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1.
Annu Rev Immunol ; 35: 285-311, 2017 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-28446061

RESUMO

IgG antibodies mediate a diversity of immune functions by coupling of antigen specificity through the Fab domain to signal transduction via Fc-Fc receptor interactions. Indeed, balanced IgG signaling through type I and type II Fc receptors is required for the control of proinflammatory, anti-inflammatory, and immunomodulatory processes. In this review, we discuss the mechanisms that govern IgG-Fc receptor interactions, highlighting the diversity of Fc receptor-mediated effector functions that regulate immunity and inflammation as well as determine susceptibility to infection and autoimmunity and responsiveness to antibody-based therapeutics and vaccines.


Assuntos
Anticorpos/uso terapêutico , Doenças Autoimunes/imunologia , Imunoglobulina G/metabolismo , Imunoterapia/métodos , Infecções/imunologia , Receptores Fc/metabolismo , Animais , Doenças Autoimunes/terapia , Suscetibilidade a Doenças , Humanos , Imunidade Humoral , Infecções/terapia , Inflamação , Transdução de Sinais
2.
Cell ; 187(17): 4790-4811.e22, 2024 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-39047727

RESUMO

Characterizing the compositional and phenotypic characteristics of tumor-infiltrating B cells (TIBs) is important for advancing our understanding of their role in cancer development. Here, we establish a comprehensive resource of human B cells by integrating single-cell RNA sequencing data of B cells from 649 patients across 19 major cancer types. We demonstrate substantial heterogeneity in their total abundance and subtype composition and observe immunoglobulin G (IgG)-skewness of antibody-secreting cell isotypes. Moreover, we identify stress-response memory B cells and tumor-associated atypical B cells (TAABs), two tumor-enriched subpopulations with prognostic potential, shared in a pan-cancer manner. In particular, TAABs, characterized by a high clonal expansion level and proliferative capacity as well as by close interactions with activated CD4 T cells in tumors, are predictive of immunotherapy response. Our integrative resource depicts distinct clinically relevant TIB subsets, laying a foundation for further exploration of functional commonality and diversity of B cells in cancer.


Assuntos
Neoplasias , Análise de Célula Única , Humanos , Neoplasias/imunologia , Neoplasias/patologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Fenótipo , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Imunoterapia , Prognóstico
3.
Nat Immunol ; 25(9): 1678-1691, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39060650

RESUMO

Whole-exome sequencing of two unrelated kindreds with systemic autoimmune disease featuring antinuclear antibodies with IgG4 elevation uncovered an identical ultrarare heterozygous TNIP1Q333P variant segregating with disease. Mice with the orthologous Q346P variant developed antinuclear autoantibodies, salivary gland inflammation, elevated IgG2c, spontaneous germinal centers and expansion of age-associated B cells, plasma cells and follicular and extrafollicular helper T cells. B cell phenotypes were cell-autonomous and rescued by ablation of Toll-like receptor 7 (TLR7) or MyD88. The variant increased interferon-ß without altering nuclear factor kappa-light-chain-enhancer of activated B cells signaling, and impaired MyD88 and IRAK1 recruitment to autophagosomes. Additionally, the Q333P variant impaired TNIP1 localization to damaged mitochondria and mitophagosome formation. Damaged mitochondria were abundant in the salivary epithelial cells of Tnip1Q346P mice. These findings suggest that TNIP1-mediated autoimmunity may be a consequence of increased TLR7 signaling due to impaired recruitment of downstream signaling molecules and damaged mitochondria to autophagosomes and may thus respond to TLR7-targeted therapeutics.


Assuntos
Doenças Autoimunes , Proteínas de Ligação a DNA , Imunoglobulina G , Fator 88 de Diferenciação Mieloide , Receptor 7 Toll-Like , Animais , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Humanos , Receptor 7 Toll-Like/metabolismo , Receptor 7 Toll-Like/genética , Receptor 7 Toll-Like/imunologia , Camundongos , Fator 88 de Diferenciação Mieloide/metabolismo , Fator 88 de Diferenciação Mieloide/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Feminino , Masculino , Transdução de Sinais , Mitocôndrias/metabolismo , Sequenciamento do Exoma , Anticorpos Antinucleares/imunologia , Linfócitos B/imunologia , Camundongos Knockout , Camundongos Endogâmicos C57BL , Centro Germinativo/imunologia , Linhagem , Glândulas Salivares/imunologia , Glândulas Salivares/metabolismo , Glândulas Salivares/patologia , Glicoproteínas de Membrana
4.
Cell ; 184(15): 3936-3948.e10, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34192529

