RESUMO
OBJECTIVES: The role of B cells in COVID-19, beyond the production of specific antibodies against SARS-CoV-2, is still not well understood. Here, we describe the novel landscape of circulating double-negative (DN) CD27- IgD- B cells in COVID-19 patients, representing a group of atypical and neglected subpopulations of this cell lineage. METHODS: Using multiparametric flow cytometry, we determined DN B cell subset amounts from 91 COVID-19 patients, correlated those with cytokines, clinical and laboratory parameters, and segregated them by principal components analysis. RESULTS: We detected significant increments in the DN2 and DN3 B cell subsets, while we found a relevant decrease in the DN1 B cell subpopulation, according to disease severity and patient outcomes. These DN cell numbers also appeared to correlate with pro- or anti-inflammatory signatures, respectively, and contributed to the segregation of the patients into disease severity groups. CONCLUSION: This study provides insights into DN B cell subsets' potential role in immune responses against SARS-CoV-2, particularly linked to the severity of COVID-19.
Assuntos
COVID-19/sangue , COVID-19/imunologia , Imunoglobulina D/sangue , SARS-CoV-2 , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos B/citologia , COVID-19/diagnóstico , COVID-19/virologia , Linhagem da Célula , Biologia Computacional , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Componente Principal , Prognóstico , Respiração Artificial , Índice de Gravidade de Doença , Adulto JovemRESUMO
The thymus is home to a significant number of resident B cells which possess several unique characteristics regarding their origin, phenotype and function. Evidence shows that they originate both from precursors that mature intrathymically and as the entry of recirculating mature B cells. Under steady-state conditions they exhibit hallmark signatures of activated B cells, undergo immunoglobulin class-switch, and express the Aire transcription factor. These features are imprinted within the thymus and enable B cells to act as specialized antigen-presenting cells in the thymic medulla that contribute negative selection of self-reactive T cells. Though, most studies have focused on B cells located in the medulla, a second contingent of B cells is also present in non-epithelial perivascular spaces of the thymus. This latter group of B cells, which includes memory B cells and plasma cells, is not readily detected in the thymus of infants or young mice but gradually accumulates during normal aging. Remarkably, in many autoimmune diseases the thymus suffers severe structural atrophy and infiltration of B cells in the perivascular spaces, which organize into follicles similar to those typically found in secondary lymphoid organs. This review provides an overview of the pathways involved in thymic B cell origin and presents an integrated view of both thymic medullary and perivascular B cells and their respective physiological and pathological roles in central tolerance and autoimmune diseases.
Assuntos
Autoimunidade/imunologia , Linfócitos B/imunologia , Tolerância Imunológica/imunologia , Ativação Linfocitária/imunologia , Timo/imunologia , Animais , Linfócitos B/citologia , Linfócitos B/metabolismo , Movimento Celular/imunologia , Humanos , Plasmócitos/imunologia , Plasmócitos/metabolismo , Timo/citologia , Timo/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia , Fatores de Transcrição/metabolismo , Proteína AIRERESUMO
Cell migration is a dynamic process that involves adhesion molecules and the deformation of the moving cell that depends on cytoskeletal remodeling and actin-modulating proteins such as myosins. In this work, we analyzed the role of the class I Myosin-1 g (Myo1g) in migratory processes of LPS + IL-4 activated B lymphocytes in vivo and in vitro. In vivo, the absence of Myo1g reduced homing of activated B lymphocytes into the inguinal lymph node. Using microchannel chambers and morphology analysis, we found that the lack of Myo1g caused adhesion and chemotaxis defects. Additionally, deficiency in Myo1g causes flaws in adopting a migratory morphology. Our results highlight the importance of Myo1g during B cell migration.
Assuntos
Linfócitos B/imunologia , Linfonodos/imunologia , Ativação Linfocitária , Antígenos de Histocompatibilidade Menor/imunologia , Miosinas/imunologia , Animais , Linfócitos B/citologia , Adesão Celular , Movimento Celular , Células Cultivadas , Feminino , Camundongos Endogâmicos C57BLRESUMO
PURPOSE: Immune cells in the immune microenvironment of lung cancer have a great impact on the development of lung cancer. Our purpose was to analyze the immune cell infiltration features and related marker genes for lung cancer. METHODS: Single cell RNA sequencing data of 11,485 lung cancer cells were retrieved from the Gene Expression Omnibus. After quality control and data normalization, cell clustering was performed using the Seurat package. Based on the marker genes of each cell type from the CellMarker database, each cell was divided into G1, G2M, and S phases. Then, differential expression and functional enrichment analyses were performed. CIBERSORT was used to reconstruct immune cell types. RESULTS: Following cell filtering, highly variable genes were identified for all cells. 14 cell types were clustered. Among them, CD4 + T cell, B cell, plasma cell, natural killer cell and cancer stem cell were the top five cell types. Up-regulated genes were mainly enriched in immune-related biological processes and pathways. Using CIBERSORT, we identified the significantly higher fractions of naïve B cell, memory CD4 + T cell, T follicular helper cell, T regulatory helper cell and M1 macrophage in lung cancer tissues compared to normal tissues. Furthermore, the fractions of resting NK cell, monocyte, M0 macrophage, resting mast cell, eosinophil and neutrophil were significantly lower in tumor tissues than normal tissues. CONCLUSION: Our findings dissected the immune cell infiltration features and related marker genes for lung cancer, which might provide novel insights for the immunotherapy of lung cancer.
