Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 19 de 19
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Exp Med ; 218(12)2021 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-34623376

RESUMO

Broadly protective vaccines against SARS-related coronaviruses that may cause future outbreaks are urgently needed. The SARS-CoV-2 spike receptor-binding domain (RBD) comprises two regions, the core-RBD and the receptor-binding motif (RBM); the former is structurally conserved between SARS-CoV-2 and SARS-CoV. Here, in order to elicit humoral responses to the more conserved core-RBD, we introduced N-linked glycans onto RBM surfaces of the SARS-CoV-2 RBD and used them as immunogens in a mouse model. We found that glycan addition elicited higher proportions of the core-RBD-specific germinal center (GC) B cells and antibody responses, thereby manifesting significant neutralizing activity for SARS-CoV, SARS-CoV-2, and the bat WIV1-CoV. These results have implications for the design of SARS-like virus vaccines.

2.
Immunity ; 2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34508662

RESUMO

Potent neutralizing SARS-CoV-2 antibodies often target the spike protein receptor-binding site (RBS), but the variability of RBS epitopes hampers broad neutralization of multiple sarbecoviruses and drifted viruses. Here, using humanized mice, we identified an RBS antibody with a germline VH gene that potently neutralized SARS-related coronaviruses, including SARS-CoV and SARS-CoV-2 variants. X-ray crystallography revealed coordinated recognition by the heavy chain of non-RBS conserved sites and the light chain of RBS with a binding angle mimicking the angiotensin-converting enzyme 2 (ACE2) receptor. The minimum footprints in the hypervariable region of RBS contributed to the breadth of neutralization, which was enhanced by immunoglobulin G3 (IgG3) class switching. The coordinated binding resulted in broad neutralization of SARS-CoV and emerging SARS-CoV-2 variants of concern. Low-dose therapeutic antibody treatment in hamsters reduced the virus titers and morbidity during SARS-CoV-2 challenge. The structural basis for broad neutralizing activity may inform the design of a broad spectrum of therapeutics and vaccines.

3.
Immunity ; 54(8): 1841-1852.e4, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34246326

RESUMO

Antibody titers against SARS-CoV-2 slowly wane over time. Here, we examined how time affects antibody potency. To assess the impact of antibody maturation on durable neutralizing activity against original SARS-CoV-2 and emerging variants of concern (VOCs), we analyzed receptor binding domain (RBD)-specific IgG antibodies in convalescent plasma taken 1-10 months after SARS-CoV-2 infection. Longitudinal evaluation of total RBD IgG and neutralizing antibody revealed declining total antibody titers but improved neutralization potency per antibody to original SARS-CoV-2, indicative of antibody response maturation. Neutralization assays with authentic viruses revealed that early antibodies capable of neutralizing original SARS-CoV-2 had limited reactivity toward B.1.351 (501Y.V2) and P.1 (501Y.V3) variants. Antibodies from late convalescents exhibited increased neutralization potency to VOCs, suggesting persistence of cross-neutralizing antibodies in plasma. Thus, maturation of the antibody response to SARS-CoV-2 potentiates cross-neutralizing ability to circulating variants, suggesting that declining antibody titers may not be indicative of declining protection.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/imunologia , COVID-19/virologia , SARS-CoV-2/imunologia , Anticorpos Monoclonais/imunologia , Especificidade de Anticorpos , COVID-19/epidemiologia , Humanos , Imunoglobulina G , Testes de Neutralização , SARS-CoV-2/genética , Carga Viral
4.
Commun Biol ; 4(1): 820, 2021 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-34188173

