2, 3% G3), mucositis (25% G1-2, 6% G3), vomiting (17% G1-2), and dyspepsia (14% G1-2). Dual mTORC1/2 inhibitors do not clearly confer an advantage over mTORC1 inhibitors in relapsed or refractory DLBCL. Potential resistance mechanisms are discussed within.


Assuntos
Antineoplásicos/efeitos adversos , Benzamidas/efeitos adversos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 2 de Rapamicina/antagonistas & inibidores , Terapia de Alvo Molecular , Morfolinas/efeitos adversos , Proteínas de Neoplasias/antagonistas & inibidores , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/efeitos adversos , Terapia de Salvação , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Subpopulações de Linfócitos B/patologia , Benzamidas/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Feminino , Gastroenteropatias/induzido quimicamente , Humanos , Estimativa de Kaplan-Meier , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Morfolinas/uso terapêutico , Células-Tronco Neoplásicas/patologia , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Rituximab/administração & dosagem , Rituximab/efeitos adversos
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.
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
4.
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
5.
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
6.
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
7.
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
8.
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
9.
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
10.
J Autoimmun ; 95: 179-190, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30385081

RESUMO

Autoimmunity occurs when an adaptive immune response is directed against a self-antigen. As such, autoimmune reactions associated with the production of autoantibodies are common. These autoantibodies may either be pathogenic by inducing the initial damage to self, or exacerbate the reaction secondarily to the initial damage. In both cases, the pathway(s) leading to exposure of the immune system to the self-antigen inducing the production of autoantibodies is largely unknown. The latter is largely complicating the setting of putative prophylactic treatments. As a consequence, one possible way to control these diseases is to eliminate the cells producing antibodies. We will see that this approach is not yet part of any treatment in autoimmunity. Indeed, all the currently available non-specific immunosuppressive treatments do not target directly quiescent antibody-producing plasma cells. However, treatments aimed at depleting precursors of plasma cells, mature B-lymphocytes and/or antigen-experienced B cells not yet fully differentiated into plasma cells, are emerging. Such strategies were recently proven to be highly successful in several autoimmune disorders by two independent ways. The first way is by induction of B-cell cytotoxicity with an antibody directed against the surface antigen CD20. The second way is by antagonism of a key B-cell survival factor, the B-cell activation factor from the TNF superfamily (BAFF). In the present review, we will focus on the current knowledge regarding the role of a molecule related to BAFF, a proliferation-inducing ligand (APRIL), in autoimmune diseases, which acts on antibody-producing plasma cells. We will discuss expectations deriving from APRIL targeting in autoimmune diseases.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Doenças Autoimunes/terapia , Autoimunidade/efeitos dos fármacos , Fator Ativador de Células B/imunologia , Terapia de Alvo Molecular/métodos , Plasmócitos/efeitos dos fármacos , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/imunologia , Antígenos CD20/genética , Antígenos CD20/imunologia , Autoanticorpos , Autoantígenos/genética , Autoantígenos/imunologia , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Fator Ativador de Células B/antagonistas & inibidores , Fator Ativador de Células B/genética , Subpopulações de Linfócitos B/efeitos dos fármacos , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/patologia , Citotoxicidade Imunológica , Regulação da Expressão Gênica , Humanos , Imunidade Humoral/efeitos dos fármacos , Imunossupressores/uso terapêutico , Plasmócitos/imunologia , Plasmócitos/patologia , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/antagonistas & inibidores , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética
11.
Clin Cancer Res ; 24(24): 6125-6135, 2018 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-30049748

RESUMO

There is abundant evidence that tumor-infiltrating CD8+ T cells contribute positively to antitumor immunity; however, the role of tumor-infiltrating B cells (TIL-B) and plasma cells (PC) remains controversial, leading to differing opinions about whether immunotherapies should be designed to enhance or inhibit these cells. Through a comprehensive PubMed search, we reviewed publications with cohorts of 50 or more cases in which the prognostic value of TIL-B/PC was assessed by immunohistochemistry and/or gene-expression analysis. Sixty-nine studies representing 19 cancers met our review criteria. The large majority of studies assessed TIL-B by immunohistochemical detection of CD20. Of these, 50.0% reported a positive prognostic effect for CD20+ TIL-B, whereas the remainder found a neutral (40.7%) or negative (9.3%) effect. These differences in prognostic effect were not attributable to cancer type, other clinicopathologic factors, or differing technical approaches. The prognostic significance of TIL-B/PC was generally concordant with that of CD3+ and/or CD8+ T cells, and the prognostic effect of T cells was generally stronger when TIL-B and/or PC were also present. Additionally, 21 studies inferred the presence of TIL-B/PC from gene-expression data, and a large majority reported a positive prognostic effect. Although more studies are required involving additional cancer types and independent patient cohorts, the weight of evidence supports a positive role for TIL-B and PC in antitumor immunity, suggesting that enhancement of these responses should be considered in the design of cancer immunotherapies.