RESUMO

In this study we profiled vaccine-induced polyclonal antibodies as well as plasmablast-derived mAbs from individuals who received SARS-CoV-2 spike mRNA vaccine. Polyclonal antibody responses in vaccinees were robust and comparable to or exceeded those seen after natural infection. However, the ratio of binding to neutralizing antibodies after vaccination was greater than that after natural infection and, at the monoclonal level, we found that the majority of vaccine-induced antibodies did not have neutralizing activity. We also found a co-dominance of mAbs targeting the NTD and RBD of SARS-CoV-2 spike and an original antigenic-sin like backboost to spikes of seasonal human coronaviruses OC43 and HKU1. Neutralizing activity of NTD mAbs but not RBD mAbs against a clinical viral isolate carrying E484K as well as extensive changes in the NTD was abolished, suggesting that a proportion of vaccine-induced RBD binding antibodies may provide substantial protection against viral variants carrying single E484K RBD mutations.


Assuntos
Anticorpos Antivirais/imunologia , Vacinas contra COVID-19/imunologia , RNA Mensageiro/imunologia , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinação , Substituição de Aminoácidos , Enzima de Conversão de Angiotensina 2/imunologia , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/isolamento & purificação , Anticorpos Neutralizantes/imunologia , Formação de Anticorpos/imunologia , Ligação Competitiva , Humanos , Imunoglobulina G/metabolismo , Mutação/genética , Domínios Proteicos , Hipermutação Somática de Imunoglobulina/genética
5.
Cell ; 184(13): 3486-3501.e21, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34077751

RESUMO

Crimean-Congo hemorrhagic fever virus (CCHFV) is a World Health Organization priority pathogen. CCHFV infections cause a highly lethal hemorrhagic fever for which specific treatments and vaccines are urgently needed. Here, we characterize the human immune response to natural CCHFV infection to identify potent neutralizing monoclonal antibodies (nAbs) targeting the viral glycoprotein. Competition experiments showed that these nAbs bind six distinct antigenic sites in the Gc subunit. These sites were further delineated through mutagenesis and mapped onto a prefusion model of Gc. Pairwise screening identified combinations of non-competing nAbs that afford synergistic neutralization. Further enhancements in neutralization breadth and potency were attained by physically linking variable domains of synergistic nAb pairs through bispecific antibody (bsAb) engineering. Although multiple nAbs protected mice from lethal CCHFV challenge in pre- or post-exposure prophylactic settings, only a single bsAb, DVD-121-801, afforded therapeutic protection. DVD-121-801 is a promising candidate suitable for clinical development as a CCHFV therapeutic.


Assuntos
Anticorpos Neutralizantes/imunologia , Febre Hemorrágica da Crimeia/imunologia , Sobreviventes , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/imunologia , Antígenos Virais/metabolismo , Fenômenos Biofísicos , Chlorocebus aethiops , Mapeamento de Epitopos , Epitopos/metabolismo , Feminino , Vírus da Febre Hemorrágica da Crimeia-Congo/imunologia , Febre Hemorrágica da Crimeia/prevenção & controle , Humanos , Imunoglobulina G/metabolismo , Masculino , Camundongos , Testes de Neutralização , Ligação Proteica , Engenharia de Proteínas , Proteínas Recombinantes/imunologia , Células Vero , Proteínas Virais/química
6.
Cell ; 184(9): 2316-2331.e15, 2021 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-33773105