RESUMO

Host lipid metabolism and viral responses are intimately connected. However, the process by which the acquired immune systems adapts lipid metabolism to meet demands, and whether or not the metabolic rewiring confers a selective advantage to host immunity, remains unclear. Here we show that viral infection attenuates the expression of genes related to lipid metabolism in murine CD4+ T cells, which in turn increases the expression of antiviral genes. Inhibition of the fatty acid synthesis pathway substantially increases the basal expression of antiviral genes via the spontaneous production of type I interferon (IFN). Using a combination of CRISPR/Cas9-mediated genome editing technology and a global lipidomics analysis, we found that the decrease in monounsaturated fatty acid caused by genetic deletion of Scd2 in mice was crucial for the induction of an antiviral response through activation of the cGAS-STING pathway. These findings demonstrate the important relationship between fatty acid biosynthesis and type I IFN responses that enhances the antiviral response.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Ácidos Graxos Monoinsaturados/metabolismo , Interferon Tipo I/farmacologia , Proteínas de Membrana/fisiologia , Nucleotidiltransferases/fisiologia , Estearoil-CoA Dessaturase/fisiologia , Viroses/imunologia , Animais , Interações Hospedeiro-Patógeno , Metabolismo dos Lipídeos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Transdução de Sinais , Viroses/metabolismo
5.
HLA ; 98(1): 37-42, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33734601

RESUMO

HLA-A, -C, -B, and -DRB1 genotypes were analyzed in 178 Japanese COVID-19 patients to investigate the association of HLA with severe COVID-19. Analysis of 32 common HLA alleles at four loci revealed a significant association between HLA-DRB1*09:01 and severe COVID-19 (odds ratio [OR], 3.62; 95% CI, 1.57-8.35; p = 0.00251 [permutation p value = 0.0418]) when age, sex, and other common HLA alleles at the DRB1 locus were adjusted. The DRB1*09:01 allele was more significantly associated with risk for severe COVID-19 compared to preexisting medical conditions such as hypertension, diabetes, and cardiovascular diseases. These results indicate a potential role for HLA in predisposition to severe COVID-19.


Assuntos
COVID-19 , Cadeias HLA-DRB1 , Alelos , COVID-19/diagnóstico , COVID-19/genética , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Cadeias HLA-DRB1/genética , Humanos
6.
Int Immunol ; 33(4): 241-247, 2021 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-33538817

RESUMO

An expanded myeloid cell compartment is a hallmark of severe coronavirus disease 2019 (COVID-19). However, data regarding myeloid cell expansion have been collected in Europe, where the mortality rate by COVID-19 is greater than those in other regions including Japan. Thus, characteristics of COVID-19-induced myeloid cell subsets remain largely unknown in the regions with low mortality rates. Here, we analyzed cellular dynamics of myeloid-derived suppressor cell (MDSC) subsets and examined whether any of them correlate with disease severity and prognosis, using blood samples from Japanese COVID-19 patients. We observed that polymorphonuclear (PMN)-MDSCs, but not other MDSC subsets, transiently expanded in severe cases but not in mild or moderate cases. Contrary to previous studies in Europe, this subset selectively expanded in survivors of severe cases and subsided before discharge, but such transient expansion was not observed in non-survivors in Japanese cohort. Analysis of plasma cytokine/chemokine levels revealed positive correlation of PMN-MDSC frequencies with IL-8 levels, indicating the involvement of IL-8 on recruitment of PMN-MDSCs to peripheral blood following the onset of severe COVID-19. Our data indicate that transient expansion of the PMN-MDSC subset results in improved clinical outcome. Thus, this myeloid cell subset may be a predictor of prognosis in cases of severe COVID-19 in Japan.


Assuntos
COVID-19/patologia , Interleucina-8/sangue , Células Supressoras Mieloides/imunologia , Neutrófilos/imunologia , SARS-CoV-2/imunologia , Humanos , Interleucina-8/imunologia , Japão , Contagem de Leucócitos , Células Mieloides/imunologia , Ativação de Neutrófilo/imunologia
7.
J Virol ; 2020 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-33298539