Assuntos
Subpopulações de Linfócitos B/imunologia , Linfócitos do Interstício Tumoral/imunologia , Neoplasias/imunologia , Neoplasias/mortalidade , Plasmócitos/imunologia , Animais , Subpopulações de Linfócitos B/metabolismo , Subpopulações de Linfócitos B/patologia , Biomarcadores , Humanos , Imunofenotipagem , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Neoplasias/patologia , Neoplasias/terapia , Fenótipo , Plasmócitos/metabolismo , Plasmócitos/patologia , Prognóstico , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologia , Microambiente Tumoral/imunologia
12.
J Autoimmun ; 93: 76-88, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30007842

RESUMO

Autoreactive lymphocytes that escape central immune tolerance may be silenced via an endogenous peripheral tolerance mechanism known as anergy. Antigen-specific therapies capable of inducing anergy may restore patients with autoimmune diseases to a healthy phenotype while avoiding deleterious side effects associated with global immunosuppression. Inducing anergy in B cells may be a particularly potent intervention, as B cells can contribute to autoimmune diseases through multiple mechanisms and offer the potential for direct antigen-specific targeting through the B cell receptor (BCR). Our previous results suggested autoreactive B cells may be silenced by multivalent 'soluble antigen arrays' (SAgAs), which are polymer conjugates displaying multiple copies of autoantigen with or without a secondary peptide that blocks intracellular cell-adhesion molecule-1 (ICAM-1). Here, key therapeutic molecular properties of SAgAs were identified and linked to the immunological mechanism through comprehensive cellular and in vivo analyses. We determined non-hydrolyzable 'cSAgAs' displaying multivalent 'click'-conjugated antigen more potently suppressed experimental autoimmune encephalomyelitis (EAE) compared to hydrolyzable SAgAs capable of releasing conjugated antigen. cSAgAs restored a healthy phenotype in disease-specific antigen presenting cells (APCs) by inducing an anergic response in B cells and a subset of B cells called autoimmune-associated B cells (ABCs) that act as potent APCs in autoimmune disease. Accompanied by a cytokine response skewed towards a Th2/regulatory phenotype, this generated an environment of autoantigenic tolerance. By identifying key therapeutic molecular properties and an immunological mechanism that drives SAgA efficacy, this work guides the design of antigen-specific immunotherapies capable of inducing anergy.


Assuntos
Autoantígenos/genética , Subpopulações de Linfócitos B/efeitos dos fármacos , Anergia Clonal/efeitos dos fármacos , Encefalomielite Autoimune Experimental/terapia , Imunoconjugados/farmacologia , Imunoterapia/métodos , Fragmentos de Peptídeos/farmacologia , Animais , Autoantígenos/imunologia , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/patologia , Química Click , Células Dendríticas/imunologia , Células Dendríticas/patologia , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/imunologia , Feminino , Hidrólise , Imunoconjugados/química , Injeções Subcutâneas , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/imunologia , Camundongos , Proteína Proteolipídica de Mielina/administração & dosagem , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/síntese química , Fragmentos de Peptídeos/imunologia , Análise Serial de Proteínas , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos B/imunologia , Baço/imunologia , Baço/patologia , Células Th2/imunologia , Células Th2/patologia
13.
J Clin Invest ; 128(7): 2996-3007, 2018 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-29889102

