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1.
Annu Rev Immunol ; 40: 221-247, 2022 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-35061510

RESUMO

As central effectors of the adaptive immune response, immunoglobulins, or antibodies, provide essential protection from pathogens through their ability to recognize foreign antigens, aid in neutralization, and facilitate elimination from the host. Mammalian immunoglobulins can be classified into five isotypes-IgA, IgD, IgE, IgG, and IgM-each with distinct roles in mediating various aspects of the immune response. Of these isotypes, IgA and IgM are the only ones capable of multimerization, arming them with unique biological functions. Increased valency of polymeric IgA and IgM provides high avidity for binding low-affinity antigens, and their ability to be transported across the mucosal epithelium into secretions by the polymeric immunoglobulin receptor allows them to play critical roles in mucosal immunity. Here we discuss the molecular assembly, structure, and function of these multimeric antibodies.


Assuntos
Imunoglobulina A , Receptores de Imunoglobulina Polimérica , Animais , Humanos , Imunidade nas Mucosas , Imunoglobulina M/química , Imunoglobulina M/metabolismo , Mamíferos/metabolismo , Mucosa , Receptores de Imunoglobulina Polimérica/química
2.
Cell ; 185(25): 4826-4840.e17, 2022 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-36402135

RESUMO

Congenital Zika virus (ZIKV) infection results in neurodevelopmental deficits in up to 14% of infants born to ZIKV-infected mothers. Neutralizing antibodies are a critical component of protective immunity. Here, we demonstrate that plasma IgM contributes to ZIKV immunity in pregnancy, mediating neutralization up to 3 months post-symptoms. From a ZIKV-infected pregnant woman, we isolated a pentameric ZIKV-specific IgM (DH1017.IgM) that exhibited ultrapotent ZIKV neutralization dependent on the IgM isotype. DH1017.IgM targets an envelope dimer epitope within domain II. The epitope arrangement on the virion is compatible with concurrent engagement of all ten antigen-binding sites of DH1017.IgM, a solution not available to IgG. DH1017.IgM protected mice against viremia upon lethal ZIKV challenge more efficiently than when expressed as an IgG. Our findings identify a role for antibodies of the IgM isotype in protection against ZIKV and posit DH1017.IgM as a safe and effective candidate immunotherapeutic, particularly during pregnancy.


Assuntos
Imunoglobulina M , Gravidez , Infecção por Zika virus , Zika virus , Animais , Feminino , Camundongos , Gravidez/imunologia , Anticorpos Neutralizantes , Anticorpos Antivirais , Epitopos , Testes de Neutralização , Infecção por Zika virus/imunologia , Imunoglobulina M/imunologia , Imunoglobulina M/isolamento & purificação
3.
Cell ; 184(2): 476-488.e11, 2021 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-33412089

RESUMO

Coronavirus disease 2019 (COVID-19) exhibits variable symptom severity ranging from asymptomatic to life-threatening, yet the relationship between severity and the humoral immune response is poorly understood. We examined antibody responses in 113 COVID-19 patients and found that severe cases resulting in intubation or death exhibited increased inflammatory markers, lymphopenia, pro-inflammatory cytokines, and high anti-receptor binding domain (RBD) antibody levels. Although anti-RBD immunoglobulin G (IgG) levels generally correlated with neutralization titer, quantitation of neutralization potency revealed that high potency was a predictor of survival. In addition to neutralization of wild-type SARS-CoV-2, patient sera were also able to neutralize the recently emerged SARS-CoV-2 mutant D614G, suggesting cross-protection from reinfection by either strain. However, SARS-CoV-2 sera generally lacked cross-neutralization to a highly homologous pre-emergent bat coronavirus, WIV1-CoV, which has not yet crossed the species barrier. These results highlight the importance of neutralizing humoral immunity on disease progression and the need to develop broadly protective interventions to prevent future coronavirus pandemics.