RESUMO

Hepatitis B virus (HBV) infection is a major public health problem. Human hepatocytes are infected with HBV via binding between the preS1 region in the large envelope protein of HBV and sodium taurocholate cotransporting polypeptide. Although several monoclonal antibodies (MAbs) that recognize the receptor binding domain in preS1 and neutralize HBV infection have been isolated, details of neutralizing epitopes are not understood. In this study, we generated 13 MAbs targeting the preS1 receptor binding domain from preS1-specific memory B cells derived from DNA immunized mice. The MAbs were classified into three groups according to the epitope regions, designated epitopes I-III. A virus neutralization assay revealed that MAbs recognizing epitopes I and III neutralized HBV infection, suggesting that these domains are critical epitopes for viral neutralization. In addition, a neutralization assay against multiple genotypes of HBV revealed that epitope I is a semi-pangenotypic neutralizing epitope, whereas epitope III is a genotype-specific epitope. We also showed that neutralizing MAbs against preS1 could neutralize HBV bearing vaccine-induced escape mutation. These findings provide insight into novel immunoprophylaxis for the prevention and treatment of HBV infection.IMPORTANCE The HBV preS1 2-47 aa region (preS1/2-47) is essential for virus binding with sodium taurocholate cotransporting polypeptide. Several MAbs targeting preS1/2-47 have been reported to neutralize HBV infection; however, which region in preS1/2-47 contains the critical neutralizing epitope for HBV infection is unclear. Here, we generated several MAbs targeting preS1/2-47 and found that MAbs recognizing the N- or C-terminus of preS1/2-47 remarkably neutralized HBV infection. We further confirmed the neutralizing activity of anti-preS1 MAbs against HBV with vaccine escape mutation. These data clarified the relationship between the antibody epitope and the virus neutralizing activity and also suggested the potential ability of a vaccine antigen containing the preS1 region to overcome the weakness of current HB vaccines comprising the small S protein.

8.
J Immunol ; 203(12): 3282-3292, 2019 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-31704880

RESUMO

Virus-like particles (VLPs) provide a well-established vaccine platform; however, the immunogenic properties acquired by VLP structure remain poorly understood. In this study, we showed that systemic vaccination with norovirus VLP recalls human IgA responses at higher magnitudes than IgG responses under a humanized mouse model that was established by introducing human PBMCs in severely immunodeficient mice. The recall responses elicited by VLP vaccines depended on VLP structure and the disruption of VLP attenuated recall responses, with a more profound reduction being observed in IgA responses. The IgA-focusing property was also conserved in a murine norovirus-primed model under which murine IgA responses were recalled in a manner dependent on VLP structure. Importantly, the VLP-driven IgA response preferentially targeted virus-neutralizing epitopes located in the receptor-binding domain. Consequently, VLP-driven IgA responses were qualitatively superior to IgG responses in terms of the virus-neutralizing activity in vitro. Furthermore, the IgA in mucosa obtained remarkable protective function toward orally administrated virus in vivo. Thus, our results indicate the immune-focusing properties of the VLP vaccine that improve the quality/quantity of mucosal IgA responses, a finding with important implications for developing mucosal vaccines.


Assuntos
Anticorpos Antivirais/imunologia , Imunoglobulina A/imunologia , Vacinas de Partículas Semelhantes a Vírus/imunologia , Animais , Formação de Anticorpos/imunologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Infecções por Caliciviridae/prevenção & controle , Humanos , Imunidade nas Mucosas , Switching de Imunoglobulina/genética , Switching de Imunoglobulina/imunologia , Imunoglobulina G/imunologia , Memória Imunológica , Camundongos , Camundongos Transgênicos , Norovirus/imunologia
9.
Cell ; 177(5): 1124-1135.e16, 2019 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-31100267

RESUMO

Vaccines to generate durable humoral immunity against antigenically evolving pathogens such as the influenza virus must elicit antibodies that recognize conserved epitopes. Analysis of single memory B cells from immunized human donors has led us to characterize a previously unrecognized epitope of influenza hemagglutinin (HA) that is immunogenic in humans and conserved among influenza subtypes. Structures show that an unrelated antibody from a participant in an experimental infection protocol recognized the epitope as well. IgGs specific for this antigenic determinant do not block viral infection in vitro, but passive administration to mice affords robust IgG subtype-dependent protection against influenza infection. The epitope, occluded in the pre-fusion form of HA, is at the contact surface between HA head domains; reversible molecular "breathing" of the HA trimer can expose the interface to antibody and B cells. Antigens that present this broadly immunogenic HA epitope may be good candidates for inclusion in "universal" flu vaccines.


Assuntos
Anticorpos Antivirais/imunologia , Epitopos/imunologia , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Imunoglobulina G/imunologia , Vírus da Influenza A/imunologia , Vacinas contra Influenza/imunologia , Infecções por Orthomyxoviridae , Adulto , Animais , Cães , Feminino , Humanos , Células Madin Darby de Rim Canino , Masculino , Camundongos , Pessoa de Meia-Idade , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/patologia , Infecções por Orthomyxoviridae/prevenção & controle
10.
Cell Host Microbe ; 25(6): 827-835.e6, 2019 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-31104946

RESUMO

Viral glycoproteins are under constant immune surveillance by a host's adaptive immune responses. Antigenic variation including glycan introduction or removal is among the mechanisms viruses have evolved to escape host immunity. Understanding how glycosylation affects immunodominance on complex protein antigens may help decipher underlying B cell biology. To determine how B cell responses can be altered by such modifications, we engineered glycans onto the influenza virus hemagglutinin (HA) and characterized the molecular features of the elicited humoral immunity in mice. We found that glycan addition changed the initially diverse antibody repertoire into an epitope-focused, genetically restricted response. Structural analyses showed that one antibody gene family targeted a previously subdominant, occluded epitope at the head interface. Passive transfer of this antibody conferred Fc-dependent protection to influenza virus-challenged mice. These results have potential implications for next-generation viral vaccines aimed at directing B cell responses to preferred epitope(s).


Assuntos
Anticorpos Antivirais/imunologia , Epitopos/imunologia , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Vírus da Influenza A Subtipo H3N2/imunologia , Polissacarídeos/metabolismo , Animais , Anticorpos Antivirais/metabolismo , Cristalografia por Raios X , Epitopos/química , Epitopos/genética , Epitopos/metabolismo , Glicosilação , Glicoproteínas de Hemaglutininação de Vírus da Influenza/química , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Glicoproteínas de Hemaglutininação de Vírus da Influenza/metabolismo , Imunização Passiva , Vírus da Influenza A Subtipo H3N2/genética , Camundongos Endogâmicos BALB C , Infecções por Orthomyxoviridae/prevenção & controle , Ligação Proteica , Conformação Proteica , Análise de Sobrevida
11.
Viral Immunol ; 30(6): 431-437, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28661720

RESUMO

Adaptive B cell response is a key arm of protective immunity against influenza viruses. Owing to the acutely infectious and cytopathic nature of these viruses, efficient containment of viral spread relies on the prompt provision of protective antibodies to the site of virus infection, the respiratory tract (RT). To accelerate the protective antibody response, B cell responses can be ectopically induced, maintained, and reactivated in the lungs after primary and secondary infection, thereby providing an anatomical advantage in supplying neutralizing antibodies against reinfecting viruses with faster kinetics. However, the prompt supply of protective antibodies may be insufficient to protect against reinfection because influenza viruses can easily change their antigenic profiles to escape antibody surveillance. B cell responses have multiple strategies for adjusting antibody repertoires according to viral fitness, one of which is the formation of local germinal centers capable of selecting B cell repertoires for antigenically subdominant, but conserved, epitopes. In this review, we discuss several unique aspects of B cell responses that take place at local sites to combat acutely infectious and rapidly mutating influenza viruses.


Assuntos
Imunidade Adaptativa , Linfócitos B/imunologia , Influenza Humana/imunologia , Pulmão/imunologia , Infecções por Orthomyxoviridae/imunologia , Orthomyxoviridae/imunologia , Animais , Humanos , Influenza Humana/virologia , Infecções por Orthomyxoviridae/virologia
12.
J Immunol ; 196(10): 4172-84, 2016 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-27053762

RESUMO

Inactivated influenza vaccines have two formulations, whole- and split-virion types; however, how differential formulations impact their booster effects remain unknown. In this study, we demonstrate that whole-virion vaccines recall two waves of Ab responses, early T cell-independent (TI) and late T cell-dependent responses, whereas split-virion vaccines elicit the late T cell-dependent response only. Notably, higher-affinity Abs with improved neutralizing activity are provided from the early TI response, which emphasizes the important contribution of the formulation-dependent response in the protective immunity. Moreover, we show that the early TI response completely requires B cell-intrinsic TLR7 signaling, which can be delivered through viral RNAs within whole-virion vaccine. Thus, our results indicate that TLR agonists in whole-virion type improve recall Ab responses by directly targeting memory B cells, a finding with important implications for vaccine strategies aimed at the prompt recall of high-affinity neutralizing Abs.


Assuntos
Linfócitos B/imunologia , Vacinas contra Influenza/imunologia , RNA Viral/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Vírion/imunologia , Animais , Anticorpos Antivirais/metabolismo , Afinidade de Anticorpos , Linfócitos B/transplante , Células Cultivadas , Humanos , Imunidade Humoral , Memória Imunológica , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais , Receptor 7 Toll-Like/genética , Receptor 7 Toll-Like/metabolismo , Vacinação
13.
J Exp Med ; 212(10): 1709-23, 2015 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-26324444

RESUMO

Respiratory influenza virus infection induces cross-reactive memory B cells targeting invariant regions of viral escape mutants. However, cellular events dictating the cross-reactive memory B cell responses remain to be fully defined. Here, we demonstrated that lung-resident memory compartments at the site of infection, rather than those in secondary lymphoid organs, harbor elevated frequencies of cross-reactive B cells that mediate neutralizing antibody responses to viral escape. The elevated cross-reactivity in the lung memory compartments was correlated with high numbers of VH mutations and was dependent on a developmental pathway involving persistent germinal center (GC) responses. The persistent GC responses were focused in the infected lungs in association with prolonged persistence of the viral antigens. Moreover, the persistent lung GCs supported the exaggerated B cell proliferation and clonal selection for cross-reactive repertoires, which served as the predominant sites for the generation of cross-reactive memory progenitors. Thus, we identified the distinct GC selection at local sites as a key cellular event for cross-reactive memory B cell response to viral escape, a finding with important implications for developing broadly protective influenza vaccines.


Assuntos
Linfócitos B/imunologia , Centro Germinativo/imunologia , Memória Imunológica , Infecções por Orthomyxoviridae/imunologia , Animais , Linfócitos B/virologia , Reações Cruzadas , Imunoglobulina G/imunologia , Vírus da Influenza A/patogenicidade , Pulmão/imunologia , Pulmão/virologia , Camundongos Endogâmicos BALB C , Dados de Sequência Molecular , Mutação , Anticorpos de Domínio Único/genética , Anticorpos de Domínio Único/imunologia
14.
J Virol ; 88(21): 12364-73, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25122788

RESUMO

UNLABELLED: We determined the antigenic structure of pandemic influenza A(H1N1)pdm09 virus hemagglutinin (HA) using 599 escape mutants that were selected using 16 anti-HA monoclonal antibodies (MAbs) against A/Narita/1/2009. The sequencing of mutant HA genes revealed 43 amino acid substitutions at 24 positions in three antigenic sites, Sa, Sb, and Ca2, which were previously mapped onto A/Puerto Rico/8/34 (A/PR/8/34) HA (A. J. Caton, G. G. Brownlee, J. W. Yewdell, and W. Gerhard, Cell 31:417-427, 1982), and an undesignated site, i.e., amino acid residues 141, 142, 143, 171, 172, 174, 177, and 180 in the Sa site, residues 170, 173, 202, 206, 210, 211, and 212 in the Sb site, residues 151, 154, 156, 157, 158, 159, 200, and 238 in the Ca2 site, and residue 147 in the undesignated site (numbering begins at the first methionine). Sixteen MAbs were classified into four groups based on their cross-reactivity with the panel of escape mutants in the hemagglutination inhibition test. Among them, six MAbs targeting the Sa and Sb sites recognized both residues at positions 172 and 173. MAb n2 lost reactivity when mutations were introduced at positions 147, 159 (site Ca2), 170 (site Sb), and 172 (site Sa). We designated the site consisting of these residues as site Pa. From 2009 to 2013, no antigenic drift was detected for the A(H1N1)pdm09 viruses. However, if a novel variant carrying a mutation at a position involved in the epitopes of several MAbs, such as 172, appeared, such a virus would have the advantage of becoming a drift strain. IMPORTANCE: The first influenza pandemic of the 21st century occurred in 2009 with the emergence of a novel virus originating with swine influenza, A(H1N1)pdm09. Although HA of A(H1N1)pdm09 has a common origin (1918 H1N1) with seasonal H1N1, the antigenic divergence of HA between the seasonal H1N1 and A(H1N1)pdm09 viruses gave rise to the influenza pandemic in 2009. To take precautions against the antigenic drift of the A(H1N1)pdm09 virus in the near future, it is important to identify its precise antigenic structure. To obtain various mutants that are not neutralized by MAbs, it is important to neutralize several plaque-cloned parent viruses rather than only a single parent virus. We characterized 599 escape mutants that were obtained by neutralizing four parent viruses of A(H1N1)pdm09 in the presence of 16 MAbs. Consequently, we were able to determine the details of the antigenic structure of HA, including a novel epitope.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Antivirais/imunologia , Mapeamento de Epitopos/métodos , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Vírus da Influenza A Subtipo H1N1/imunologia , Animais , Testes de Inibição da Hemaglutinação , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Vírus da Influenza A Subtipo H1N1/genética , Camundongos Endogâmicos BALB C , Dados de Sequência Molecular , Proteínas Mutantes/genética , Proteínas Mutantes/imunologia , RNA Viral/genética , Seleção Genética , Análise de Sequência de DNA , Cultura de Vírus
15.
Infect Disord Drug Targets ; 12(3): 232-40, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22394179

RESUMO

Viruses form particulate structures possessing high-density B-cell epitopes and viral RNA/DNA, which are ligands for multiple Toll-like receptors (TLRs). B cells are able to sense these viral antigenic signatures through B-cell antigen receptors (BCRs) and TLRs, both of which synergistically shape the magnitude and quality of virus-specific B-cell responses. In many viruses, B-cell recognition of these virus signatures is often hampered by tissue tropisms toward nonlymphoid organs. However, ectopic localizations of B cells at virus replication sites facilitate the efficient recognition of intact virus particles. Following pulmonary infection by influenza virus, virus-specific B-cell responses occur in the tertiary lymphoid organs of lungs near the sites of virus replication as well as in the draining lymph nodes. Lungs then begin to support the germinal center response and the formation of niches for plasma cells and memory B cells, thus potentiating B-cell intrinsic recognition of virus particles at these sites. In this review, we discuss how the anatomical location and virus- sensing properties of B cells coordinate protective B-cell responses against pulmonary virus infection.


Assuntos
Linfócitos B/imunologia , Pneumopatias/imunologia , Viroses/imunologia , Animais , DNA Viral/metabolismo , Humanos , Influenza Humana/imunologia , Influenza Humana/virologia , Pneumopatias/virologia , Linfonodos/imunologia , RNA Viral/metabolismo , Receptores de Antígenos de Linfócitos B , Receptores Toll-Like/imunologia , Viroses/virologia , Replicação Viral/imunologia
16.
Proc Natl Acad Sci U S A ; 109(7): 2485-90, 2012 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-22308386

RESUMO

After pulmonary virus infection, virus-binding B cells ectopically accumulate in the lung. However, their contribution to protective immunity against reinfecting viruses remains unknown. Here, we show the phenotypes and protective functions of virus-binding memory B cells that persist in the lung following pulmonary infection with influenza virus. A fraction of virus-binding B-cell population in the lung expressed surface markers for splenic mature memory B cells (CD73, CD80, and CD273) along with CD69 and CXCR3 that are up-regulated on lung effector/memory T cells. The lung B-cell population with memory phenotype persisted for more than 5 mo after infection, and on reinfection promptly differentiated into plasma cells that produced virus-neutralizing antibodies locally. This production of local IgG and IgA neutralizing antibody was correlated with reduced virus spread in adapted hosts. Our data demonstrates that infected lungs harbor a memory B-cell subset with distinctive phenotype and ability to provide protection against pulmonary virus reinfection.


Assuntos
Formação de Anticorpos , Linfócitos B/imunologia , Memória Imunológica , Influenza Humana/imunologia , Pneumopatias/imunologia , Pulmão/imunologia , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Humanos , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Pulmão/citologia
17.
PLoS One ; 5(1): e8815, 2010 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-20098688

RESUMO

IgG-containing B cell antigen receptor (IgG-BCR), the BCR mostly expressed on memory B cells, contains a distinct signaling function from IgM-BCR or IgD-BCR expressed on naïve B cells. Because naïve B cells transgenic for IgG exhibit augmented response to antigens similar to memory B cells, the distinct signaling function of IgG-BCR appears to play a role in augmented antibody responses of memory B cells. However, how IgG-BCR signaling augments B cell responses is not yet well understood. Here we demonstrate that B cells from IgG-transgenic mice are anergic with defect in generation of BCR signaling upon BCR ligation. However, these IgG-transgenic B cells generate markedly augmented antibody response to a T cell-dependent antigen, probably due to hyper-responsiveness to a T cell-derived signal through CD40. Both BCR signaling defect and augmented response to CD40 ligation are partially restored in xid IgG-transgenic mice in which BCR signaling is down-modulated due to a loss-of-function mutation in the tyrosine kinase Btk crucial for BCR signaling. Thus, IgG-BCR induces augmented B cell responses in the absence of antigen-induced BCR signaling probably through high ligand-independent BCR signaling that may "idle" B cells to make them ready to respond to T cell help. This finding strongly suggests a crucial role of ligand-independent signaling in receptor function.


Assuntos
Antígenos/imunologia , Linfócitos B/imunologia , Imunoglobulina G/imunologia , Transdução de Sinais , Tirosina Quinase da Agamaglobulinemia , Animais , Anergia Clonal , Imunoglobulina G/genética , Camundongos , Camundongos Transgênicos , Proteínas Tirosina Quinases/genética
18.
J Immunol ; 180(2): 907-13, 2008 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-18178830

RESUMO

Because pathogens induce infectious symptoms in a time-dependent manner, a rapid immune response is beneficial for defending hosts from pathogens, especially those inducing acute infectious diseases. However, it is largely unknown how the time course of immune responses is regulated. In this study, we demonstrate that B cells deficient in the inhibitory coreceptor CD22 undergo accelerated cell division after Ag stimulation, resulting in rapid generation of plasma cells and Ab production. This finding indicates that CD22 regulates the time course of B cell responses and suggests that CD22 is a good target to shorten the time required for Ab production, thereby augmenting host defense against acute infectious diseases as "universal vaccination."


Assuntos
Formação de Anticorpos/genética , Linfócitos B/imunologia , Divisão Celular/genética , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/fisiologia , Animais , Antígenos/imunologia , Antígenos/farmacologia , Linfócitos B/citologia , Linfócitos B/efeitos dos fármacos , Ativação Linfocitária/genética , Camundongos , Camundongos Mutantes , Plasmócitos/imunologia , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...