RESUMO

Very few B cells in germinal centers (GCs) and extrafollicular (EF) regions of lymph nodes express CD30. Their specific features and relationship to CD30-expressing Hodgkin and Reed/Sternberg (HRS) cells of Hodgkin lymphoma are unclear but highly relevant, because numerous patients with lymphoma are currently treated with an anti-CD30 immunotoxin. We performed a comprehensive analysis of human CD30+ B cells. Phenotypic and IgV gene analyses indicated that CD30+ GC B lymphocytes represent typical GC B cells, and that CD30+ EF B cells are mostly post-GC B cells. The transcriptomes of CD30+ GC and EF B cells largely overlapped, sharing a strong MYC signature, but were strikingly different from conventional GC B cells and memory B and plasma cells, respectively. CD30+ GC B cells represent MYC+ centrocytes redifferentiating into centroblasts; CD30+ EF B cells represent active, proliferating memory B cells. HRS cells shared typical transcriptome patterns with CD30+ B cells, suggesting that they originate from these lymphocytes or acquire their characteristic features during lymphomagenesis. By comparing HRS to normal CD30+ B cells we redefined aberrant and disease-specific features of HRS cells. A remarkable downregulation of genes regulating genomic stability and cytokinesis in HRS cells may explain their genomic instability and multinuclearity.


Assuntos
Subpopulações de Linfócitos B/imunologia , Doença de Hodgkin/imunologia , Antígeno Ki-1/metabolismo , Subpopulações de Linfócitos B/classificação , Subpopulações de Linfócitos B/patologia , Genes de Cadeia Pesada de Imunoglobulina , Genes myc , Centro Germinativo/imunologia , Centro Germinativo/patologia , Doença de Hodgkin/genética , Doença de Hodgkin/patologia , Humanos , Switching de Imunoglobulina , Região Variável de Imunoglobulina/genética , Memória Imunológica , Imunofenotipagem , Linfonodos/imunologia , Linfonodos/patologia , Mutação , Células de Reed-Sternberg/imunologia , Células de Reed-Sternberg/patologia , Transcriptoma , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo
14.
Iran J Allergy Asthma Immunol ; 17(2): 188-200, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29757592

RESUMO

Common variable immunodeficiency (CVID) is the most common clinical primary antibody deficiency, characterized by increased susceptibility to recurrent bacterial infections. Since Toll-like receptors (TLRs) play an important role in the maturation and differentiation of B-cells, TLRs' defect can be involved in the pathogenesis of CVID. Therefore, we evaluated the expression of TLR2 and TLR4 and their signaling pathway; also their association with autoimmunity, B-cell subtypes and response to pneumovax-23 were assessed in CVID patients. Sixteen CVID patients were enrolled in the study. Flow cytometry was used for assessing the protein expression of TLR2 and TLR4, and real-time PCR was used for gene expression of myeloid differentiation primary response 88 (MyD88) and toll interacting protein (Tollip). We found a higher protein expression of TLR2 in CVID patients which was associated with lower number of end stage B-cells and hyporesponse to pneumovax-23 vaccination. We showed a lower mRNA expression of MyD88 and an almost equal Tollip mRNA expression in CVID patients compared with controls. There was a profound association between MyD88 gene expression and autoimmunity in CVID patients. According to the presence of the lower number of end stage B-cells and poor vaccine response in CVID patients and their correlation with the higher expression of TLR2, we hypothesized that there is a functional defect in this receptor and/or its downstream in the peripheral blood mononuclear cells (PBMCs) of CVID patients.


Assuntos
Imunodeficiência de Variável Comum/imunologia , Transdução de Sinais/imunologia , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo , Adolescente , Adulto , Autoimunidade/imunologia , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/patologia , Linfócitos B/imunologia , Linfócitos B/patologia , Imunodeficiência de Variável Comum/sangue , Imunodeficiência de Variável Comum/patologia , Feminino , Citometria de Fluxo , Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Masculino , Fator 88 de Diferenciação Mieloide/genética , Vacinas Pneumocócicas/imunologia , Adulto Jovem
15.
Mol Med Rep ; 18(2): 1704-1709, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29845274