Assuntos
Anticorpos Neutralizantes/imunologia , Biomarcadores/análise , COVID-19/imunologia , COVID-19/fisiopatologia , Adulto , Anticorpos Neutralizantes/análise , Anticorpos Antivirais/análise , Anticorpos Antivirais/sangue , Biomarcadores/sangue , COVID-19/sangue , COVID-19/epidemiologia , Comorbidade , Coronavirus/classificação , Coronavirus/fisiologia , Reações Cruzadas , Citocinas/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imunoglobulina A/análise , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Imunoglobulina M/sangue , Imunoglobulina M/imunologia , Masculino , Massachusetts/epidemiologia , Pessoa de Meia-Idade , Domínios Proteicos , SARS-CoV-2/química , SARS-CoV-2/fisiologia , Índice de Gravidade de Doença , Glicoproteína da Espícula de Coronavírus/química , Análise de Sobrevida , Resultado do Tratamento
4.
Cell ; 183(4): 1024-1042.e21, 2020 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-32991844

RESUMO

Analysis of the specificity and kinetics of neutralizing antibodies (nAbs) elicited by SARS-CoV-2 infection is crucial for understanding immune protection and identifying targets for vaccine design. In a cohort of 647 SARS-CoV-2-infected subjects, we found that both the magnitude of Ab responses to SARS-CoV-2 spike (S) and nucleoprotein and nAb titers correlate with clinical scores. The receptor-binding domain (RBD) is immunodominant and the target of 90% of the neutralizing activity present in SARS-CoV-2 immune sera. Whereas overall RBD-specific serum IgG titers waned with a half-life of 49 days, nAb titers and avidity increased over time for some individuals, consistent with affinity maturation. We structurally defined an RBD antigenic map and serologically quantified serum Abs specific for distinct RBD epitopes leading to the identification of two major receptor-binding motif antigenic sites. Our results explain the immunodominance of the receptor-binding motif and will guide the design of COVID-19 vaccines and therapeutics.


Assuntos
Anticorpos Neutralizantes/imunologia , Mapeamento de Epitopos/métodos , Glicoproteína da Espícula de Coronavírus/imunologia , Enzima de Conversão de Angiotensina 2 , Anticorpos Monoclonais/química , Anticorpos Monoclonais/genética , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/química , Anticorpos Antivirais/sangue , Anticorpos Antivirais/química , Anticorpos Antivirais/imunologia , Reações Antígeno-Anticorpo , Betacoronavirus/imunologia , Betacoronavirus/isolamento & purificação , Betacoronavirus/metabolismo , Sítios de Ligação , COVID-19 , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Epitopos/química , Epitopos/imunologia , Humanos , Imunoglobulina A/sangue , Imunoglobulina A/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Imunoglobulina M/sangue , Imunoglobulina M/imunologia , Cinética , Simulação de Dinâmica Molecular , Pandemias , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Ligação Proteica , Domínios Proteicos/imunologia , Estrutura Quaternária de Proteína , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo
5.
Cell ; 183(6): 1508-1519.e12, 2020 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-33207184

RESUMO

The urgent need for an effective SARS-CoV-2 vaccine has forced development to progress in the absence of well-defined correlates of immunity. While neutralization has been linked to protection against other pathogens, whether neutralization alone will be sufficient to drive protection against SARS-CoV-2 in the broader population remains unclear. Therefore, to fully define protective humoral immunity, we dissected the early evolution of the humoral response in 193 hospitalized individuals ranging from moderate to severe. Although robust IgM and IgA responses evolved in both survivors and non-survivors with severe disease, non-survivors showed attenuated IgG responses, accompanied by compromised Fcɣ receptor binding and Fc effector activity, pointing to deficient humoral development rather than disease-enhancing humoral immunity. In contrast, individuals with moderate disease exhibited delayed responses that ultimately matured. These data highlight distinct humoral trajectories associated with resolution of SARS-CoV-2 infection and the need for early functional humoral immunity.


Assuntos
COVID-19 , Imunidade Humoral , Imunoglobulina A/imunologia , Imunoglobulina M/imunologia , Receptores de IgG/imunologia , SARS-CoV-2/imunologia , COVID-19/imunologia , COVID-19/mortalidade , Feminino , Células HL-60 , Humanos , Masculino
6.
Nat Immunol ; 23(11): 1564-1576, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36316480

RESUMO

Durable antibody immunity depends on long-lived plasma cells (LLPCs) that primarily reside in the bone marrow (BM). However, due to LLPC rarity, it has not been possible to define their phenotypes or determine their heterogeneity. By single-cell mRNA sequencing, cytometry and a genetic pulse-chase mouse model, we show that IgG and IgM LLPCs display an EpCAMhiCXCR3- phenotype, whereas IgA LLPCs are Ly6AhiTigit-. While IgG and IgA LLPCs are mainly contributed by somatically hypermutated cells following immunization or infection, cells with innate properties and public antibodies are found in IgA and IgM LLPC compartments. Particularly, IgM LLPCs are highly enriched with public clones shared among different individual animals, differentiated in a T cell-independent manner and have affinity for self-antigens and microbial-derived antigens. Taken together, our work reveals different routes toward LLPC development and paves the way for deeper understanding of cellular and molecular underpinnings of long-term antibody immunity.


Assuntos
Microbiota , Plasmócitos , Camundongos , Animais , Autoantígenos , Imunização , Imunoglobulina M , Imunoglobulina A , Imunoglobulina G
7.
Nat Immunol ; 22(12): 1515-1523, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34811542

RESUMO

Development of an effective tuberculosis (TB) vaccine has suffered from an incomplete understanding of the correlates of protection against Mycobacterium tuberculosis (Mtb). Intravenous (i.v.) vaccination with Bacille Calmette-Guérin (BCG) provides nearly complete protection against TB in rhesus macaques, but the antibody response it elicits remains incompletely defined. Here we show that i.v. BCG drives superior antibody responses in the plasma and the lungs of rhesus macaques compared to traditional intradermal BCG administration. While i.v. BCG broadly expands antibody titers and functions, IgM titers in the plasma and lungs of immunized macaques are among the strongest markers of reduced bacterial burden. IgM was also enriched in macaques that received protective vaccination with an attenuated strain of Mtb. Finally, an Mtb-specific IgM monoclonal antibody reduced Mtb survival in vitro. Collectively, these data highlight the potential importance of IgM responses as a marker and mediator of protection against TB.


Assuntos
Anticorpos Antibacterianos/sangue , Vacina BCG/administração & dosagem , Imunogenicidade da Vacina , Imunoglobulina M/sangue , Mycobacterium tuberculosis/imunologia , Tuberculose/prevenção & controle , Vacinação , Administração Intravenosa , Animais , Biomarcadores/sangue , Modelos Animais de Doenças , Interações Hospedeiro-Patógeno , Macaca mulatta , Mycobacterium tuberculosis/patogenicidade , Fatores de Tempo , Tuberculose/imunologia , Tuberculose/microbiologia
8.
Nat Immunol ; 22(1): 25-31, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33154590

RESUMO

Clinical manifestations of COVID-19 caused by the new coronavirus SARS-CoV-2 are associated with age1,2. Adults develop respiratory symptoms, which can progress to acute respiratory distress syndrome (ARDS) in the most severe form, while children are largely spared from respiratory illness but can develop a life-threatening multisystem inflammatory syndrome (MIS-C)3-5. Here, we show distinct antibody responses in children and adults after SARS-CoV-2 infection. Adult COVID-19 cohorts had anti-spike (S) IgG, IgM and IgA antibodies, as well as anti-nucleocapsid (N) IgG antibody, while children with and without MIS-C had reduced breadth of anti-SARS-CoV-2-specific antibodies, predominantly generating IgG antibodies specific for the S protein but not the N protein. Moreover, children with and without MIS-C had reduced neutralizing activity as compared to both adult COVID-19 cohorts, indicating a reduced protective serological response. These results suggest a distinct infection course and immune response in children independent of whether they develop MIS-C, with implications for developing age-targeted strategies for testing and protecting the population.


Assuntos
Anticorpos Antivirais/imunologia , Formação de Anticorpos/imunologia , COVID-19/imunologia , Proteínas do Nucleocapsídeo/imunologia , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Adolescente , Adulto , Idoso , COVID-19/virologia , Criança , Pré-Escolar , Feminino , Humanos , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/fisiologia , Adulto Jovem
9.
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
10.
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
11.
Immunity ; 54(5): 988-1001.e5, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33857421

RESUMO

Positive selection of high-affinity B cells within germinal centers (GCs) drives affinity maturation of antibody responses. Here, we examined the mechanism underlying the parallel transition from immunoglobulin M (IgM) to IgG. Early GCs contained mostly unswitched IgM+ B cells; IgG+ B cells subsequently increased in frequency, dominating GC responses 14-21 days after antigen challenge. Somatic hypermutation and generation of high-affinity clones occurred with equal efficiency among IgM+ and IgG+ GC B cells, and inactivation of Ig class-switch recombination did not prevent depletion of IgM+ GC B cells. Instead, high-affinity IgG+ GC B cells outcompeted high-affinity IgM+ GC B cells via a selective advantage associated with IgG antigen receptor structure but independent of the extended cytoplasmic tail. Thus, two parallel forms of GC B-cell-positive selection, based on antigen receptor variable and constant regions, respectively, operate in tandem to ensure high-affinity IgG antibodies predominate in mature serum antibody responses.


Assuntos
Linfócitos B/imunologia , Centro Germinativo/imunologia , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Animais , Formação de Anticorpos/imunologia , Antígenos/imunologia , Feminino , Switching de Imunoglobulina/imunologia , Região Variável de Imunoglobulina/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Ovinos/imunologia , Hipermutação Somática de Imunoglobulina/imunologia
12.
Immunity ; 54(2): 235-246.e5, 2021 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-33357409

RESUMO

The interleukin-6 (IL-6) membrane receptor and its circulating soluble form, sIL-6R, can be targeted by antibody therapy to reduce deleterious immune signaling caused by chronic overexpression of the pro-inflammatory cytokine IL-6. This strategy may also hold promise for treating acute hyperinflammation, such as observed in coronavirus disease 2019 (COVID-19), highlighting a need to define regulators of IL-6 homeostasis. We found that conventional dendritic cells (cDCs), defined in mice via expression of the transcription factor Zbtb46, were a major source of circulating sIL-6R and, thus, systemically regulated IL-6 signaling. This was uncovered through identification of a cDC-dependent but T cell-independent modality that naturally adjuvants plasma cell differentiation and antibody responses to protein antigens. This pathway was then revealed as part of a broader biological buffer system in which cDC-derived sIL-6R set the in-solution persistence of IL-6. This control axis may further inform the development of therapeutic agents to modulate pro-inflammatory immune reactions.


Assuntos
Células Dendríticas/imunologia , Interleucina-6/sangue , Interleucina-6/imunologia , Proteína ADAM17 , Animais , Diferenciação Celular , Imunidade Humoral , Imunoglobulina M/imunologia , Inflamação , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/imunologia , Interleucina-6/genética , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Plasmócitos/imunologia , Receptores de Interleucina-6/sangue , Receptores de Interleucina-6/imunologia , Transdução de Sinais/imunologia , Receptor 4 Toll-Like/imunologia , Receptor 7 Toll-Like/imunologia
13.
Nat Immunol ; 18(3): 321-333, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28135254

RESUMO

The FcµR receptor for the crystallizable fragment (Fc) of immunoglobulin M (IgM) can function as a cell-surface receptor for secreted IgM on a variety of cell types. We found here that FcµR was also expressed in the trans-Golgi network of developing B cells, where it constrained transport of the IgM-isotype BCR (IgM-BCR) but not of the IgD-isotype BCR (IgD-BCR). In the absence of FcµR, the surface expression of IgM-BCR was increased, which resulted in enhanced tonic BCR signaling. B-cell-specific deficiency in FcµR enhanced the spontaneous differentiation of B-1 cells, which resulted in increased serum concentrations of natural IgM and dysregulated homeostasis of B-2 cells; this caused the spontaneous formation of germinal centers, increased titers of serum autoantibodies and excessive accumulation of B cells. Thus, FcµR serves as a critical regulator of B cell biology by constraining the transport and cell-surface expression of IgM-BCR.


Assuntos
Linfócitos B/fisiologia , Imunoglobulina M/metabolismo , Células Precursoras de Linfócitos B/fisiologia , Receptores de Antígenos de Linfócitos B/metabolismo , Receptores Fc/metabolismo , Animais , Diferenciação Celular , Células Cultivadas , Citocinas/metabolismo , Feminino , Regulação da Expressão Gênica , Imunoglobulina M/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Antígenos de Linfócitos B/genética , Transdução de Sinais , Células Th1/imunologia , Células Th2/imunologia
14.
Nat Immunol ; 18(10): 1150-1159, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28805811

RESUMO

Caveolin-1 (Cav1) regulates the nanoscale organization and compartmentalization of the plasma membrane. Here we found that Cav1 controlled the distribution of nanoclusters of isotype-specific B cell antigen receptors (BCRs) on the surface of B cells. In mature B cells stimulated with antigen, the immunoglobulin M BCR (IgM-BCR) gained access to lipid domains enriched for GM1 glycolipids, by a process that was dependent on the phosphorylation of Cav1 by the Src family of kinases. Antigen-induced reorganization of nanoclusters of IgM-BCRs and IgD-BCRs regulated BCR signaling in vivo. In immature Cav1-deficient B cells, altered nanoscale organization of IgM-BCRs resulted in a failure of receptor editing and a skewed repertoire of B cells expressing immunoglobulin-µ heavy chains with hallmarks of poly- and auto-reactivity, which ultimately led to autoimmunity in mice. Thus, Cav1 emerges as a cell-intrinsic regulator that prevents B cell-induced autoimmunity by means of its role in plasma-membrane organization.


Assuntos
Linfócitos B/imunologia , Linfócitos B/metabolismo , Caveolina 1/metabolismo , Tolerância Imunológica , Receptores de Antígenos de Linfócitos B/metabolismo , Animais , Autoimunidade/genética , Autoimunidade/imunologia , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Caveolina 1/genética , Expressão Gênica , Tolerância Imunológica/genética , Imunoglobulina D/imunologia , Imunoglobulina D/metabolismo , Imunoglobulina M/imunologia , Imunoglobulina M/metabolismo , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Fosforilação , Ligação Proteica , Receptores de Antígenos de Linfócitos B/genética
15.
Immunity ; 52(3): 557-570.e6, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32160523

RESUMO

The intestine contains some of the most diverse and complex immune compartments in the body. Here we describe a method for isolating human gut-associated lymphoid tissues (GALTs) that allows unprecedented profiling of the adaptive immune system in submucosal and mucosal isolated lymphoid follicles (SM-ILFs and M-ILFs, respectively) as well as in GALT-free intestinal lamina propria (LP). SM-ILF and M-ILF showed distinct patterns of distribution along the length of the intestine, were linked to the systemic circulation through MAdCAM-1+ high endothelial venules and efferent lymphatics, and had immune profiles consistent with immune-inductive sites. IgA sequencing analysis indicated that human ILFs are sites where intestinal adaptive immune responses are initiated in an anatomically restricted manner. Our findings position ILFs as key inductive hubs for regional immunity in the human intestine, and the methods presented will allow future assessment of these compartments in health and disease.


Assuntos
Imunidade Adaptativa/imunologia , Imunidade nas Mucosas/imunologia , Mucosa Intestinal/imunologia , Intestinos/imunologia , Tecido Linfoide/imunologia , Imunidade Adaptativa/genética , Animais , Citometria de Fluxo , Mucosa Gástrica/imunologia , Mucosa Gástrica/metabolismo , Mucosa Gástrica/ultraestrutura , Humanos , Imunidade nas Mucosas/genética , Imunoglobulina A/genética , Imunoglobulina A/imunologia , Imunoglobulina M/genética , Imunoglobulina M/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/ultraestrutura , Intestinos/ultraestrutura , Linfócitos/imunologia , Linfócitos/metabolismo , Tecido Linfoide/metabolismo , Tecido Linfoide/ultraestrutura , Microscopia Confocal , Microscopia Eletrônica de Varredura , Nódulos Linfáticos Agregados/imunologia , Nódulos Linfáticos Agregados/metabolismo , Nódulos Linfáticos Agregados/ultraestrutura , Análise de Sequência de DNA
16.
Cell ; 159(6): 1277-89, 2014 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-25480293

RESUMO

Glycosylation processes are under high natural selection pressure, presumably because these can modulate resistance to infection. Here, we asked whether inactivation of the UDP-galactose:ß-galactoside-α1-3-galactosyltransferase (α1,3GT) gene, which ablated the expression of the Galα1-3Galß1-4GlcNAc-R (α-gal) glycan and allowed for the production of anti-α-gal antibodies (Abs) in humans, confers protection against Plasmodium spp. infection, the causative agent of malaria and a major driving force in human evolution. We demonstrate that both Plasmodium spp. and the human gut pathobiont E. coli O86:B7 express α-gal and that anti-α-gal Abs are associated with protection against malaria transmission in humans as well as in α1,3GT-deficient mice, which produce protective anti-α-gal Abs when colonized by E. coli O86:B7. Anti-α-gal Abs target Plasmodium sporozoites for complement-mediated cytotoxicity in the skin, immediately after inoculation by Anopheles mosquitoes. Vaccination against α-gal confers sterile protection against malaria in mice, suggesting that a similar approach may reduce malaria transmission in humans.