RESUMO

Most human monoclonal antibodies (mAbs) neutralizing SARS-CoV-2 recognize the spike (S) protein receptor-binding domain and block virus interactions with the cellular receptor angiotensin-converting enzyme 2. We describe a panel of human mAbs binding to diverse epitopes on the N-terminal domain (NTD) of S protein from SARS-CoV-2 convalescent donors and found a minority of these possessed neutralizing activity. Two mAbs (COV2-2676 and COV2-2489) inhibited infection of authentic SARS-CoV-2 and recombinant VSV/SARS-CoV-2 viruses. We mapped their binding epitopes by alanine-scanning mutagenesis and selection of functional SARS-CoV-2 S neutralization escape variants. Mechanistic studies showed that these antibodies neutralize in part by inhibiting a post-attachment step in the infection cycle. COV2-2676 and COV2-2489 offered protection either as prophylaxis or therapy, and Fc effector functions were required for optimal protection. Thus, natural infection induces a subset of potent NTD-specific mAbs that leverage neutralizing and Fc-mediated activities to protect against SARS-CoV-2 infection using multiple functional attributes.


Assuntos
Anticorpos Monoclonais/farmacologia , Anticorpos Neutralizantes/farmacologia , Substâncias Protetoras/farmacologia , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/imunologia , Animais , Ligação Competitiva , COVID-19/imunologia , COVID-19/virologia , Quimiocinas/metabolismo , Chlorocebus aethiops , Células HEK293 , Humanos , Fragmentos Fab das Imunoglobulinas/metabolismo , Imunoglobulina G/metabolismo , Pulmão/metabolismo , Camundongos Endogâmicos C57BL , Modelos Moleculares , Mutagênese/genética , Testes de Neutralização , Domínios Proteicos , Células Vero
7.
Cell ; 183(7): 1867-1883.e26, 2020 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-33248023

RESUMO

Biliary atresia (BA) is a severe cholangiopathy that leads to liver failure in infants, but its pathogenesis remains to be fully characterized. By single-cell RNA profiling, we observed macrophage hypo-inflammation, Kupffer cell scavenger function defects, cytotoxic T cell expansion, and deficiency of CX3CR1+effector T and natural killer (NK) cells in infants with BA. More importantly, we discovered that hepatic B cell lymphopoiesis did not cease after birth and that tolerance defects contributed to immunoglobulin G (IgG)-autoantibody accumulation in BA. In a rhesus-rotavirus induced BA model, depleting B cells or blocking antigen presentation ameliorated liver damage. In a pilot clinical study, we demonstrated that rituximab was effective in depleting hepatic B cells and restoring the functions of macrophages, Kupffer cells, and T cells to levels comparable to those of control subjects. In summary, our comprehensive immune profiling in infants with BA had educed that B-cell-modifying therapies may alleviate liver pathology.


Assuntos
Atresia Biliar/imunologia , Atresia Biliar/terapia , Fígado/imunologia , Animais , Antígenos CD20/metabolismo , Linfócitos B/imunologia , Atresia Biliar/sangue , Atresia Biliar/tratamento farmacológico , Biópsia , Receptor 1 de Quimiocina CX3C/metabolismo , Morte Celular , Linhagem Celular , Proliferação de Células , Transdiferenciação Celular , Criança , Pré-Escolar , Estudos de Coortes , Citotoxicidade Imunológica , Modelos Animais de Doenças , Feminino , Humanos , Imunoglobulina G/metabolismo , Lactente , Inflamação/patologia , Células Matadoras Naturais/imunologia , Células de Kupffer/patologia , Fígado/patologia , Cirrose Hepática/sangue , Cirrose Hepática/complicações , Cirrose Hepática/imunologia , Cirrose Hepática/patologia , Depleção Linfocítica , Linfopoese , Masculino , Camundongos Endogâmicos BALB C , Fagocitose , RNA/metabolismo , Rituximab/administração & dosagem , Rituximab/farmacologia , Rituximab/uso terapêutico , Rotavirus/fisiologia , Análise de Célula Única , Células Th1/imunologia , Células Th17/imunologia
8.
Cell ; 178(1): 202-215.e14, 2019 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-31204102

RESUMO

Despite the worldwide success of vaccination, newborns remain vulnerable to infections. While neonatal vaccination has been hampered by maternal antibody-mediated dampening of immune responses, enhanced regulatory and tolerogenic mechanisms, and immune system immaturity, maternal pre-natal immunization aims to boost neonatal immunity via antibody transfer to the fetus. However, emerging data suggest that antibodies are not transferred equally across the placenta. To understand this, we used systems serology to define Fc features associated with antibody transfer. The Fc-profile of neonatal and maternal antibodies differed, skewed toward natural killer (NK) cell-activating antibodies. This selective transfer was linked to digalactosylated Fc-glycans that selectively bind FcRn and FCGR3A, resulting in transfer of antibodies able to efficiently leverage innate immune cells present at birth. Given emerging data that vaccination may direct antibody glycosylation, our study provides insights for the development of next-generation maternal vaccines designed to elicit antibodies that will most effectively aid neonates.


Assuntos
Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Imunoglobulina G/metabolismo , Placenta/metabolismo , Polissacarídeos/metabolismo , Receptores Fc/imunologia , Receptores Fc/metabolismo , Adolescente , Adulto , Bélgica , Degranulação Celular , Estudos de Coortes , Feminino , Glicosilação , Humanos , Recém-Nascido , Células Matadoras Naturais/imunologia , Ativação Linfocitária/imunologia , Masculino , Gravidez , Receptores de IgG/metabolismo , Células THP-1 , Estados Unidos , Vacinação , Adulto Jovem
9.
Cell ; 179(5): 1191-1206.e21, 2019 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-31730857

RESUMO

This study identifies mechanisms mediating responses to immune checkpoint inhibitors using mouse models of triple-negative breast cancer. By creating new mammary tumor models, we find that tumor mutation burden and specific immune cells are associated with response. Further, we developed a rich resource of single-cell RNA-seq and bulk mRNA-seq data of immunotherapy-treated and non-treated tumors from sensitive and resistant murine models. Using this, we uncover that immune checkpoint therapy induces T follicular helper cell activation of B cells to facilitate the anti-tumor response in these models. We also show that B cell activation of T cells and the generation of antibody are key to immunotherapy response and propose a new biomarker for immune checkpoint therapy. In total, this work presents resources of new preclinical models of breast cancer with large mRNA-seq and single-cell RNA-seq datasets annotated for sensitivity to therapy and uncovers new components of response to immune checkpoint inhibitors.


Assuntos
Linfócitos B/imunologia , Imunoterapia , Neoplasias Mamárias Animais/genética , Neoplasias Mamárias Animais/imunologia , Mutação/genética , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Antígeno CTLA-4/metabolismo , Modelos Animais de Doenças , Feminino , Regulação Neoplásica da Expressão Gênica , Engenharia Genética , Genoma , Humanos , Imunoglobulina G/metabolismo , Ativação Linfocitária/imunologia , Neoplasias Mamárias Animais/terapia , Receptores de Antígenos de Linfócitos B/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/terapia
10.
Nat Immunol ; 22(11): 1452-1464, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34611361

RESUMO

There is limited understanding of the viral antibody fingerprint following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children. Herein, SARS-CoV-2 proteome-wide immunoprofiling of children with mild/moderate or severe coronavirus disease 2019 (COVID-19) versus multisystem inflammatory syndrome in children versus hospitalized control patients revealed differential cytokine responses, IgM/IgG/IgA epitope diversity, antibody binding and avidity. Apart from spike and nucleocapsid, IgG/IgA recognized epitopes in nonstructural protein (NSP) 2, NSP3, NSP12-NSP14 and open reading frame (ORF) 3a-ORF9. Peptides representing epitopes in NSP12, ORF3a and ORF8 demonstrated SARS-CoV-2 serodiagnosis. Antibody-binding kinetics with 24 SARS-CoV-2 proteins revealed antibody parameters that distinguish children with mild/moderate versus severe COVID-19 or multisystem inflammatory syndrome in children. Antibody avidity to prefusion spike correlated with decreased illness severity and served as a clinical disease indicator. The fusion peptide and heptad repeat 2 region induced SARS-CoV-2-neutralizing antibodies in rabbits. Thus, we identified SARS-CoV-2 antibody signatures in children associated with disease severity and delineate promising serodiagnostic and virus neutralization targets. These findings might guide the design of serodiagnostic assays, prognostic algorithms, therapeutics and vaccines in this important but understudied population.