RESUMO

B cell activating factor (BAFF), a member of the tumor necrosis factor family, is a key cytokine for B cell survival, a function that is essential for B cell maturation and memory. The expression levels of BAFF and its potential contribution to B cell maturation remain elusive in patients with tuberculous pleural effusion (TPE). The present study enrolled 40 healthy controls (HC) and 45 TPE patients, and investigated the levels of BAFF in the plasma and pleural effusion. Concomitantly, B cell subsets including naïve B cell (CD19+IgD+CD27­), unswitched B cell (CD19+IgD+CD27+), switched B cell (CD19+IgD­CD27+), total memory B cell (CD19+CD27+), plasma B cell (CD19+IgD­CD38+CD27+) and transitional B cell (CD19+IgDdim CD38+) in peripheral blood mononuclear cells (PBMCs) and pleural fluid mononuclear cells (PFMCs) were assessed using multicolor flow cytometry. Finally, the associations between BAFF and each sub­group of B cells in TPE patients were analyzed. Compared with HC cases, an increased BAFF level and elevated frequency of switched B cell were observed in the blood and pleural effusion from patients with TPE. The proportions of naïve B cell, plasma B cell and transitional B cell were lower in the PFMCs of TPE patients. Furthermore, a significant correlation was observed between the level of BAFF, and the proportion of switched B cell in the peripheral blood and pleural effusion of TPE patients. These findings indicated that the B cell profile may be different in the pleural effusion, and BAFF may activate switched B cells to enhance the humoral immune responses in patients with TPE. Further studies are required to elucidate the underlying mechanisms and determine the potential immunotherapy of the BAFF­switched B cell axis.


Assuntos
Fator Ativador de Células B/imunologia , Subpopulações de Linfócitos B/imunologia , Linhagem da Célula/imunologia , Derrame Pleural/imunologia , Tuberculose Pulmonar/imunologia , Adolescente , Adulto , Antígenos CD/genética , Antígenos CD/imunologia , Fator Ativador de Células B/genética , Subpopulações de Linfócitos B/patologia , Estudos de Casos e Controles , Feminino , Citometria de Fluxo , Expressão Gênica , Humanos , Imunidade Humoral , Memória Imunológica , Imunofenotipagem , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/patologia , Masculino , Pessoa de Meia-Idade , Derrame Pleural/genética , Derrame Pleural/patologia , Tuberculose Pulmonar/genética , Tuberculose Pulmonar/patologia
16.
Immunol Res ; 66(2): 281-287, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29392553

RESUMO

Acute respiratory distress syndrome (ARDS) is a rapid onset life-threatening condition involving uncontrolled propagation of inflammatory responses. Here, we observed that ARDS patients that survived presented significantly higher frequencies of TIM-1+ B cells, especially the CD27+TIM-1+ B cells, than the ARDS patients who succumbed to the condition. We then found that using BCR/CD40 antigen-dependent stimulation or Staphylococcus aureus Cowan (SAC) antigen-independent stimulation, TIM-1+ B cells presented significantly higher IL-10 secretion and/or TGF-ß1 secretion, with SAC stimulation being more effective. CD4+ T cells that incubated with TIM-1+ B cells presented significantly elevated IL-10 secretion, TGF-ß1 secretion, and Foxp3 expression, than CD4+ T cells that incubated with TIM-1- B cells, suggesting TIM-1+ B cells promoted the in vitro development of Foxp3+ Treg cells. Interestingly, this TIM-1+ B cell-mediated promotion of Foxp3 expression was mostly dependent on TGF-ß1 but not IL-10, since neutralization of TGF-ß1, but not IL-10, resulted in the suppression of Foxp3 expression. We further showed that in TIM-1+ B cells, the CD27+ classical memory B cell subset demonstrated more regulatory potency than the CD27- subset. Together, our results suggested that the TIM-1+ B cells, especially those that expressed CD27, could promote Foxp3 expression. Their clinical efficacy in treating ARDS should be examined in in vivo experiments.


Assuntos
Subpopulações de Linfócitos B/imunologia , Memória Imunológica , Síndrome do Desconforto Respiratório do Adulto/imunologia , Síndrome do Desconforto Respiratório do Adulto/mortalidade , Linfócitos T Reguladores/imunologia , Subpopulações de Linfócitos B/patologia , Intervalo Livre de Doença , Feminino , Fatores de Transcrição Forkhead/imunologia , Receptor Celular 1 do Vírus da Hepatite A/imunologia , Humanos , Interleucina-10/imunologia , Masculino , Síndrome do Desconforto Respiratório do Adulto/patologia , Taxa de Sobrevida , Linfócitos T Reguladores/patologia , Fator de Crescimento Transformador beta1/imunologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia
17.
Nat Immunol ; 19(4): 407-419, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29483597