Assuntos
Escherichia coli/fisiologia , Imunoglobulina M/imunologia , Malária Falciparum/imunologia , Malária Falciparum/transmissão , Plasmodium/fisiologia , Polissacarídeos/imunologia , Adulto , Animais , Anopheles/parasitologia , Anticorpos Antibacterianos/sangue , Anticorpos Antibacterianos/imunologia , Anticorpos Antiprotozoários/sangue , Anticorpos Antiprotozoários/imunologia , Autoantígenos/imunologia , Linhagem Celular Tumoral , Criança , Escherichia coli/classificação , Escherichia coli/imunologia , Feminino , Galactosiltransferases/genética , Galactosiltransferases/metabolismo , Trato Gastrointestinal/microbiologia , Vida Livre de Germes , Humanos , Imunoglobulina M/sangue , Malária Falciparum/microbiologia , Malária Falciparum/parasitologia , Camundongos , Plasmodium/classificação , Plasmodium/crescimento & desenvolvimento , Plasmodium/imunologia , Plasmodium falciparum/imunologia , Plasmodium falciparum/fisiologia , Esporozoítos/imunologia , Receptor Toll-Like 9/agonistas
17.
Nature ; 623(7985): 149-156, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37880367

RESUMO

Host factors that mediate Leishmania genetic exchange are not well defined. Here we demonstrate that natural IgM (IgMn)1-4 antibodies mediate parasite genetic exchange by inducing the transient formation of a spherical parasite clump that promotes parasite fusion and hybrid formation. We establish that IgMn from Leishmania-free animals binds to the surface of Leishmania parasites to induce significant changes in the expression of parasite transcripts and proteins. Leishmania binding to IgMn is partially lost after glycosidase treatment, although parasite surface phosphoglycans, including lipophosphoglycan, are not required for IgMn-induced parasite clumping. Notably, the transient formation of parasite clumps is essential for Leishmania hybridization in vitro. In vivo, we observed a 12-fold increase in hybrid formation in sand flies provided a second blood meal containing IgMn compared with controls. Furthermore, the generation of recombinant progeny from mating hybrids and parental lines were only observed in sand flies provided with IgMn. Both in vitro and in vivo IgM-induced Leishmania crosses resulted in full genome hybrids that show equal patterns of biparental contribution. Leishmania co-option of a host natural antibody to facilitate mating in the insect vector establishes a new paradigm of parasite-host-vector interdependence that contributes to parasite diversity and fitness by promoting genetic exchange.


Assuntos
Interações Hospedeiro-Parasita , Imunoglobulina M , Leishmania , Psychodidae , Reprodução , Animais , Hibridização Genética , Imunoglobulina M/imunologia , Leishmania/genética , Leishmania/imunologia , Psychodidae/imunologia , Psychodidae/parasitologia , Reprodução/genética , Interações Hospedeiro-Parasita/genética , Interações Hospedeiro-Parasita/imunologia , Regulação da Expressão Gênica , Glicosídeo Hidrolases/metabolismo
18.
Nature ; 615(7954): 907-912, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36949194

RESUMO

Immunoglobulin M (IgM) is the first antibody to emerge during embryonic development and the humoral immune response1. IgM can exist in several distinct forms, including monomeric, membrane-bound IgM within the B cell receptor (BCR) complex, pentameric and hexameric IgM in serum and secretory IgM on the mucosal surface. FcµR, the only IgM-specific receptor in mammals, recognizes different forms of IgM to regulate diverse immune responses2-5. However, the underlying molecular mechanisms remain unknown. Here we delineate the structural basis of the FcµR-IgM interaction by crystallography and cryo-electron microscopy. We show that two FcµR molecules interact with a Fcµ-Cµ4 dimer, suggesting that FcµR can bind to membrane-bound IgM with a 2:1 stoichiometry. Further analyses reveal that FcµR-binding sites are accessible in the context of IgM BCR. By contrast, pentameric IgM can recruit four FcµR molecules to bind on the same side and thereby facilitate the formation of an FcµR oligomer. One of these FcµR molecules occupies the binding site of the secretory component. Nevertheless, four FcµR molecules bind to the other side of secretory component-containing secretory IgM, consistent with the function of FcµR in the retrotransport of secretory IgM. These results reveal intricate mechanisms of IgM perception by FcµR.