Assuntos
Teste Sorológico para COVID-19/métodos , COVID-19/complicações , COVID-19/imunologia , SARS-CoV-2/imunologia , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Adolescente , Anticorpos Neutralizantes/metabolismo , Anticorpos Antivirais/metabolismo , COVID-19/diagnóstico , Criança , Pré-Escolar , Progressão da Doença , Epitopos/metabolismo , Feminino , Hospitalização , Humanos , Imunidade Humoral , Imunoglobulina A/metabolismo , Imunoglobulina G/metabolismo , Imunoglobulina M/metabolismo , Masculino , Prognóstico , Proteoma , Índice de Gravidade de Doença , Síndrome de Resposta Inflamatória Sistêmica/diagnóstico
11.
Nat Immunol ; 22(1): 67-73, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33169014

RESUMO

Severe acute respiratory syndrome coronavirus 2 infections can cause coronavirus disease 2019 (COVID-19), which manifests with a range of severities from mild illness to life-threatening pneumonia and multi-organ failure. Severe COVID-19 is characterized by an inflammatory signature, including high levels of inflammatory cytokines, alveolar inflammatory infiltrates and vascular microthrombi. Here we show that patients with severe COVID-19 produced a unique serologic signature, including an increased likelihood of IgG1 with afucosylated Fc glycans. This Fc modification on severe acute respiratory syndrome coronavirus 2 IgGs enhanced interactions with the activating Fcγ receptor FcγRIIIa; when incorporated into immune complexes, Fc afucosylation enhanced production of inflammatory cytokines by monocytes, including interleukin-6 and tumor necrosis factor. These results show that disease severity in COVID-19 correlates with the presence of proinflammatory IgG Fc structures, including afucosylated IgG1.


Assuntos
COVID-19/imunologia , Citocinas/imunologia , Imunoglobulina G/imunologia , Receptores de IgG/imunologia , SARS-CoV-2/imunologia , Adolescente , Adulto , Idoso , COVID-19/metabolismo , COVID-19/virologia , Criança , Citocinas/metabolismo , Feminino , Glicosilação , Humanos , Imunoglobulina G/metabolismo , Interleucina-6 , Masculino , Pessoa de Meia-Idade , Receptores de IgG/metabolismo , SARS-CoV-2/metabolismo , SARS-CoV-2/fisiologia , Índice de Gravidade de Doença , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo
12.
Cell ; 172(3): 564-577.e13, 2018 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-29275858

RESUMO

Self-reactive IgGs contribute to the pathology of autoimmune diseases, including systemic lupus erythematosus and rheumatoid arthritis. Paradoxically, IgGs are used to treat inflammatory diseases in the form of high-dose intravenous immunoglobulin (IVIG). Distinct glycoforms on the IgG crystallizable fragment (Fc) dictate these divergent functions. IgG anti-inflammatory activity is attributed to sialylation of the Fc glycan. We therefore sought to convert endogenous IgG to anti-inflammatory mediators in vivo by engineering solubilized glycosyltransferases that attach galactose or sialic acid. When both enzymes were administered in a prophylactic or therapeutic fashion, autoimmune inflammation was markedly attenuated in vivo. The enzymes worked through a similar pathway to IVIG, requiring DC-SIGN, STAT6 signaling, and FcγRIIB. Importantly, sialylation was highly specific to pathogenic IgG at the site of inflammation, driven by local platelet release of nucleotide-sugar donors. These results underscore the therapeutic potential of glycoengineering in vivo.


Assuntos
Doenças Autoimunes/imunologia , Imunoglobulina G/metabolismo , Imunoterapia/métodos , Processamento de Proteína Pós-Traducional , Ácidos Siálicos/metabolismo , Animais , Doenças Autoimunes/terapia , Células Cultivadas , Feminino , Glicosilação , Células HEK293 , Humanos , Imunoglobulina G/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Sialiltransferases/genética , Sialiltransferases/metabolismo
13.
Cell ; 173(1): 166-180.e14, 2018 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-29502969

RESUMO

Brain-wide fluctuations in local field potential oscillations reflect emergent network-level signals that mediate behavior. Cracking the code whereby these oscillations coordinate in time and space (spatiotemporal dynamics) to represent complex behaviors would provide fundamental insights into how the brain signals emotional pathology. Using machine learning, we discover a spatiotemporal dynamic network that predicts the emergence of major depressive disorder (MDD)-related behavioral dysfunction in mice subjected to chronic social defeat stress. Activity patterns in this network originate in prefrontal cortex and ventral striatum, relay through amygdala and ventral tegmental area, and converge in ventral hippocampus. This network is increased by acute threat, and it is also enhanced in three independent models of MDD vulnerability. Finally, we demonstrate that this vulnerability network is biologically distinct from the networks that encode dysfunction after stress. Thus, these findings reveal a convergent mechanism through which MDD vulnerability is mediated in the brain.


Assuntos
Encéfalo/fisiologia , Depressão/patologia , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Depressão/fisiopatologia , Modelos Animais de Doenças , Estimulação Elétrica , Eletrodos Implantados , Imunoglobulina G/genética , Imunoglobulina G/metabolismo , Ketamina/farmacologia , Aprendizado de Máquina , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fenômenos Fisiológicos/efeitos dos fármacos , Córtex Pré-Frontal/fisiologia , Estresse Psicológico
14.
Cell ; 173(7): 1742-1754.e17, 2018 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-29906449

RESUMO

Osmotic diarrhea is a prevalent condition in humans caused by food intolerance, malabsorption, and widespread laxative use. Here, we assess the resilience of the gut ecosystem to osmotic perturbation at multiple length and timescales using mice as model hosts. Osmotic stress caused reproducible extinction of highly abundant taxa and expansion of less prevalent members in human and mouse microbiotas. Quantitative imaging revealed decimation of the mucus barrier during osmotic perturbation, followed by recovery. The immune system exhibited temporary changes in cytokine levels and a lasting IgG response against commensal bacteria. Increased osmolality prevented growth of commensal strains in vitro, revealing one mechanism contributing to extinction. Environmental availability of microbiota members mitigated extinction events, demonstrating how species reintroduction can affect community resilience. Our findings (1) demonstrate that even mild osmotic diarrhea can cause lasting changes to the microbiota and host and (2) lay the foundation for interventions that increase system-wide resilience.


Assuntos
Diarreia/patologia , Microbioma Gastrointestinal/efeitos dos fármacos , Polietilenoglicóis/farmacologia , Animais , Bacteroidetes/efeitos dos fármacos , Bacteroidetes/genética , Bacteroidetes/isolamento & purificação , Ceco/química , Ceco/metabolismo , Ceco/microbiologia , Ceco/patologia , Colo/química , Colo/microbiologia , Colo/patologia , Citocinas/metabolismo , Diarreia/imunologia , Diarreia/microbiologia , Diarreia/veterinária , Fezes/microbiologia , Glicosídeo Hidrolases/metabolismo , Humanos , Imunidade Humoral/efeitos dos fármacos , Imunoglobulina G/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Metagenômica , Camundongos , Concentração Osmolar , Polietilenoglicóis/metabolismo , Proteoma/análise , RNA Ribossômico 16S/química , RNA Ribossômico 16S/genética , Verrucomicrobia/efeitos dos fármacos , Verrucomicrobia/genética , Verrucomicrobia/isolamento & purificação
15.
Nat Immunol ; 20(10): 1360-1371, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31477921

RESUMO

Follicular regulatory T (TFR) cells have specialized roles in modulating follicular helper T (TFH) cell activation of B cells. However, the precise role of TFR cells in controlling antibody responses to foreign antigens and autoantigens in vivo is still unclear due to a lack of specific tools. A TFR cell-deleter mouse was developed that selectively deletes TFR cells, facilitating temporal studies. TFR cells were found to regulate early, but not late, germinal center (GC) responses to control antigen-specific antibody and B cell memory. Deletion of TFR cells also resulted in increased self-reactive immunoglobulin (Ig) G and IgE. The increased IgE levels led us to interrogate the role of TFR cells in house dust mite models. TFR cells were found to control TFH13 cell-induced IgE. In vivo, loss of TFR cells increased house-dust-mite-specific IgE and lung inflammation. Thus, TFR cells control IgG and IgE responses to vaccines, allergens and autoantigens, and exert critical immunoregulatory functions before GC formation.