RESUMO

Age-associated B cells (ABCs) are a subset of B cells dependent on the transcription factor T-bet that accumulate prematurely in autoimmune settings. The pathways that regulate ABCs in autoimmunity are largely unknown. SWAP-70 and DEF6 (also known as IBP or SLAT) are the only two members of the SWEF family, a unique family of Rho GTPase-regulatory proteins that control both cytoskeletal dynamics and the activity of the transcription factor IRF4. Notably, DEF6 is a newly identified human risk variant for systemic lupus erythematosus. Here we found that the lupus syndrome that developed in SWEF-deficient mice was accompanied by the accumulation of ABCs that produced autoantibodies after stimulation. ABCs from SWEF-deficient mice exhibited a distinctive transcriptome and a unique chromatin landscape characterized by enrichment for motifs bound by transcription factors of the IRF and AP-1 families and the transcription factor T-bet. Enhanced ABC formation in SWEF-deficient mice was controlled by the cytokine IL-21 and IRF5, whose variants are strongly associated with lupus. The lack of SWEF proteins led to dysregulated activity of IRF5 in response to stimulation with IL-21. These studies thus elucidate a previously unknown signaling pathway that controls ABCs in autoimmunity.


Assuntos
Autoimunidade/imunologia , Subpopulações de Linfócitos B/imunologia , Fatores Reguladores de Interferon/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Animais , Subpopulações de Linfócitos B/patologia , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/imunologia , Feminino , Fatores de Troca do Nucleotídeo Guanina/deficiência , Fatores de Troca do Nucleotídeo Guanina/imunologia , Lúpus Eritematoso Sistêmico/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Antígenos de Histocompatibilidade Menor/imunologia , Proteínas Nucleares/deficiência , Proteínas Nucleares/imunologia
18.
Mol Immunol ; 94: 166-175, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29324237

RESUMO

The study is aimed to investigate the role of MDM2 in the pathogenesis of lupus nephritis (LN) in pediatric SLE (pSLE). We confirmed that MDM2 expression was increased in peripheral blood mononuclear cells (PBMCs) as well as renal specimen of SLE compared with that of controls by western blot and immunofluorescence staining. Percentage of apoptotic and necrotic CD4+T, CD8+T and B cells were detected by flow cytometry respectively and levels of plasma cell free DNA (cfDNA) were quantified in SLE and healthy controls (HC). We also proved that elevated apoptotic and necrotic CD4+T cells were the main cause for increased plasma levels of cfDNA in pSLE. Additionally, upon DNA transfection MDM2 increased while P53 and P21 decreased in human renal mesangial cells (HRMC), with concomitant increase in proliferation rate and proportion of cells in S phase, as demonstrated by cell proliferation assay and cell cycle analysis. However, MDM2 inhibition reversed the trend. Furthermore, percentage of switched memory B cells decreased and proportion of double negative B cells increased upon blockage of MDM2 in PBMC. In summary, our study provided the first evidence that DNA induction of MDM2 promotes proliferation of HRMC and alters peripheral B cells subsets in pSLE. Thus our study has not only elucidated the pathogenesis of MDM2 in pediatric LN but also provided a novel target for drug development. In conclusion, our data suggested that apoptosis, cfDNA and MDM2 could form a pathological axis in SLE, especially in pSLE.


Assuntos
Subpopulações de Linfócitos B/patologia , Proliferação de Células/genética , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Células Mesangiais/fisiologia , Proteínas Proto-Oncogênicas c-mdm2/genética , Subpopulações de Linfócitos B/fisiologia , Linfócitos B/patologia , Linfócitos B/fisiologia , Estudos de Casos e Controles , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Células Cultivadas , Criança , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Lúpus Eritematoso Sistêmico/patologia , Contagem de Linfócitos , Células Mesangiais/patologia
19.
J Immunol ; 199(9): 3063-3073, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28972092

