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1.
Nat Commun ; 11(1): 2465, 2020 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-32424289

RESUMO

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare lymphoma of B-cell origin with frequent expression of functional B-cell receptors (BCRs). Here we report that expression cloning followed by antigen screening identifies DNA-directed RNA polymerase beta' (RpoC) from Moraxella catarrhalis as frequent antigen of BCRs of IgD+ LP cells. Patients show predominance of HLA-DRB1*04/07 and the IgVH genes encode extraordinarily long CDR3s. High-titer, light-chain-restricted anti-RpoC IgG1/κ-type serum-antibodies are additionally found in these patients. RpoC and MID/hag, a superantigen co-expressed by Moraxella catarrhalis that is known to activate IgD+ B cells by binding to the Fc domain of IgD, have additive activation effects on the BCR, the NF-κB pathway and the proliferation of IgD+ DEV cells expressing RpoC-specific BCRs. This suggests an additive antigenic and superantigenic stimulation of B cells with RpoC-specific IgD+ BCRs under conditions of a permissive MHC-II haplotype as a model of NLPHL lymphomagenesis, implying future treatment strategies.


Assuntos
Antígenos de Bactérias/imunologia , Linfócitos B/imunologia , Doença de Hodgkin/imunologia , Doença de Hodgkin/microbiologia , Moraxella catarrhalis/imunologia , Adolescente , Adulto , Idoso , Autoantígenos/imunologia , Linhagem Celular Tumoral , Proliferação de Células , Criança , RNA Polimerases Dirigidas por DNA/metabolismo , Antígenos de Histocompatibilidade Classe II/metabolismo , Doença de Hodgkin/sangue , Humanos , Imunoglobulina D/metabolismo , Fragmentos Fab das Imunoglobulinas/imunologia , Região Variável de Imunoglobulina/genética , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Receptores de Antígenos de Linfócitos B/metabolismo
2.
PLoS Comput Biol ; 16(4): e1007837, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32339161

RESUMO

Immunoglobulin genes are formed through V(D)J recombination, which joins the variable (V), diversity (D), and joining (J) germline genes. Since variations in germline genes have been linked to various diseases, personalized immunogenomics focuses on finding alleles of germline genes across various patients. Although reconstruction of V and J genes is a well-studied problem, the more challenging task of reconstructing D genes remained open until the IgScout algorithm was developed in 2019. In this work, we address limitations of IgScout by developing a probabilistic MINING-D algorithm for D gene reconstruction, apply it to hundreds of immunosequencing datasets from multiple species, and validate the newly inferred D genes by analyzing diverse whole genome sequencing datasets and haplotyping heterozygous V genes.


Assuntos
Biologia Computacional/métodos , Genes de Imunoglobulinas/genética , Imunoglobulina D/genética , Algoritmos , Animais , Bases de Dados Genéticas , Humanos , Imunidade/genética
4.
Cell Immunol ; 349: 104048, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32014271

RESUMO

NFAT2 activity was shown to be of critical importance in B cell receptor signaling, development and proliferation; however its role in B cell development in the periphery is still not completely understood. We confirmed that NFAT2 deletion leads to impaired B1 B cell development, supported by our finding of limited B1 progenitors in the bone marrow and spleen of NFAT2 deficient mice. Moreover, we show for the first time that loss of NFAT2 increases immature B cells in particular transitional T2 and T3 as well as mature follicular B cells while marginal zone B cells are decreased. We further demonstrate that NFAT2 regulates the expression of B220, CD23, CD38, IgM/IgD and ZAP70 in murine B cells. In vivo analyses revealed decreased proliferation and increased apoptosis of NFAT2 deficient B cells. In summary, this study provides an extensive analysis of the role of NFAT2 in peripheral B lymphocyte development.