Assuntos
Linfócitos B/imunologia , Centro Germinativo/imunologia , Hipersensibilidade/imunologia , Pneumonia/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia , Animais , Antígenos de Dermatophagoides/imunologia , Autoantígenos/imunologia , Deleção Clonal/genética , Modelos Animais de Doenças , Humanos , Tolerância Imunológica , Imunidade Humoral , Imunoglobulina E/metabolismo , Imunoglobulina G/metabolismo , Memória Imunológica , Interleucina-13/metabolismo , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pyroglyphidae/imunologia
16.
Immunity ; 55(10): 1872-1890.e9, 2022 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-36130603

RESUMO

Memory B cells (MBCs) can persist for a lifetime, but the mechanisms that allow their long-term survival remain poorly understood. Here, we isolated and analyzed human splenic smallpox/vaccinia protein B5-specific MBCs in individuals who were vaccinated more than 40 years ago. Only a handful of clones persisted over such an extended period, and they displayed limited intra-clonal diversity with signs of extensive affinity-based selection. These long-lived MBCs appeared enriched in a CD21hiCD20hi IgG+ splenic B cell subset displaying a marginal-zone-like NOTCH/MYC-driven signature, but they did not harbor a unique longevity-associated transcriptional or metabolic profile. Finally, the telomeres of B5-specific, long-lived MBCs were longer than those in patient-paired naive B cells in all the samples analyzed. Overall, these results imply that separate mechanisms such as early telomere elongation, affinity selection during the contraction phase, and access to a specific niche contribute to ensuring the functional longevity of MBCs.


Assuntos
Memória Imunológica , Células B de Memória , Linfócitos B/metabolismo , Centro Germinativo , Humanos , Imunoglobulina G/metabolismo
17.
Nat Immunol ; 19(9): 1001-1012, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30104633

RESUMO

Immunoglobulin G3 (IgG3) has an uncertain role in the response to infection with and vaccination against human immunodeficiency virus (HIV). Here we describe a regulatory role for IgG3 in dampening the immune system-activating effects of chronic HIV viremia on B cells. Secreted IgG3 was bound to IgM-expressing B cells in vivo in HIV-infected chronically viremic individuals but not in early-viremic or aviremic individuals. Tissue-like memory (TLM) B cells, a population expanded by persistent HIV viremia, bound large amounts of IgG3. IgG3 induced clustering of B cell antigen receptors (BCRs) on the IgM+ B cells, which was mediated by direct interactions between soluble IgG3 and membrane IgM of the BCR (IgM-BCR). The inhibitory IgG receptor CD32b (FcγRIIb), complement component C1q and inflammatory biomarker CRP contributed to the binding of secreted IgG3 onto IgM-expressing B cells of HIV-infected individuals. Notably, IgG3-bound TLM B cells were refractory to IgM-BCR stimulation, thus demonstrating that IgG3 can regulate B cells during chronic activation of the immune system.


Assuntos
Linfócitos B/imunologia , Infecções por HIV/imunologia , HIV-1/fisiologia , Imunoglobulina G/metabolismo , Receptores de Antígenos de Linfócitos B/metabolismo , Adulto , Proteína C-Reativa/metabolismo , Células Cultivadas , Complemento C1q/metabolismo , Feminino , Humanos , Imunoglobulina M/metabolismo , Memória Imunológica , Imunomodulação , Masculino , Pessoa de Meia-Idade , Ligação Proteica , Agregação de Receptores , Receptores de IgG/metabolismo , Adulto Jovem
18.
Immunity ; 54(12): 2756-2771.e10, 2021 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-34879220

RESUMO

In contrast to other antibody isotypes, B cells switched to IgE respond transiently and do not give rise to long-lived plasma cells (PCs) or memory B cells. To better understand IgE-BCR-mediated control of IgE responses, we developed whole-genome CRISPR screening that enabled comparison of IgE+ and IgG1+ B cell requirements for proliferation, survival, and differentiation into PCs. IgE+ PCs exhibited dependency on the PI3K-mTOR axis that increased protein amounts of the transcription factor IRF4. In contrast, loss of components of the calcium-calcineurin-NFAT pathway promoted IgE+ PC differentiation. Mice bearing a B cell-specific deletion of calcineurin B1 exhibited increased production of IgE+ PCs. Mechanistically, sustained elevation of intracellular calcium in IgE+ PCs downstream of the IgE-BCR promoted BCL2L11-dependent apoptosis. Thus, chronic calcium signaling downstream of the IgE-BCR controls the self-limiting character of IgE responses and may be relevant to the accumulation of IgE-producing cells in allergic disease.