Assuntos
Marcadores Genéticos/genética , Imunidade Celular , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , RNA-Seq/métodos , Linfócitos B/citologia , Linfócitos T CD4-Positivos/citologia , Ciclo Celular , Bases de Dados Genéticas , Expressão Gênica , Humanos , Imunidade Celular/genética , Células Matadoras Naturais/citologia , Macrófagos/citologia , Células-Tronco Neoplásicas/citologia , Plasmócitos/citologia , Células T Auxiliares Foliculares/citologia , Linfócitos T Reguladores/citologia , Microambiente Tumoral/imunologia , Regulação para CimaRESUMO
The coronavirus SARS-CoV-2 pandemia is infecting millions of people and some studies relate conditions that might increase the risk of developing a fatal course for the disease, such as diabetes, cardiovascular diseases and obesity. In COVID-19 physiopathology, one of the main inflammation mechanisms is the "cytokine storm", causing a pro-inflammatory state, related to cardiac and pulmonary damage. There is also a less effective role of lymphocyte B and T in the humoral immunity due to the reduction of their proliferative response. The physiopathology of ASD (Autism Spectrum Disorder) involves several modifications at the genetic and at the immune level, such as the increase of inflammatory cytokines and abnormal immune response in several levels. We hypothesize that ASD could be a risk-factor as the other conditions are.
Assuntos
Transtorno do Espectro Autista/complicações , COVID-19/complicações , COVID-19/epidemiologia , Linfócitos B/citologia , Comorbidade , Citocinas/metabolismo , Feminino , Humanos , Imunidade Humoral , Inflamação , Masculino , Fenótipo , Fatores de Risco , Fatores Sexuais , Linfócitos T/citologiaRESUMO
In adults, B-lymphocytes comprise approximately 10% of circulating lymphocytes. The majority of peripheral B cells are B2 cells ("Mature" B-cells), which function as part of the humoral adaptive immune system. B1 cells ("Innate-like" B cells) are another sub-class of B lymphocytes, considered as innate immune cells with a characteristic phenotype (CD20+, CD27+, CD43+, CD70-, CD11b+, sIgM++, sIgD+) which can be divided into two subtypes; B1a (CD5+): spontaneously produce broadly reactive natural IgM, and B1b (CD5-): can generate T-cell independent, long-lasting IgM. There is very limited data available, indicating a correlation between allogeneic bone marrow transplantation and an increase in B1a cells. Here we present a case of a 17-year-old female with homozygous sickle cell disease (HbSS disease) who underwent hematopoietic stem cell transplant (HSCT). Approximately seven months post-transplant, she was found to have 16% immature mononuclear cells on complete blood count (CBC)-differential report. A follow-up peripheral blood flow cytometry showed that these cells were polyclonal CD5+/CD20+ B-cells, and comprised 66% of lymphocytes. Further workup and follow up failed to reveal any lymphoproliferative disorders. It is important not to misdiagnose these cells as an atypical CD5+ lymphoproliferative disorder. The presence of B1a cells has not been widely reported in non-neoplastic post-stem cell transplanted patients. This case also adds to and expands our knowledge regarding the presence of increased circulating B1a cells after stem cell transplant in a patient with no history of hematological malignancy.
Assuntos
Humanos , Feminino , Adolescente , Transplante de Células-Tronco/efeitos adversos , Contagem de Células Sanguíneas , Células-Tronco Hematopoéticas , Linfócitos B/citologia , Subpopulações de Linfócitos B/patologia , Citometria de Fluxo , Anemia Falciforme , Transtornos Linfoproliferativos/diagnósticoRESUMO
The mechanisms by which immunoglobulin (Ig)G can modulate immunity have been investigated over the past few decades. In the past three years, some studies have demonstrated that IgG can play a pivotal role in mediating complex interactions that result in functional lymphocyte modulation during maturation in self or offspring primary lymphoid organs. This effect appears to be dependent on the IgG repertoire in the absence of the influence of antigens and the functionality of diverse cell populations, including B, αßT (CD4 T and CD8 T), invariant natural killer T and γδT cells, in mice and humans. Based on the literature, especially on findings resulting from the therapeutic use of purified IgG (intravenous Ig) and recent pieces of evidence obtained by my group, the "hooks without bait" theory is described here to guide the future development of therapies for specific immune regulation.
Assuntos
Linfócitos B/citologia , Imunoglobulina G , Imunomodulação , Linfócitos T , Animais , Humanos , Imunoglobulina G/imunologia , Camundongos , Linfócitos T/citologiaRESUMO
The conduit system was described in lymphoid organs as a tubular and reticular set of structures compounded by collagen, laminin, perlecan, and heparin sulfate proteoglycan wrapped by reticular fibroblasts. This tubular system is capable of rapidly transport small molecules such as viruses, antigens, chemokines, cytokines, and immunoglobulins through lymphoid organs. This structure plays an important role in guiding the cells to their particular niches, therefore participating in cell cooperation, antigen presentation, and cellular activation. The remodeling of conduits has been described in chronic inflammation and infectious diseases to improve the transport of antigens to specific T and B cells in lymphoid tissue. However, malnutrition and infectious agents may induce extracellular matrix remodeling directly or indirectly, leading to the microarchitecture disorganization of secondary lymphoid organs and their conduit system. In this process, the fibers and cells that compound the conduit system may also be altered, which affects the development of a specific immune response. This review aims to discuss the extracellular matrix remodeling during infectious diseases with an emphasis on the alterations of molecules from the conduit system, which damages the cellular and molecular transit in secondary lymphoid organs compromising the immune response.
Assuntos
Linfócitos B/citologia , Doenças Transmissíveis/imunologia , Matriz Extracelular/metabolismo , Fibroblastos/citologia , Apresentação de Antígeno/imunologia , Quimiocinas/imunologia , Quimiocinas/metabolismo , Doenças Transmissíveis/microbiologia , Fibroblastos/imunologia , HumanosRESUMO
It is known that growth hormone (GH) is expressed in immune cells, where it exerts immunomodulatory effects. However, the mechanisms of expression and release of GH in the immune system remain unclear. We analyzed the effect of growth hormone-releasing hormone (GHRH), thyrotropin-releasing hormone (TRH), ghrelin (GHRL), and somatostatin (SST) upon GH mRNA expression, intracellular and released GH, Ser133-phosphorylation of CREB (pCREBS133), intracellular Ca2+ levels, as well as B-cell activating factor (BAFF) mRNA expression in bursal B-lymphocytes (BBLs) cell cultures since several GH secretagogues, as well as their corresponding receptors (-R), are expressed in B-lymphocytes of several species. The expression of TRH/TRH-R, ghrelin/GHS-R1a, and SST/SST-Rs (Subtypes 1 to 5) was observed in BBLs by RT-PCR and immunocytochemistry (ICC), whereas GHRH/GHRH-R were absent in these cells. We found that TRH treatment significantly increased local GH mRNA expression and CREB phosphorylation. Conversely, SST decreased GH mRNA expression. Additionally, when added together, SST prevented TRH-induced GH mRNA expression, but no changes were observed in pCREBS133 levels. Furthermore, TRH stimulated GH release to the culture media, while SST increased the intracellular content of this hormone. Interestingly, SST inhibited TRH-induced GH release in a dose-dependent manner. The coaddition of TRH and SST decreased the intracellular content of GH. After 10 min. of incubation with either TRH or SST, the intracellular calcium levels significantly decreased, but they were increased at 60 min. However, the combined treatment with both peptides maintained the Ca2+ levels reduced up to 60-min. of incubation. On the other hand, BAFF cytokine mRNA expression was significantly increased by TRH administration. Altogether, our results suggest that TRH and SST are implicated in the regulation of GH expression and release in BBL cultures, which also involve changes in pCREBS133 and intracellular Ca2+ concentration. It is likely that TRH, SST, and GH exert autocrine/paracrine immunomodulatory actions and participate in the maturation of chicken BBLs.
Assuntos
Proteínas Aviárias/imunologia , Linfócitos B/imunologia , Bolsa de Fabricius/imunologia , Galinhas/imunologia , Grelina/imunologia , Hormônio Liberador de Hormônio do Crescimento/imunologia , Hormônio do Crescimento/imunologia , Somatostatina/imunologia , Hormônio Liberador de Tireotropina/imunologia , Animais , Linfócitos B/citologia , Bolsa de Fabricius/citologia , Técnicas de Cultura de Células , Células CultivadasRESUMO
BACKGROUND: The transcription factor MYC regulates several biological cellular processes, and its target gene network comprises approximately 15% of all human genes, including microRNAs (miRNAs), that also contribute to MYC regulatory activity. Although miRNAs are emerging as key regulators of immune functions, the specific roles of miRNAs in the regulation/dysregulation of germinal centre B-cells and B-cell lymphomas are still being uncovered. The regulatory network that integrates MYC, target genes and miRNAs is a field of intense study, highlighting potential pathways to be explored in the context of future clinical approaches. METHODS: The scientific literature that is indexed in PUBMED was consulted for publications involving MYC and miRNAs with validated bioinformatics analyses or experimental protocols. Additionally, seminal studies on germinal centre B-cell functions and lymphomagenesis were reported. CONCLUSIONS: This review summarizes the interactions between MYC and miRNAs through regulatory loops and circuits involving target genes in germinal centre B-cell lymphomas with MYC alterations. Moreover, we provide an overview of the understanding of the regulatory networks between MYC and miRNAs, highlighting the potential implication of this approach for the comprehension of germinal centre B-cell lymphoma pathogenesis. Therefore, circuits involving MYC, target genes and miRNAs provide novel insight into lymphomagenesis that could be useful for new improved therapeutic strategies.