Assuntos
Subpopulações de Linfócitos B/citologia , Linfopoese/fisiologia , Fatores de Transcrição NFATC/deficiência , Animais , Antígenos de Diferenciação de Linfócitos B/análise , Subpopulações de Linfócitos B/metabolismo , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Técnicas de Inativação de Genes , Genes Letais , Heterozigoto , Imunoglobulina D/biossíntese , Imunoglobulina D/genética , Imunoglobulina M/biossíntese , Imunoglobulina M/genética , Antígenos Comuns de Leucócito/biossíntese , Antígenos Comuns de Leucócito/genética , Ativação Linfocitária , Tecido Linfoide/crescimento & desenvolvimento , Tecido Linfoide/patologia , Linfopoese/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Transcrição NFATC/fisiologia , Especificidade de Órgãos , Organismos Livres de Patógenos Específicos
5.
Nat Rev Immunol ; 20(5): 294-307, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31988391

RESUMO

Recent data show that B cells and plasma cells located in tumours or in tumour-draining lymph nodes can have important roles in shaping antitumour immune responses. In tumour-associated tertiary lymphoid structures, T cells and B cells interact and undergo cooperative selection, specialization and clonal expansion. Importantly, B cells can present cognate tumour-derived antigens to T cells, with the functional consequences of such interactions being shaped by the B cell phenotype. Furthermore, the isotype and specificity of the antibodies produced by plasma cells can drive distinct immune responses. Here we summarize our current knowledge of the roles of B cells and antibodies in the tumour microenvironment. Moreover, we discuss the potential of using immunoglobulin repertoires as a source of tumour-specific receptors for immunotherapy or as biomarkers to predict the efficacy of immunotherapeutic interventions.


Assuntos
Anticorpos Antineoplásicos/imunologia , Linfócitos B/imunologia , Linfócitos do Interstício Tumoral/imunologia , Neoplasias/imunologia , Microambiente Tumoral/imunologia , Anticorpos/imunologia , Antineoplásicos Imunológicos/uso terapêutico , Humanos , Imunoglobulina A/imunologia , Imunoglobulina D/imunologia , Imunoglobulina E/imunologia , Imunoglobulina G/imunologia , Depleção Linfocítica , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Plasmócitos/imunologia , Linfócitos T/imunologia , Evasão Tumoral/imunologia
6.
PLoS Biol ; 17(12): e3000569, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31825964

RESUMO

Membrane proteins are organized in nanoscale compartments. Their reorganization plays a crucial role in receptor activation and cell signaling. To monitor the organization and reorganization of membrane proteins, we developed a new branched proximity hybridization assay (bPHA) allowing better quantification of the nanoscale protein-protein proximity. In this assay, oligo-coupled binding probes, such as aptamer, nanobody, and antibodies, are used to translate the proximity of target proteins to the proximity of oligos. The closely positioned oligos then serve as a template for a maximum of 400-fold branched DNA (bDNA) signal amplification. The amplified bPHA signal is recorded by flow cytometer, thus enabling proximity studies with high throughput, multiplexing, and single-cell resolution. To demonstrate the potential of the bPHA method, we measured the reorganization of the immunoglobulin M (IgM)- and immunoglobulin D (IgD)-class B cell antigen receptor (BCR) on the plasma membrane and the recruitment of spleen tyrosine kinase (Syk) to the BCR upon B lymphocyte activation.


Assuntos
Microdomínios da Membrana/metabolismo , Proteínas de Membrana/fisiologia , Mapeamento de Interação de Proteínas/métodos , Animais , Linfócitos B/metabolismo , Linhagem Celular , Membrana Celular/metabolismo , Feminino , Humanos , Imunoglobulina D , Imunoglobulina M , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Ativação Linfocitária/imunologia , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Antígenos de Linfócitos B/genética , Transdução de Sinais/imunologia , Quinase Syk
7.
Nat Immunol ; 20(11): 1517-1529, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31591571

RESUMO

The establishment of a diverse B cell antigen receptor (BCR) repertoire by V(D)J recombination also generates autoreactive B cells. Anergy is one tolerance mechanism; it renders autoreactive B cells insensitive to stimulation by self-antigen, whereas Toll-like receptor (TLR) signaling can reactivate anergic B cells. Here, we describe a critical role of the transcription factor Ikaros in controlling BCR anergy and TLR signaling. Mice with specific deletion of Ikaros in mature B cells developed systemic autoimmunity. Ikaros regulated many anergy-associated genes, including Zfp318, which is implicated in the attenuation of BCR responsiveness by promoting immunoglobulin D expression in anergic B cells. TLR signaling was hyperactive in Ikaros-deficient B cells, which failed to upregulate feedback inhibitors of the MyD88-nuclear factor κB signaling pathway. Systemic inflammation was lost on expression of a non-self-reactive BCR or loss of MyD88 in Ikaros-deficient B cells. Thus, Ikaros acts as a guardian preventing autoimmunity by promoting BCR anergy and restraining TLR signaling.