Assuntos
Subpopulações de Linfócitos B/imunologia , Calcineurina/metabolismo , Hipersensibilidade/imunologia , Plasmócitos/imunologia , Animais , Apoptose , Proteína 11 Semelhante a Bcl-2/metabolismo , Calcineurina/genética , Sinalização do Cálcio , Diferenciação Celular , Sobrevivência Celular , Células Cultivadas , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Humanos , Imunoglobulina E/metabolismo , Imunoglobulina G/metabolismo , Memória Imunológica , Camundongos , Camundongos Endogâmicos C57BL , Fosfatidilinositol 3-Quinases/metabolismo , Receptores de Antígenos de Linfócitos B/metabolismo
19.
Cell ; 162(6): 1379-90, 2015 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-26359989

RESUMO

The HIV-1 envelope (Env) spike contains limited epitopes for broadly neutralizing antibodies (bNAbs); thus, most neutralizing antibodies are strain specific. The 8ANC195 epitope, defined by crystal and electron microscopy (EM) structures of bNAb 8ANC195 complexed with monomeric gp120 and trimeric Env, respectively, spans the gp120 and gp41 Env subunits. To investigate 8ANC195's gp41 epitope at higher resolution, we solved a 3.58 Å crystal structure of 8ANC195 complexed with fully glycosylated Env trimer, revealing 8ANC195 insertion into a glycan shield gap to contact gp120 and gp41 glycans and protein residues. To determine whether 8ANC195 recognizes the CD4-bound open Env conformation that leads to co-receptor binding and fusion, one of several known conformations of virion-associated Env, we solved EM structures of an Env/CD4/CD4-induced antibody/8ANC195 complex. 8ANC195 binding partially closed the CD4-bound trimer, confirming structural plasticity of Env by revealing a previously unseen conformation. 8ANC195's ability to bind different Env conformations suggests advantages for potential therapeutic applications.


Assuntos
Anticorpos Neutralizantes/metabolismo , Proteína gp120 do Envelope de HIV/química , Proteína gp120 do Envelope de HIV/metabolismo , HIV-1/química , Anticorpos Neutralizantes/ultraestrutura , Epitopos , Proteína gp120 do Envelope de HIV/ultraestrutura , Humanos , Imunoglobulina G/química , Imunoglobulina G/metabolismo , Microscopia Eletrônica de Transmissão , Modelos Moleculares , Conformação Proteica , Difração de Raios X
20.
Nat Immunol ; 18(1): 104-113, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27820809

RESUMO

The checkpoints and mechanisms that contribute to autoantibody-driven disease are as yet incompletely understood. Here we identified the axis of interleukin 23 (IL-23) and the TH17 subset of helper T cells as a decisive factor that controlled the intrinsic inflammatory activity of autoantibodies and triggered the clinical onset of autoimmune arthritis. By instructing B cells in an IL-22- and IL-21-dependent manner, TH17 cells regulated the expression of ß-galactoside α2,6-sialyltransferase 1 in newly differentiating antibody-producing cells and determined the glycosylation profile and activity of immunoglobulin G (IgG) produced by the plasma cells that subsequently emerged. Asymptomatic humans with rheumatoid arthritis (RA)-specific autoantibodies showed identical changes in the activity and glycosylation of autoreactive IgG antibodies before shifting to the inflammatory phase of RA; thus, our results identify an IL-23-TH17 cell-dependent pathway that controls autoantibody activity and unmasks a preexisting breach in immunotolerance.


Assuntos
Artrite Reumatoide/imunologia , Autoanticorpos/metabolismo , Linfócitos B/imunologia , Tolerância Imunológica , Imunoglobulina G/metabolismo , Interleucina-23/metabolismo , Células Th17/imunologia , Animais , Diferenciação Celular , Células Cultivadas , Modelos Animais de Doenças , Glicosilação , Humanos , Interleucinas/metabolismo , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Sialiltransferases/genética , Sialiltransferases/metabolismo , Transdução de Sinais , beta-D-Galactosídeo alfa 2-6-Sialiltransferase , Interleucina 22
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