Assuntos
Proteínas Reguladoras de Apoptose , Imunoglobulina M , Proteínas de Membrana , Animais , Linfócitos B/citologia , Linfócitos B/metabolismo , Sítios de Ligação , Membrana Celular/metabolismo , Microscopia Crioeletrônica , Cristalografia por Raios X , Imunoglobulina M/química , Imunoglobulina M/metabolismo , Imunoglobulina M/ultraestrutura , Mamíferos , Ligação Proteica , Multimerização Proteica , Receptores de Antígenos de Linfócitos B/química , Receptores de Antígenos de Linfócitos B/metabolismo , Receptores de Antígenos de Linfócitos B/ultraestrutura , Componente Secretório/química , Componente Secretório/metabolismo , Componente Secretório/ultraestrutura , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Proteínas de Membrana/ultraestrutura , Proteínas Reguladoras de Apoptose/química , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Reguladoras de Apoptose/ultraestrutura
19.
Nature ; 613(7945): 735-742, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36473496

RESUMO

Feedback inhibition of humoral immunity by antibodies was first documented in 19091. Subsequent studies showed that, depending on the context, antibodies can enhance or inhibit immune responses2,3. However, little is known about how pre-existing antibodies influence the development of memory B cells. Here we examined the memory B cell response in individuals who received two high-affinity anti-SARS-CoV-2 monoclonal antibodies and subsequently two doses of an mRNA vaccine4-8. We found that the recipients of the monoclonal antibodies produced antigen-binding and neutralizing titres that were only fractionally lower compared than in control individuals. However, the memory B cells of the individuals who received the monoclonal antibodies differed from those of control individuals in that they predominantly expressed low-affinity IgM antibodies that carried small numbers of somatic mutations and showed altered receptor binding domain (RBD) target specificity, consistent with epitope masking. Moreover, only 1 out of 77 anti-RBD memory antibodies tested neutralized the virus. The mechanism underlying these findings was examined in experiments in mice that showed that germinal centres formed in the presence of the same antibodies were dominated by low-affinity B cells. Our results indicate that pre-existing high-affinity antibodies bias germinal centre and memory B cell selection through two distinct mechanisms: (1) by lowering the activation threshold for B cells, thereby permitting abundant lower-affinity clones to participate in the immune response; and (2) through direct masking of their cognate epitopes. This may in part explain the shifting target profile of memory antibodies elicited by booster vaccinations9.


Assuntos
Anticorpos Antivirais , Linfócitos B , Vacinas contra COVID-19 , COVID-19 , Retroalimentação Fisiológica , Memória Imunológica , Vacinação , Vacinas de mRNA , Animais , Camundongos , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/imunologia , COVID-19/prevenção & controle , COVID-19/terapia , COVID-19/virologia , SARS-CoV-2/imunologia , Vacinas de mRNA/imunologia , Vacinas contra COVID-19/imunologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Epitopos de Linfócito B/química , Epitopos de Linfócito B/imunologia , Imunoglobulina M/imunologia , Centro Germinativo/citologia , Centro Germinativo/imunologia , Imunização Secundária , Hipermutação Somática de Imunoglobulina
20.
Immunity ; 51(6): 1088-1101.e5, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31732168

RESUMO

The B cell response to Ehrlichia muris is dominated by plasmablasts (PBs), with few-if any-germinal centers (GCs), yet it generates protective immunoglobulin M (IgM) memory B cells (MBCs) that express the transcription factor T-bet and harbor V-region mutations. Because Ehrlichia prominently infects the liver, we investigated the nature of liver B cell response and that of the spleen. B cells within infected livers proliferated and underwent somatic hypermutation (SHM). Vh-region sequencing revealed trafficking of clones between the spleen and liver and often subsequent local clonal expansion and intraparenchymal localization of T-bet+ MBCs. T-bet+ MBCs expressed MBC subset markers CD80 and PD-L2. Many T-bet+ MBCs lacked CD11b or CD11c expression but had marginal zone (MZ) B cell phenotypes and colonized the splenic MZ, revealing T-bet+ MBC plasticity. Hence, liver and spleen are generative sites of B cell responses, and they include V-region mutation and result in liver MBC localization.


Assuntos
Linfócitos B/imunologia , Ehrlichia/imunologia , Ehrlichiose/imunologia , Imunoglobulina M/imunologia , Fígado/imunologia , Baço/imunologia , Animais , Antígeno B7-1/biossíntese , Região Variável de Imunoglobulina/genética , Memória Imunológica/imunologia , Fígado/citologia , Camundongos , Camundongos Endogâmicos C57BL , Proteína 2 Ligante de Morte Celular Programada 1/biossíntese , Hipermutação Somática de Imunoglobulina/genética , Baço/citologia , Proteínas com Domínio T/metabolismo
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