Assuntos
Autoimunidade/genética , Linfócitos B/imunologia , Anergia Clonal/genética , Fator de Transcrição Ikaros/metabolismo , Receptores Toll-Like/metabolismo , Animais , Linfócitos B/metabolismo , Proteínas de Ligação a DNA/metabolismo , Regulação da Expressão Gênica/imunologia , Fator de Transcrição Ikaros/genética , Fator de Transcrição Ikaros/imunologia , Imunoglobulina D/imunologia , Imunoglobulina D/metabolismo , Camundongos , Modelos Animais , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Receptores de Antígenos de Linfócitos B/imunologia , Receptores de Antígenos de Linfócitos B/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Receptores Toll-Like/imunologia
8.
J Immunol ; 203(6): 1650-1664, 2019 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-31391234

RESUMO

IgD-CD27- double negative (DN) B cells with proinflammatory characteristics are abnormally elevated in a proportion of multiple sclerosis (MS) patients. In this study, the origin and selection characteristics of DN B cells were studied in MS patients and healthy controls (HC). Expression of developmental markers on peripheral blood DN, IgD-CD27+ class-switched memory (CSM) and IgD+CD27- naive B cells of HC (n = 48) and MS patients (n = 96) was determined by flow cytometry. High-throughput adaptive immune receptor repertoire sequencing was performed on peripheral blood DN and CSM B cells of HC and MS patients (n = 3 each). DN B cells from HC and MS patients showed similar phenotypic and Ig repertoire characteristics. Phenotypic analysis indicated a mature state of DN B cells by low CD5, CD10, and CD38 expression. However, the frequency of CD95+ and IgA+ cells was lower in DN versus CSM B cells. DN B cells are Ag experienced, as shown by somatic hypermutation of their Ig genes in adaptive immune receptor repertoire sequencing, although they showed a lower mutation load than CSM B cells. Shared clones were found between DN and CSM B cells, although >95% of the clones were unique to each population, and differences in V(D)J usage and CDR3 physicochemical properties were found. Thus, DN B cells arise in HC and MS patients via a common developmental pathway that is probably linked to immune aging. However, DN and CSM B cells develop through unique differentiation pathways, with most DN B cells representing an earlier maturation state.


Assuntos
Linfócitos B/imunologia , Imunoglobulina D/imunologia , Esclerose Múltipla/imunologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia , Imunidade Adaptativa/imunologia , Adulto , Feminino , Genes de Imunoglobulinas/imunologia , Humanos , Switching de Imunoglobulina/imunologia , Memória Imunológica/imunologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
9.
Hematology ; 24(1): 544-551, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31315540

RESUMO

Objective: Immunoglobulin D (IgD) levels are often elevated in patients with autoimmune diseases. However, the oncogenic activities of IgD and IgD receptor (IgDR) in diffuse large B-cell lymphoma (DLBCL) have not been reported in detail. Therefore, we aimed to investigate the expression of IgD and IgDR in patients with DLBCL. Methods: Membrane IgD (mIgD) and IgDR expression in tissue samples was analyzed using IHC, mIgD and IgDR expression on peripheral blood mononuclear cells (PBMCs) was analyzed by FCM, and secreted IgD (sIgD) level was analyzed by ELISA. Fisher's exact test and Spearman correlation analysis were used to evaluate the relationship between IgD, IgDR, and clinical parameters. Results: The pathological lymph nodes of 34 patients with DLBCL were studied, and mIgD and IgDR expression was found in 16 and 19 patients. mIgD and IgDR expression was upregulated in patients with DLBCL and mIgD expression was significantly associated with IgDR expression. Further correlation analysis showed that mIgD expression was correlated with serum ß2-MG level and Hans algorithm as germinal center B (GCB), whereas IgDR expression correlated with serum LDH level, IPI score and GCB. ELISA showed that sIgD level was significantly increased in DLBCL patients and it correlated with serum ß2-MG and LDH levels. FCM showed that mIgD and IgDR expression in PBMCs of patients with DLBCL was significantly higher than that in healthy controls. Conclusion: Our findings suggest that overexpression of IgD and IgDR is an abnormal activation state in DLBCL.


Assuntos
Regulação Neoplásica da Expressão Gênica , Imunoglobulina D/biossíntese , Leucócitos Mononucleares/química , Receptores Fc/biossíntese , Estudos de Casos e Controles , Linhagem Celular Tumoral , Membrana Celular/imunologia , Feminino , Humanos , Imunoglobulina D/análise , Imunoglobulina D/genética , L-Lactato Desidrogenase/sangue , Linfonodos/química , Linfonodos/patologia , Linfoma Difuso de Grandes Células B/sangue , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pseudolinfoma/sangue , Pseudolinfoma/patologia , Receptores Fc/análise , Receptores Fc/genética , Regulação para Cima , Microglobulina beta-2/análise
10.
Vox Sang ; 114(7): 740-748, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31321786

RESUMO

BACKGROUND AND OBJECTIVES: The purpose of the study was to evaluate a lyophilized anti-D immunoglobulin preparation to serve as a replacement WHO International Standard for the calibration of potency assays of anti-D immunoglobulin products. Such products are used to prevent haemolytic disease of the foetus and newborn due to maternal alloanti-D. MATERIALS AND METHODS: The candidate 3rd International Standard for anti-D immunoglobulin (16/332) was evaluated and calibrated against the 2nd International Standard for anti-D immunoglobulin (01/572), along with a coded duplicate, a second candidate preparation (16/278) and a comparability sample (16/272) in an international collaborative study. Twenty of 21 laboratories in 15 countries performed one or more of the three European Pharmacopoeia reference methods. RESULTS: The overall geometric mean potency (from all methods) of the candidate 3rd International Standard, 16/332, was 296·6 IU/ampoule, with inter-laboratory variability, expressed as % GCV, of 4·7%. SE-HPLC of the immunoglobulin preparations demonstrated combined monomeric and dimeric IgG peak areas of >95% for all samples. Accelerated stability studies have shown both 16/332 and 16/278 to be very stable for long-term storage at -20°C. CONCLUSIONS: Preparation 16/332 was established by the World Health Organisation Expert Committee on Biological Standardization as the 3rd International Standard for anti-D immunoglobulin with an assigned potency of 297 IU/ampoule.


Assuntos
Eritroblastose Fetal/sangue , Técnicas Imunoenzimáticas/normas , Técnicas de Diagnóstico Molecular/normas , Imunoglobulina rho(D)/imunologia , Eritroblastose Fetal/imunologia , Humanos , Imunoglobulina D/imunologia , Indicadores e Reagentes/normas , Padrões de Referência , Organização Mundial da Saúde
11.
Inflammopharmacology ; 27(4): 845-856, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31165333

RESUMO

Previously, ginsenoside metabolite compound K (C-K) was able to reduce B cell proliferation and serum anti-type II collagen (anti-CII) antibody to normal levels in mice with collagen-induced arthritis (CIA); however, the mechanism by which C-K restores B cell balance is unclear. In the present work, C-K treatment not only alleviated the polyarthritis index, swollen joint count, pathological scores of spleen and joints, spleen index, B cell proliferation and the level of serum antibodies (IgG1, IgG2a and anti-collagen II), but C-K treatment also restored B cell subsets including regulatory B cells, plasma cells, memory B cells, mature B cells, and follicular B cells in CIA mice. Interestingly, C-K did not change the expression level of immunoglobulin D-type B-cell receptor (IgD-BCR) but promoted IgD-BCR endocytosis. C-K treatment enhanced ß-arrestin1 expression, facilitating the colocalization between IgD and ß-arrestin1, as well as colocalization between IgD and adaptor protein 2 (AP2). Inhibition of the ß-arrestin1-AP2 interaction with barbadin significantly reduced the ability of C-K to attenuate IgD-BCR plasma membrane localization. These results taken together depict that C-K ameliorates CIA in part by inhibiting B cell activation through the triggering of IgD-BCR internalization in a ß-arrestin1-AP2 dependent manner.


Assuntos
Artrite Experimental/tratamento farmacológico , Linfócitos B/efeitos dos fármacos , Endocitose/efeitos dos fármacos , Ginsenosídeos/farmacologia , Imunoglobulina D/metabolismo , Receptores de Antígenos de Linfócitos B/metabolismo , Complexo 2 de Proteínas Adaptadoras/metabolismo , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/metabolismo , Linfócitos B/metabolismo , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Colágeno/farmacologia , Imunoglobulina G/metabolismo , Articulações/efeitos dos fármacos , Articulações/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Masculino , Camundongos , Baço/efeitos dos fármacos , Baço/metabolismo , beta-Arrestina 1/metabolismo
12.
Scand J Immunol ; 90(2): e12792, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31141193

RESUMO

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


Assuntos
Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Subpopulações de Linfócitos B/imunologia , Imunoglobulina D/metabolismo , Receptores de Complemento 3d/metabolismo , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo , Adulto , Quimiocina CXCL10/sangue , Quimiocina CXCL10/metabolismo , Quimiocina CXCL9/sangue , Quimiocina CXCL9/metabolismo , Feminino , Humanos , Articulações/imunologia , Articulações/patologia , Masculino , Pessoa de Meia-Idade , Ligante RANK/biossíntese , Receptores CXCR3/biossíntese , Líquido Sinovial/metabolismo
13.
Vet Immunol Immunopathol ; 211: 25-34, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31084890

RESUMO

Red Mark Syndrome (RMS) is a skin disease reported from farmed rainbow trout. Since the turn of the millennium it has been spreading through Europe. RMS is probably a bacterial disease caused by a Midichloria-like organism (MLO). It is non-lethal and causes little obvious changes in appetite or behavior but results in red hyperaemic skin lesions, which may lead to economic losses due to downgrading. Here we transfer RMS to naïve specific pathogen free (SPF) fish by cohabitation with RMS-affected seeder fish. During disease development we characterize local cellular immune responses and regulations of immunologically relevant genes in skin of the cohabitants by immunohistochemistry and qPCR. Skin samples from SPF controls and cohabitants (areas with and without lesions) were taken at 18, 61, 82 and 97 days post-cohabitation. Gene expression results showed that lesions had a Th1-type profile, but with concurrent high expression levels of all three classes of immunoglobulins (IgD, IgM and IgT). The marked local infiltration of IgD + cells in the skin lesions as well as a highly up-regulated expression of the genes encoding sIgD and mIgD indicate that this immunoglobulin class plays an important role in skin immunity in general and in RMS pathology in particular. The co-occurrence of an apparent B cell dominated immune reaction with a Th1-type profile suggests that the local production of antibodies is independent of the classical Th2 pathway.


Assuntos
Doenças dos Peixes/imunologia , Imunidade Humoral/imunologia , Oncorhynchus mykiss/imunologia , Pele/imunologia , Animais , Doenças dos Peixes/microbiologia , Expressão Gênica , Imunoglobulina D/imunologia , Oncorhynchus mykiss/microbiologia , Reação em Cadeia da Polimerase em Tempo Real/veterinária , Pele/metabolismo
14.
EMBO J ; 38(11)2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31015337

RESUMO

In contrast to other B-cell antigen receptor (BCR) classes, the function of IgD BCR on mature B cells remains largely elusive as mature B cells co-express IgM, which is sufficient for development, survival, and activation of B cells. Here, we show that IgD expression is regulated by the forkhead box transcription factor FoxO1, thereby shifting the responsiveness of mature B cells towards recognition of multivalent antigen. FoxO1 is repressed by phosphoinositide 3-kinase (PI3K) signaling and requires the lipid phosphatase Pten for its activation. Consequently, Pten-deficient B cells expressing knock-ins for BCR heavy and light chain genes are unable to upregulate IgD. Furthermore, in the presence of autoantigen, Pten-deficient B cells cannot eliminate the autoreactive BCR specificity by secondary light chain gene recombination. Instead, Pten-deficient B cells downregulate BCR expression and become unresponsive to further BCR-mediated stimulation. Notably, we observed a delayed germinal center (GC) reaction by IgD-deficient B cells after immunization with trinitrophenyl-ovalbumin (TNP-Ova), a commonly used antigen for T-cell-dependent antibody responses. Together, our data suggest that the activation of IgD expression by Pten/FoxO1 results in mature B cells that are selectively responsive to multivalent antigen and are capable of initiating rapid GC reactions and T-cell-dependent antibody responses.


Assuntos
Linfócitos B/fisiologia , Centro Germinativo/fisiologia , Imunoglobulina D/genética , PTEN Fosfo-Hidrolase/fisiologia , Receptores de Antígenos de Linfócitos B/genética , Animais , Células Cultivadas , Proteína Forkhead Box O1/fisiologia , Regulação da Expressão Gênica/imunologia , Centro Germinativo/metabolismo , Imunoglobulina D/imunologia , Imunoglobulina D/metabolismo , Camundongos , Camundongos Transgênicos , PTEN Fosfo-Hidrolase/genética , Receptores de Antígenos de Linfócitos B/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/imunologia
15.
Nat Commun ; 10(1): 1126, 2019 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-30850611

RESUMO

Respiratory syncytial virus (RSV) is a leading cause of hospitalization in infants and young children. Although it is widely agreed that an RSV vaccine should induce both mucosal and systemic antibody responses, little is known about the B cell response to RSV in mucosa-associated lymphoid tissues. Here, we analyze this response by isolating 806 RSV F-specific antibodies from paired adenoid and peripheral blood samples from 4 young children. Overall, the adenoid-derived antibodies show higher binding affinities and neutralization potencies compared to antibodies isolated from peripheral blood. Approximately 25% of the neutralizing antibodies isolated from adenoids originate from a unique population of IgM+ and/or IgD+ memory B cells that contain a high load of somatic mutations but lack expression of classical memory B cell markers. Altogether, the results provide insight into the local B cell response to RSV and have implications for the development of vaccines that stimulate potent mucosal responses.


Assuntos
Tonsila Faríngea/imunologia , Anticorpos Neutralizantes/biossíntese , Anticorpos Antivirais/biossíntese , Linfócitos B/imunologia , Imunidade nas Mucosas , Leucócitos Mononucleares/imunologia , Vírus Sincicial Respiratório Humano/imunologia , Tonsila Faríngea/virologia , Afinidade de Anticorpos , Especificidade de Anticorpos , Linfócitos B/virologia , Biomarcadores/metabolismo , Pré-Escolar , Clonagem Molecular , Feminino , Expressão Gênica , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Humanos , Imunoglobulina D/biossíntese , Imunoglobulina M/biossíntese , Leucócitos Mononucleares/virologia , Masculino , Mutação , Especificidade de Órgãos , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/imunologia , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo
16.
Parasit Vectors ; 12(1): 119, 2019 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-30909975

RESUMO

BACKGROUND: Canine leishmaniosis (CanL) due to Leishmania infantum is characterized by the development of both cellular and humoral immune responses. The dysfunction of T cell-mediated immunity leads to a lack of proliferation of T cells in response to Leishmania antigens with the consequence of parasite dissemination that seems to be related to a T cell exhaustion mediated by regulatory B cells expressing immunoglobulin D (IgD). The aim of this study was to determine and compare the total serum IgD in dogs with clinical leishmaniosis and in clinically healthy dogs. RESULTS: A total of 147 dog sera were studied. All dogs were tested for L. infantum-specific antibodies by quantitative ELISA. Interferon-gamma (IFN-γ) production was also determined by sandwich ELISA after blood stimulation with L. infantum soluble antigen (LSA) or concanavalin A (ConA). The quantification of total IgD was performed using a human IgD sandwich ELISA quantification set. Dogs were classified in three different groups. Group 1 included 40 clinically healthy non-infected dogs, all serologically negative to L. infantum-specific antibodies and non-producers of IFN-γ upon LSA stimulation. Group 2 included 63 clinically healthy infected dogs that were LSA IFN-γ producers (n = 61) and/or IFN-γ non-producers (n = 2) as well as negative to medium seropositive to L. infantum antigen. Finally, Group 3 included 44 dogs with clinical leishmaniosis (IFN-γ producers, n = 23; and IFN-γ non-producers, n = 21) that were negative to highly positive to L. infantum-specific antibodies. No significant differences were observed when the total IgD concentration was compared within groups. Additionally, total IgD of sick IFN-γ producers and IFN-γ non-producers was not significantly different. Finally, total IgD concentration was not statistically related to demographic parameters such as age, sex and breed. CONCLUSIONS: The results of this study demonstrated that there were no differences between groups in total serum IgD. Total serum IgD does not appear to be a marker of disease in CanL.


Assuntos
Anticorpos Antiprotozoários/sangue , Doenças do Cão/parasitologia , Imunoglobulina D/imunologia , Leishmania infantum/imunologia , Leishmaniose Visceral/veterinária , Animais , Anticorpos Antiprotozoários/imunologia , Doenças do Cão/sangue , Doenças do Cão/imunologia , Cães , Ensaio de Imunoadsorção Enzimática/veterinária , Feminino , Imunoglobulina D/sangue , Leishmaniose Visceral/imunologia , Leishmaniose Visceral/parasitologia , Masculino , Estudos Retrospectivos
17.
Ann Biol Clin (Paris) ; 77(1): 107-111, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30799291

RESUMO

Immunoglobulin D multiple myeloma (IgD MM) is a rare entity of monoclonal gammopathies. We report the case of a IgD MM, associated with excessive excretion of lambda free light chains (FLL λ) diagnosed and managed at the University Hospital Mohammed VI of Marrakech among an adult hospitalized in the hematology department for bone pain and alteration of the general condition. Indeed, IgD MM is characterized by its clinical severity and poor prognosis. The discretion or absence of a monoclonal peak in the electrophoresis of serum proteins makes detection difficult. The present case demonstrates that IgD MM may be associated with excessive production of CLL and may therefore be erroneously diagnosed as CLL MM. Knowledge of this rare subtype of MM and its epidemiological, clinical and especially biological characteristics is crucial for establishing the correct diagnosis.


Assuntos
Imunoglobulina D/sangue , Cadeias Leves de Imunoglobulina/sangue , Cadeias lambda de Imunoglobulina/sangue , Mieloma Múltiplo/sangue , Mieloma Múltiplo/diagnóstico , Paraproteinemias/diagnóstico , Diagnóstico Diferencial , Humanos , Masculino , Pessoa de Meia-Idade , Paraproteinemias/sangue
18.
Nat Commun ; 10(1): 190, 2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-30643147

RESUMO

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


Assuntos
Subpopulações de Linfócitos B/imunologia , Dermatite de Contato/imunologia , Regulação da Expressão Gênica no Desenvolvimento/imunologia , Tolerância Imunológica , Linfócitos T Reguladores/imunologia , Animais , Subpopulações de Linfócitos B/metabolismo , Separação Celular/métodos , Células Cultivadas , Técnicas de Cocultura , Modelos Animais de Doenças , Citometria de Fluxo/métodos , Perfilação da Expressão Gênica , Voluntários Saudáveis , Humanos , Imunoglobulina D/metabolismo , Leucócitos Mononucleares , Camundongos , Camundongos Endogâmicos C57BL , Oxazolona/imunologia , Baço/citologia , Baço/crescimento & desenvolvimento , Baço/imunologia , Linfócitos T Reguladores/metabolismo , Fatores de Necrose Tumoral/imunologia , Fatores de Necrose Tumoral/metabolismo
19.
Ann Hematol ; 98(4): 963-970, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30610280

RESUMO

Immunoglobulin D (IgD) myeloma is a rare subtype that used to lead to a poor outcome. To investigate the current clinical features, cytogenetic changes and survival of patients with IgD myeloma under novel treatments, we analysed 47 patients with IgD myeloma, 31 men and 16 women, with a median age of 54.5 years. We found that IgD myeloma was associated with higher frequencies of anaemia, renal failure, and hypercalcemia and higher levels of serum LDH compared with non-IgD myeloma. More than 90% of patients with IgD myeloma had at least one cytogenetic abnormality demonstrated by fluorescence in situ hybridisation (FISH). IGH translocations were the most common abnormalities, which were mainly caused by t(11;14). Moreover, 36.2% of patients were at the Revised International Staging System (RISS) stage III when diagnosed. Those patients had significantly shorter PFS and OS compared with patients at RISS stages I and II. In conclusion, IgD myeloma has specific clinical characteristics. The RISS grade was shown to be a simple and effective method to predict the prognosis of patients with IgD myeloma.


Assuntos
Cromossomos Humanos/genética , Imunoglobulina D , Mieloma Múltiplo , Proteínas de Neoplasias , Translocação Genética , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Imunoglobulina D/sangue , Imunoglobulina D/genética , Cadeias Pesadas de Imunoglobulinas , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Mieloma Múltiplo/genética , Mieloma Múltiplo/mortalidade , Proteínas de Neoplasias/sangue , Proteínas de Neoplasias/genética , Taxa de Sobrevida
20.
Vaccine ; 37(1): 176-186, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30054160

RESUMO

BACKGROUND: We assessed 2 investigational 11- and 12-valent vaccines, containing capsular polysaccharides of 10 serotypes as in the pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) and CRM197-conjugated capsular polysaccharides of serotypes 19A (11-valent) or 19A and 6A (12-valent). METHODS: In this phase II, partially-blind, multicentre study (NCT01204658), healthy infants were randomised (1:1:1:1) to receive 11vPHiD-CV, 12vPHiD-CV, PHiD-CV, or 13-valent CRM197-conjugate pneumococcal vaccine (PCV13), at 2, 3, and 4 (primary series), and 12-15 months of age (booster dose), co-administered with DTPa-HBV-IPV/Hib. Confirmatory objectives assessed non-inferiority of investigational vaccines to comparators (PHiD-CV for common serotypes; PCV13 for 19A and 6A), in terms of percentage of infants with pneumococcal antibody concentrations ≥0.2 µg/mL and antibody geometric mean concentrations, post-primary vaccination. Reactogenicity and safety were assessed. RESULTS: 951 children received ≥1 primary dose, 919 a booster dose. Pre-defined immunological non-inferiority criteria were met simultaneously for 9/11 11vPHiD-CV serotypes (all except 23F and 19A) and 10/12 12vPHiD-CV serotypes (all except 19A and 6A); thus, non-inferiority objectives were reached. For each PHiD-CV serotype, percentages of children with antibody concentrations ≥0.2 µg/mL were ≥96.7% post-primary (except 6B [≥75.2%] and 23F [≥81.1%]), and ≥98.1% post-booster vaccination. For each PHiD-CV serotype except serotype 1, ≥81.0% and ≥93.9% of children had opsonophagocytic activity titres ≥8, post-primary and booster vaccination. AEs incidence was similar across all groups. SAEs were reported for 117 children (29 in the 11vPHiD-CV group, 26 in the 12vPHiD-CV group, 38 in the PHiD-CV group and 24 in the PCV13 group); 4 SAEs were considered vaccination-related. No fatal events were recorded. CONCLUSION: Addition of 19A and 6A CRM197-conjugates did not alter immunogenicity of the PHiD-CV conjugates; for both investigational vaccines post-booster immune responses to 10 common serotypes appeared similar to those elicited by PHiD-CV. Safety and reactogenicity profiles of the investigational vaccines were comparable to PHiD-CV. Clinical trial registry: NCT01204658.


Assuntos
Anticorpos Antibacterianos/sangue , Proteínas de Bactérias/imunologia , Proteínas de Transporte/imunologia , Imunogenicidade da Vacina , Imunoglobulina D/imunologia , Lipoproteínas/imunologia , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas/imunologia , Proteínas de Bactérias/genética , Proteínas de Transporte/genética , Vacina contra Difteria, Tétano e Coqueluche/administração & dosagem , Feminino , Haemophilus influenzae , Vacinas contra Hepatite B/administração & dosagem , Humanos , Imunização Secundária , Imunoglobulina D/genética , Lactente , Lipoproteínas/genética , Masculino , Infecções Pneumocócicas/imunologia , Vacinas Pneumocócicas/efeitos adversos , Vacina Antipólio de Vírus Inativado/administração & dosagem , Sorogrupo , Streptococcus pneumoniae , Vacinas Combinadas/administração & dosagem , Vacinas Conjugadas/efeitos adversos , Vacinas Conjugadas/imunologia
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