RESUMO

Unlike conventional B cells, regulatory B cells exhibit immunosuppressive functions to downregulate inflammation via IL-10 production. However, the molecular mechanism regulating the production of IL-10 is not fully understood. In this study, we report the finding that activation-induced cytidine deaminase (AID) is highly upregulated in the IL-10-competent B cell (B10) cell from Innp5dfl/flAicdaCre/+ mice, whereas the 5' inositol phosphatase SHIP-1 is downregulated. Notably, SHIP-1 deficiency in AID+ B cells leads to a reduction in cell count and impaired IL-10 production by B10 cells. Furthermore, the Innp5dfl/flAicdaCre/+ mouse model shows B cell-dependent autoimmune lupus-like phenotypes, such as elevated IgG serum Abs, formation of spontaneous germinal centers, production of anti-dsDNA and anti-nuclear Abs, and the obvious deposition of IgG immune complexes in the kidney with age. We observe that these lupus-like phenotypes can be reversed by the adoptive transfer of B10 cells from control Innp5dfl/fl mice, but not from the Innp5dfl/flAicdaCre/+ mice. This finding highlights the importance of defective B10 cells in Innp5dfl/flAicdaCre/+ mice. Whereas p-Akt is significantly upregulated, MAPK and AP-1 activation is impaired in B10 cells from Innp5dfl/flAicdaCre/+ mice, resulting in the reduced production of IL-10. These results show that SHIP-1 is required for the maintenance of B10 cells and production of IL-10, and collectively suggests that SHIP-1 could be a new potential therapeutic target for the treatment of autoimmune diseases.


Assuntos
Subpopulações de Linfócitos B/imunologia , Citidina Desaminase/imunologia , Interleucina-10/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/deficiência , Transferência Adotiva , Animais , Subpopulações de Linfócitos B/patologia , Citidina Desaminase/genética , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/imunologia , Centro Germinativo/imunologia , Centro Germinativo/patologia , Interleucina-10/genética , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/patologia , Lúpus Eritematoso Sistêmico/terapia , Camundongos , Camundongos Transgênicos , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/imunologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/imunologia
20.
Clin Exp Immunol ; 190(3): 372-383, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28800164

RESUMO

Serum levels of B cell-activating factor (BAFF) rise following rituximab (RTX) therapy in patients with rheumatoid arthritis (RA). Initiation of naive B cell return to the periphery and autoreactive B cell expansion leading to relapse after RTX may therefore be linked to interactions between BAFF and BAFF-binding receptors (BBR). Relationships between serum BAFF and BBR expression [(BAFFR, calcium signal modulating cyclophilic ligand interactor (TACI) and B cell maturation antigen (BCMA)] were determined on B cell subsets, defined using immunoglobulin (Ig)D/CD38. Twenty pre-RTX and 18 RA patients relapsing after B cell depletion were included. Results were analysed with respect to timing of relapse up to 7 months after peripheral B cell return (≥ 5 B cells/µl) and to serum BAFF levels. After B cell return, B cell populations from relapsing patients had significantly lower BAFFR+ expression compared to HC and pre-RTX patients. The percentage of BAFFR+ B cells increased with time after B cell return and was correlated inversely with serum BAFF levels. BAFFR expression remained reduced. The percentage of TACI+ memory B cells were lower in RA patients after RTX compared with healthy controls (HC). BCMA expression (% and expression) did not differ between patients and HC. Relapse following B cell return appeared largely independent of the percentage of BAFFR+ or percentage of BCMA+ B cells or serum BAFF levels. The lower percentage of TACI+ memory B cells may reduce inhibitory signalling for B cell differentiation. In patients relapsing at longer periods after B cell return, recovery of the B cell pool was more complete, suggesting that selection or expansion of autoreactive B cells may be needed to precipitate relapse.


Assuntos
Artrite Reumatoide , Receptor do Fator Ativador de Células B , Subpopulações de Linfócitos B , Regulação da Expressão Gênica , Memória Imunológica , Rituximab/administração & dosagem , Artrite Reumatoide/sangue , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Fator Ativador de Células B/sangue , Fator Ativador de Células B/imunologia , Receptor do Fator Ativador de Células B/sangue , Receptor do Fator Ativador de Células B/imunologia , Antígeno de Maturação de Linfócitos B/sangue , Antígeno de Maturação de Linfócitos B/imunologia , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Subpopulações de Linfócitos B/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Memória Imunológica/efeitos dos fármacos , Memória Imunológica/imunologia , Proteína Transmembrana Ativadora e Interagente do CAML/sangue , Proteína Transmembrana Ativadora e Interagente do CAML/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA