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‣ The role of B cells in the early phase of rheumatoid arthritis

Moura, Rita Alexandra Pedra Aguiar de, 1981-
Fonte: Universidade de Lisboa Publicador: Universidade de Lisboa
Tipo: Tese de Doutorado
Publicado em //2011 Português
Relevância na Pesquisa
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Tese de doutoramento, Ciências Biomédicas (Imunologia), Universidade de Lisboa, Faculdade de Medicina, 2011; Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease of unknown aetiology that affects around 1% of the world population. RA is characterized by symmetric polyarthritis associated with pain and swelling in multiple joints. If left untreated, RA leads to joint destruction, functional disability, comorbidity and reduced life expectancy. Many autoimmune diseases are B-cell dependent, mainly through the production of autoantibodies. Previous studies have documented the importance of B cells in RA pathogenesis through diverse mechanisms. B cells produce autoantibodies, such as rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA). These autoantibodies can form immune complexes that deposit in the joints, causing inflammation. Additionally, B cells can function as antigen presenting cells and activate T cells; release cytokines once activated and participate in ectopic lymphoid organogenesis. The discovery that B cell depletion therapy with rituximab (RTX) was effective in RA patients reinforced B cells key position in this autoimmune disease and placed them in the central stage of research. Nevertheless...

‣ Frequency of B cells in normal mice which recognize self proteins

Fonte: Associação Brasileira de Divulgação Científica Publicador: Associação Brasileira de Divulgação Científica
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/02/1997 Português
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The mechanism whereby the immune system avoids self-aggression is one of the central issues of Immunology. The discovery of natural autoantibodies, mainly of IgM isotype, and of idiotypic interactions between antibodies indicates that elements of the immune system interact with self constituents and with themselves. Results of studies with soluble antibodies have indicated that the pool of circulating IgM represents the end result of a highly selective process of B cells activation and differentiation by self proteins resulting in the formation of a network. The objective of the present work was to determine the frequency of self-reacting B cells in normal mice. We were able to detect B cells that recognize self proteins present in extracts of different organs in normal adult, 2-3-month old, BALB/c and C57BL/6 mice with an ELISA spot assay. About 1% of total IgM-secreting cells among small, LPS-stimulated spleen cells reacted with organ extracts, whereas among large spleen cells the frequency was 5- to 10-fold lower. Immunization induced an increase in the frequency of IgM-secreting cells. The present results provide cellular evidence for the results of studies done at the serological level. The physiological role of these self-recognizing cells...

‣ Prolonged acceptance of skin grafts induced by B cells places regulatory T cells on the histopathology scene

Langier,S.; Galvani,R.G.; Alves,A.P.G.; Fidelis,R.; Nunes,P.H.C.; Silva,M.H.; Castilho,L.R.; Monteiro,J.P.; Bonomo,A.
Fonte: Associação Brasileira de Divulgação Científica Publicador: Associação Brasileira de Divulgação Científica
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/10/2012 Português
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The participation of regulatory T (Treg) cells in B cell-induced T cell tolerance has been claimed in different models. In skin grafts, naive B cells were shown to induce graft tolerance. However, neither the contribution of Treg cells to B cell-induced skin tolerance nor their contribution to the histopathological diagnosis of graft acceptance has been addressed. Here, using male C57BL/6 naive B cells to tolerize female animals, we show that skin graft tolerance is dependent on CD25+ Treg cell activity and independent of B cell-derived IL-10. In fact, B cells from IL-10-deficient mice were able to induce skin graft tolerance while Treg depletion of the host inhibited 100% graft survival. We questioned how Treg cell-mediated tolerance would impact on histopathology. B cell-tolerized skin grafts showed pathological scores as high as a rejected skin from naive, non-tolerized mice due to loss of skin appendages, reduced keratinization and mononuclear cell infiltrate. However, in tolerized mice, 40% of graft infiltrating CD4+ cells were FoxP3+ Treg cells with a high Treg:Teff (effector T cell) ratio (6:1) as compared to non-tolerized mice where Tregs comprise less than 8% of total infiltrating CD4 cells with a Treg:Teff ratio below 1:1. These results render Treg cells an obligatory target for histopathological studies on tissue rejection that may help to diagnose and predict the outcome of a transplanted organ.

‣ BAFF promotes regulatory T-cell apoptosis and blocks cytokine production by activating B cells in primary biliary cirrhosis

Zhang,Bo; Hu,Mintao; Zhang,Peng; Cao,Hong; Wang,Yongzhen; Wang,Zheng; Su,Tingting
Fonte: Associação Brasileira de Divulgação Científica Publicador: Associação Brasileira de Divulgação Científica
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/05/2013 Português
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Primary biliary cirrhosis (PBC) is a chronic and slowly progressive cholestatic liver disease of autoimmune etiology. A number of questions regarding its etiology are unclear. CD4+CD25+ regulatory T cells (Tregs) play a critical role in self-tolerance and, for unknown reasons, their relative number is reduced in PBC patients. B-cell-activating factor (BAFF) is a key survival factor during B-cell maturation and its concentration is increased in peripheral blood of PBC patients. It has been reported that activated B cells inhibit Treg cell proliferation and there are no BAFF receptors on Tregs. Therefore, we speculated that excessive BAFF may result in Treg reduction via B cells. To prove our hypothesis, we isolated Tregs and B cells from PBC and healthy donors. BAFF and IgM concentrations were then analyzed by ELISA and CD40, CD80, CD86, IL-10, and TGF-β expression in B cells and Tregs were measured by flow cytometry. BAFF up-regulated CD40, CD80, CD86, and IgM expression in B cells. However, BAFF had no direct effect on Treg cell apoptosis and cytokine secretion. Nonetheless, we observed that BAFF-activated B cells could induce Treg cell apoptosis and reduce IL-10 and TGF-β expression. We also showed that BAFF-activated CD4+ T cells had no effect on Treg apoptosis. Furthermore...

‣ Tolerant Anti-insulin B Cells are Effective APCs1

Kendall, Peggy L.; Case, James B.; Sullivan, Allison M.; Holderness, Jeff S.; Wells, K. Sam; Liu, Edwin; Thomas, James W.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Português
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Autoreactive B lymphocytes that are not culled by central tolerance in the bone marrow frequently enter the peripheral repertoire in a state of functional impairment, termed anergy. These cells are recognized as a liability for autoimmunity, but their contribution to disease is not well-understood. Insulin-specific 125Tg B cells support T cell-mediated Type 1 diabetes (T1D) in nonobese diabetic (NOD) mice, despite being anergic to B cell mitogens and T cell dependent immunization. Using this model, the potential of anergic, autoreactive B cells to present antigen and activate T cells was investigated. The data show that: a) insulin is captured and rapidly internalized by 125Tg BCRs, b) these antigen-exposed B cells are competent to activate both experienced and naïve CD4+ T cells, c) anergic 125Tg B cells are more efficient than naïve B cells at activating T cells when antigen is limiting, and d) 125Tg B cells are competent to generate low-affinity insulin B chain epitopes necessary for activation of diabetogenic anti-insulin BDC12-4.1 T cells, indicating the pathological relevance of anergic B cells in T1D. Thus, phenotypically tolerant B cells that are retained in the repertoire may promote autoimmunity by driving activation and expansion of autoaggressive T cells via antigen-presentation.

‣ In aged mice, low surrogate light chain promotes pro-B-cell apoptotic resistance, compromises the PreBCR checkpoint, and favors generation of autoreactive, phosphorylcholine-specific B cells

Ratliff, Michelle; Alter, Sarah; McAvoy, Kelly; Frasca, Daniela; Wright, Jacqueline A; Zinkel, Sandra S; Khan, Wasif N; Blomberg, Bonnie B; Riley, Richard L
Fonte: BlackWell Publishing Ltd Publicador: BlackWell Publishing Ltd
Tipo: Artigo de Revista Científica
Português
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In aged mice, new B-cell development is diminished and the antibody repertoire becomes more autoreactive. Our studies suggest that (i) apoptosis contributes to reduced B lymphopoiesis in old age and preferentially eliminates those B-cell precursors with higher levels of the surrogate light chain (SLC) proteins (λ5/VpreB) and (ii) λ5low B-cell precursors generate new B cells which show increased reactivity to the self-antigen/bacterial antigen phosphorylcholine (PC). Pro-B cells in old bone marrow as well as pro-B cells from young adult λ5-deficient mice are resistant to cytokine-induced apoptosis (TNFα; TGFβ), indicating that low λ5 expression in pro-B cells is sufficient to cause increased survival. Transfer of TNFα-producing ‘age-associated B cells’ (ABC; CD21/35− CD23−) or follicular (FO) B cells from aged mice into RAG-2 KO recipients led to preferential loss of λ5high pro-B cells, but retention of λ5low, apoptosis-resistant pro-B cells. In old mice, there is increased reactivity to PC in both immature bone marrow B cells and mature splenic FO B cells. In young mice, absence of λ5 expression led to a similar increase in PC reactivity among bone marrow and splenic B cells. We propose that in old age, increased apoptosis...

‣ Exacerbated experimental arthritis in Wiskott–Aldrich syndrome protein deficiency: Modulatory role of regulatory B cells

Bouma, Gerben; Carter, Natalie A; Recher, Mike; Malinova, Dessislava; Adriani, Marsilio; Notarangelo, Luigi D; Burns, Siobhan O; Mauri, Claudia; Thrasher, Adrian J
Fonte: BlackWell Publishing Ltd Publicador: BlackWell Publishing Ltd
Tipo: Artigo de Revista Científica
Português
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Patients deficient in the cytoskeletal regulator Wiskott–Aldrich syndrome protein (WASp) are predisposed to varied autoimmunity, suggesting it has an important controlling role in participating cells. IL-10-producing regulatory B (Breg) cells are emerging as important mediators of immunosuppressive activity. In experimental, antigen-induced arthritis WASp-deficient (WASp knockout [WAS KO]) mice developed exacerbated disease associated with decreased Breg cells and regulatory T (Treg) cells, but increased Th17 cells in knee-draining LNs. Arthritic WAS KO mice showed increased serum levels of B-cell-activating factor, while their B cells were unresponsive in terms of B-cell-activating factor induced survival and IL-10 production. Adoptive transfer of WT Breg cells ameliorated arthritis in WAS KO recipients and restored a normal balance of Treg and Th17 cells. Mice with B-cell-restricted WASp deficiency, however, did not develop exacerbated arthritis, despite exhibiting reduced Breg- and Treg-cell numbers during active disease, and Th17 cells were not increased over equivalent WT levels. These findings support a contributory role for defective Breg cells in the development of WAS-related autoimmunity, but demonstrate that functional competence in other regulatory populations can be compensatory. A properly regulated cytoskeleton is therefore important for normal Breg-cell activity and complementation of defects in this lineage is likely to have important therapeutic benefits.

‣ Human Anergic B Cells: IgMlo

Quach, Tam Dan ; Sanz, Inaki
Fonte: Universidade de Rochester Publicador: Universidade de Rochester
Tipo: Tese de Doutorado
Português
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Thesis (Ph.D.)--University of Rochester. Dept. of Microbiology and Immunology, 2010.; B cell anergy represents an important mechanism of peripheral immunological tolerance which censors mature autoreactive B cells that escape central tolerance enforced by receptor editing and clonal deletion. While anergy has been well documented in mice, the extent of its participation in human B cell tolerance remains to be established. In this study, we characterize the functional behavior of strictly defined human naïve B cells separated on the basis of their levels of surface IgM (sIgM). We first observed that sIgM on B cells within the mature naïve pool in the periphery is broadly expressed ranging from as low as non-detectable to a density of high sIgM levels characteristic of transitional T1 B cells. We postulated that decreased sIgM expression was likely to reflect sustained IgM downregulation induced by chronic stimulation by ubiquitous self-antigens. Alternatively, low levels of sIgM could also be present in recently activated B cells due to BCR internalization induced by acute antigenic stimulation. The former hypothesis was however supported by the finding that upon B cell receptor (BCR) stimulation, cells with lower sIgM levels (IgMlo) are impaired in their ability to flux calcium in response to either anti-IgM or anti-IgD crosslinking. The results suggest that IgMlo cells represent an anergic B-cell population similar to those seen in several mouse models of B cell anergy including the best characterized autoreactive B-cell double transgenic model (hen egg lysozyme/anti-HEL). Of significant importance for our experimental model and conclusions...

‣ B Cells in Inflamed Lymph Nodes: A Link between Inflammation and Autoimmunity

Moshkani, Safiehkhatoon ; Bottaro, Andrea
Fonte: University of Rochester Publicador: University of Rochester
Tipo: Tese de Doutorado
Português
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Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Microbiology & Immunology, 2012.; TNF- transgenic (TNFtg) mice develop a spontaneous inflammatory joint disease resembling rheumatoid arthritis (RA) in patients. Bin cells phenotypically defined as CD23+CD21highCD1dhigh B cells have been shown to accumulate in the lymph nodes (LNs) that drain inflamed tissues of TNFtg mice and are involved in the significant histological and functional LN alterations that accompany disease exacerbation. Work presented in this thesis characterizes the origin and potential function of Bin cells. Via adoptive transfer of sorted GFP+ follicular B (FoB) cells we show that Bin cells can be generated from circulating FoB that preferentially home to the inflamed LNs of TNFtg mice and rapidly change their phenotype in the node proinflammatory environment. Remarkably, we found the Bin phenotype in WT lymph nodes after challenge with a T-dependent antigen (Ag) in adjuvant. Interestingly Bin cells display a germinal center phenotype at higher rates compared to FoB cells. Moreover, Ag-free adjuvant can induce Bin phenotype in draining LN of wild type mice, indicating that Bin induction is not dependent on exogenous Ag. Furthermore...

‣ MARCH1 : new insights in the activation of B cells

Galbas, Tristan
Fonte: Université de Montréal Publicador: Université de Montréal
Tipo: Thèse ou Mémoire numérique / Electronic Thesis or Dissertation
Português
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RÉSUMÉ L’implication des cellules B dans le développement de l’auto-immunité ne cesse d’être illustrée par de récentes publications. Les cellules présentent des peptides du soi aux cellules T auto-réactives ce qui mène à la production de cytokines pro-inflammatoires et d’anticorps auto-réactifs. Dans le présent document, nous explorons la présentation antigénique et la modification post-traductionnelle du complexe majeur d’histocompatibilité II (CMH-II). MARCH1 est une E3 ubiquitine ligase qui cible le CMH-II et le relocalise le complexe vers les endosomes de recyclage. Ainsi, MARCH1 est un inhibiteur de la présentation d’antigènes exogènes. Ici, nous démontrons que MARCH1 est exprimé seulement dans la sous-population des cellules B folliculaires et que cette expression est perdue lors de l’entrée dans les centres germinatifs. Nous proposons que MARCH1 établie une barrière de formation de centres germinatifs. Nous démontrons le lien entre MARCH1 et la hausse de CMH-II à la surface des cellules B à la suite d’un traitement à l’IL-10. De plus, nous avons testé plusieurs stimuli activateurs des cellules B et démontrons que MARCH1 est régulé à la baisse dans tous les cas. De plus, nous mettons en valeurs le rôle de la voie canonique d’activation de NF-κB dans cette régulation de MARCH1. Finalement...

‣ Association between the proliferative rate of neoplastic B cells, their maturation stage, and underlying cytogenetic abnormalities in B-cell chronic lymphoproliferative disorders: analysis of a series of 432 patients; Blood

Quijano, Sandra; Rasillo, Ana; Sánchez, Maria Luz; Fernández, Carlos; Salvador Osuna, Carlos; González, Marcos; Giralt, Manuel; Martin-Antoran, José Manuel; Perdiguer, Luis; González Silva, Manuel; Cerveró, Carlos; Butrón, Rosario; Almeida, Julia;
Fonte: Pontifícia Universidade Javeriana Publicador: Pontifícia Universidade Javeriana
Formato: 5130-5141
Português
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Vol. 111, No. 10; Limited knowledge exists about the im- pact of specific genetic abnormalities on the proliferation of neoplastic B cells from chronic lymphoproliferative disorders (B- CLPDs). Here we analyze the impact of cytogenetic abnormalities on the prolifera- tion of neoplastic B cells in 432 B-CLPD patients, grouped according to diagnosis and site of sampling, versus their normal counterparts. Overall, proliferation of neo- plastic B cells highly varied among the different B-CLPD subtypes, the greatest numbers of proliferating cells being iden- tified in diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL). Compared with normal B cells, neoplastic B-CLPD cells showed significantly in- creased S

‣ CCR6 is transiently upregulated on B cells after activation and modulates the germinal center reaction in the mouse

Wiede, F.; Fromm, P.; Comerford, I.; Kara, E.; Bannan, J.; Schuh, W.; Ranasinghe, C.; Tarlinton, D.; Winkler, T.; McColl, S.; Korner, H.
Fonte: Blackwell Publishing Asia Publicador: Blackwell Publishing Asia
Tipo: Artigo de Revista Científica
Publicado em //2013 Português
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The CC-chemokine receptor 6 (CCR6) is expressed constitutively at an intermediate level on naı¨ve B cells and is upregulated after activation on pregerminal center (GC) B cells. We hypothesized that it could be involved in the events leading to GC reaction and high-affinity antibody production, and therefore investigated the potential role of CCR6 in B-cell differentiation in vivo. After antigenic challenge of CCR6_/_ mice with the T-cell-dependent antigen nitrophenyl-keyhole limpet hemocyanin (NP-KLH), GC B-cell development was found to be accelerated and the number of GC had increased significantly compared with control mice, but the antibodies produced by CCR6_/_ B cells were on average of lower affinity. We conclude from these data that the CCR6/CCL20 axis has an important role in regulating the kinetics and efficiency of the GC reaction.; Florian Wiede, Phillip D. Fromm, Iain Comerford, Ervin Kara, Jennifer Bannan, Wolfgang Schuh, Charani Ranasinghe, David Tarlinton, Thomas Winkler, Shaun R. McColl and Heinrich Körner

‣ Changes in peripheral blood B cell subsets at diagnosis and after treatment with disease-modifying anti-rheumatic drugs in patients with rheumatoid arthritis: correlation with clinical and laboratory parameters

McComish, J.; Mundy, J.; Sullivan, T.; Proudman, S.M.; Hissaria, P.
Fonte: Wiley Publicador: Wiley
Tipo: Artigo de Revista Científica
Publicado em //2015 Português
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OBJECTIVE: To assess variation in peripheral blood B lymphocyte subsets in rheumatoid arthritis (RA). METHODS: B lymphocyte subsets in disease-modifying anti-rheumatic drug (DMARD)-naïve patients with RA (n = 30), patients with RA treated with DMARDs (n = 73) and healthy controls (n = 46) were analyzed by flow cytometry. Total B cells, total memory B cells, immunoglobulin M (IgM) memory B cells, switched memory B cells, non-switched memory B cells, CD21lo B cells, transitional B cells and plasmablasts were measured. Correlation with clinical and laboratory parameters was performed. RESULTS: Total memory B cells, IgM memory B cells and non-switched memory B cells were reduced in RA patients at diagnosis compared to controls (P < 0.05). In patients with treated RA, there was a further reduction of total B cells, CD21lo cells, transitional B cells and plasmablasts, compared to controls (P < 0.05). The reduction in absolute numbers of total B cells, switched memory B cells, CD21lo cells, transitional B cells and plasmablasts in treated RA patients was significant (P < 0.05) even when compared to the DMARD-naïve patients. Only treatment responders (Disease Activity Score < 3.2) had reduced total B cells and absolute numbers of switched and IgM memory B cells (P < 0.05). In patients requiring leflunomide...

‣ Rat pancreatic 9-cells after chronic alcohol feeding. A morphometric and fine structural study

Koko, V.; Todorovic, V.; Nikolic, J.A.; Glisic, R.; Cakic, M.; Lackovic, V.; Petronijevic, L.; Stojkovic, M.; Varagic, J.; Janic, B.; Radovanovic, J.; Laban, A.
Fonte: Murcia : F. Hernández Publicador: Murcia : F. Hernández
Tipo: Artigo de Revista Científica Formato: application/pdf
Português
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Quantitative analysis of the light microscopic and fine stmcture of rat islet B-cells was carried out in chronic alcoholism. Absolute pancreatic weight and volume were similar in groups C (control) and E (ethanol), but relative pancreatic weight in group E rat was decreased. The results for fasting blood glucose and insulin levels were similar in the two groups of animals. There was a significantly reduced total pancreatic islet volume in E rats. The total number of endocrine cells both per islet and per p2of islet was similar in the two groups of animals. The volume density and number of B-cells per islet and per p2of islet were not changed in ethanol-treated rats as compared with the control. On the other hand, diameter, surface area and volume of the Bcells and their nuclei were found to be statistically significantly decreased. Histological examination revealed that islet blood vessels were dilated in alcoholic rats. Over the 4-month period of ethanol intake a significant decrease in cell profile area, nuclear profile area and volume density of cytoplasmic granules and an increase in the profile area and volume density of endoplasmic reticulum occurred. The gross histological alteration seen in most B-cells of the ethanol-treated rats was irregularity of the nuclear envelope with deep invagination and with margination of heterochromatin and many empty granules or granules without clear electron dense crystals of insulin. The present results indicate some optical and structural abnormalities of B-cells in chronic alcoholism that may be related to cell dysfunction and may contribute...

‣ Memory B cells and CD27

Agematsu, K.
Fonte: Murcia : F. Hernández Publicador: Murcia : F. Hernández
Tipo: Artigo de Revista Científica Formato: application/pdf
Português
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Following antigen activation in germinal centers, B cells develop into memory B cells or plasma cells. Triggering via B-cell immunoglobulin receptors by antigens, cytokines and direct cell-to-cell contact by B and T cells plays an important role in the B cell differentiation into memory or plasma cells. Adult human peripheral blood B cells are separated into three subtypes by the expression of IgD and CD27, which belong to the tumor necrosis factor receptor (TNFR) family: IgD+ CD27- naive B cells, IgDt CD27t and IgD- CD27t B cells. CD27+ B cells are larger cells with abundant cytoplasm carrying somatic hypermutation, and have an ability to produce immunoglobulin, indicating that CD27 is a memory marker of B cells. The ligation of CD27 yields crucial signals that positively control the entry of B cells into the pathway to plasma cells. We review observations on subpopulations and differentiation of mature B-cells by TIB cell interaction via CD27lCD70 as compared with CD40lCD154 interaction, and discuss about memory B cells.

‣ B cells expressing IL-10 mRNA modulate memory T cells after DNA-Hsp65 immunization

Fontoura,I. C.; Trombone,A.P.F.; Almeida,L. P.; Lorenzi,J. C. C.; Rossetti,R. A. M.; Malardo,T.; Padilha,E.; Schluchting,W.; Silva,R. L. L.; Gembre,A. F.; Fiuza,J. E. C.; Silva,C. L.; Panunto-Castelo,A.; Coelho-Castelo,A. A. M.
Fonte: Associação Brasileira de Divulgação Científica Publicador: Associação Brasileira de Divulgação Científica
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/12/2015 Português
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In DNA vaccines, the gene of interest is cloned into a bacterial plasmid that is engineered to induce protein production for long periods in eukaryotic cells. Previous research has shown that the intramuscular immunization of BALB/c mice with a naked plasmid DNA fragment encoding the Mycobacterium leprae 65-kDa heat-shock protein (pcDNA3-Hsp65) induces protection against M. tuberculosis challenge. A key stage in the protective immune response after immunization is the generation of memory T cells. Previously, we have shown that B cells capture plasmid DNA-Hsp65 and thereby modulate the formation of CD8+ memory T cells after M. tuberculosis challenge in mice. Therefore, clarifying how B cells act as part of the protective immune response after DNA immunization is important for the development of more-effective vaccines. The aim of this study was to investigate the mechanisms by which B cells modulate memory T cells after DNA-Hsp65 immunization. C57BL/6 and BKO mice were injected three times, at 15-day intervals, with 100 µg naked pcDNA-Hsp65 per mouse. Thirty days after immunization, the percentages of effector memory T (TEM) cells (CD4+ and CD8+/CD44high/CD62Llow) and memory CD8+ T cells (CD8+/CD44high/CD62Llow/CD127+) were measured with flow cytometry. Interferon γ...

‣ Naive and memory human B cells have distinct requirements for STAT3 activation to differentiate into antibody-secreting plasma cells

Deenick, Elissa K; Avery, Danielle T; Chan, Anna; Berglund, Lucinda J; Ives, Megan L; Moens, Leen; Stoddard, Jennifer L; Bustamante, Jacinta; Boisson-Dupuis, Stephanie; Miyuki, Tsumura; Kobayashi, Masao; Arkwright, Peter D; Averbuch, Diana; Engelhard, Dan
Fonte: Rockefeller University Press210.12 (2013): 1-15 Publicador: Rockefeller University Press210.12 (2013): 1-15
Tipo: Artigo de Revista Científica Formato: 17 pages
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Long-lived antibody memory is mediated by the combined effects of long-lived plasma cells (PCs) and memory B cells generated in response to T cell–dependent antigens (Ags). IL-10 and IL-21 can activate multiple signaling pathways, including STAT1, STAT3, and STAT5; ERK; PI3K/Akt, and potently promote human B cell differentiation. We previously showed that loss-of-function mutations in STAT3, but not STAT1, abrogate IL-10– and IL-21–mediated differentiation of human naive B cells into plasmablasts. We report here that, in contrast to naive B cells, STAT3-deficient memory B cells responded to these STAT3-activating cytokines, differentiating into plasmablasts and secreting high levels of IgM, IgG, and IgA, as well as Ag-specific IgG. This was associated with the induction of the molecular machinery necessary for PC formation. Mutations in IL21R, however, abolished IL-21–induced responses of both naive and memory human B cells and compromised memory B cell formation in vivo. These findings reveal a key role for IL-21R/STAT3 signaling in regulating human B cell function. Furthermore, our results indicate that the threshold of STAT3 activation required for differentiation is lower in memory compared with naive B cells, thereby identifying an intrinsic difference in the mechanism underlying differentiation of naive versus memory B cells.; This work was funded by project and program grants from the National Health and Medical Research Council (NHMRC) of Australia (to E.K. Deenick...

‣ Mechanisms of clonal abortion tolerogenesis. II. Clonal behaviour of immature B cells following exposure to anti-mu chain antibody.

Nossal, G J; Pike, B L; Battye, F L
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /05/1979 Português
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546.96562%
This paper uses B-lymphocyte cloning methods to quantify the effects of anti-mu chain antibody on immature and mature B cells. Nude mouse spleen lymphocytes were incubated with various concentrations of sheep anti-mouse mu chain antibody for times varying from 10 min to 24 h. They were then washed and plated in the agar B-cell colony formation assay. Five to six days later, control B cells had developed into colonies with a plating efficiency of about 5%. B cells from newborn mice pretreated with anti-mu yielded fewer colonies. Remarkably low concentrations sufficed to inhibit subsequent mitogenesis. For example, 3 microgram/ml acting for 1 h or 0.1 microgram/ml acting for 24 h gave greater than 50% inhibition. Adult B cells were about thirty-fold more resistant to negative signalling. Immature cells become more profoundly inhibited as anti-mu treatment was prolonged. Anti-Ia or anti-H2 antibodies, in the absence of complement, did not deliver a negative signal. Anti-mu pretreatment also reduced the capacity of immature B cells to form clones of anti-hapten antibody-forming cells in a liquid microculture system where the triggering stimulus was a T-cell independent antigen. Mature 'T-independent' B cells were not inhibited. Populations of hapten-specific B cells prepared by the hapten-gelatin method were investigated in the agar cloning system. Pretreatment of immature cells with anti-mu reduced their capacity to form colonies...

‣ A Gammaherpesvirus Bcl-2 Ortholog Blocks B Cell Receptor-Mediated Apoptosis and Promotes the Survival of Developing B Cells In Vivo

Coleman, Carrie B.; McGraw, Jennifer E.; Feldman, Emily R.; Roth, Alexa N.; Keyes, Lisa R.; Grau, Katrina R.; Cochran, Stephanie L.; Waldschmidt, Thomas J.; Liang, Chengyu; Forrest, J. Craig; Tibbetts, Scott A.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 06/02/2014 Português
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Gammaherpesviruses such as Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV, HHV-8) establish lifelong latency in their hosts and are associated with the development of several types of malignancies, including a subset of B cell lymphomas. These viruses are thought to co-opt the process of B cell differentiation to latently infect a fraction of circulating memory B cells, resulting in the establishment of a stable latency setpoint. However, little is known about how this infected memory B cell compartment is maintained throughout the life of the host. We have previously demonstrated that immature and transitional B cells are long-term latency reservoirs for murine gammaherpesvirus 68 (MHV68), suggesting that infection of developing B cells contributes to the maintenance of lifelong latency. During hematopoiesis, immature and transitional B cells are subject to B cell receptor (BCR)-mediated negative selection, which results in the clonal deletion of autoreactive B cells. Interestingly, numerous gammaherpesviruses encode homologs of the anti-apoptotic protein Bcl-2, suggesting that virus inhibition of apoptosis could subvert clonal deletion. To test this, we quantified latency establishment in mice inoculated with MHV68 vBcl-2 mutants. vBcl-2 mutant viruses displayed a marked decrease in the frequency of immature and transitional B cells harboring viral genome...

‣ Recirculating and germinal center B cells differentiate into cells responsive to polysaccharide-antigens

Garcia De Vinuesa, Maria Carola; Sze, Daniel M-Y; Cook, Matthew; Toellner, K-M; Klaus, Gerry G.B.; Ball, Jennifer; MacLennan, Ian C M
Fonte: Wiley-VCH Verlag GMBH Publicador: Wiley-VCH Verlag GMBH
Tipo: Artigo de Revista Científica
Português
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Antibodies against bacterial capsular polysaccharides play a critical protective role. Responses to these antigens can occur without the help or control of T cells and are associated with marginal zone (MZ) B cells. Capsular antigens are diverse and some