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1.
Front Immunol ; 12: 708523, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220870

RESUMO

Major advances have been made in understanding the dynamics of humoral immunity briefly after the acute coronavirus disease 2019 (COVID-19). However, knowledge concerning long-term kinetics of antibody responses in convalescent patients is limited. During a one-year period post symptom onset, we longitudinally collected 162 samples from 76 patients and quantified IgM and IgG antibodies recognizing the nucleocapsid (N) protein or the receptor binding domain (RBD) of the spike protein (S). After one year, approximately 90% of recovered patients still had detectable SARS-CoV-2-specific IgG antibodies recognizing N and RBD-S. Intriguingly, neutralizing activity was only detectable in ~43% of patients. When neutralization tests against the E484K-mutated variant of concern (VOC) B.1.351 (initially identified in South Africa) were performed among patients who neutralize the original virus, the capacity to neutralize was even further diminished to 22.6% of donors. Despite declining N- and S-specific IgG titers, a considerable fraction of recovered patients had detectable neutralizing activity one year after infection. However, neutralizing capacities, in particular against an E484K-mutated VOC were only detectable in a minority of patients one year after symptomatic COVID-19. Our findings shed light on the kinetics of long-term immune responses after natural SARS-CoV-2 infection and argue for vaccinations of individuals who experienced a natural infection to protect against emerging VOC.


Assuntos
Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , COVID-19/imunologia , Imunoglobulina G/sangue , Imunoglobulina M/sangue , SARS-CoV-2/imunologia , Idoso , Formação de Anticorpos/imunologia , COVID-19/terapia , Convalescença , Proteínas do Nucleocapsídeo de Coronavírus/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fosfoproteínas/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Fatores de Tempo
2.
FASEB J ; 35(7): e21746, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34151465

RESUMO

Bullous pemphigoid (BP), an autoimmune skin disease, is characterized by autoantibodies against hemidesmosomal proteins in the skin and mucous membranes. Neutrophils infiltrate BP skin lesions, however, their role in immune dysregulation remains unclear. We investigated whether BP involves aberrant neutrophil extracellular traps (NETs) formation in skin lesions and circulation; and examined the triggers and deleterious immuno-inflammatory consequences. In the present study, we found that circulating NET-related biomarker levels increased in serum and blister fluid of BP patients and significantly correlated with disease severity. Additionally, circulating neutrophils from BP patients displayed enhanced spontaneous NETs formation than healthy controls. In vitro, BP180-NC16A immune complexes-induced NETosis in neutrophils from BP patients, which was abrogated by Fcγ receptor and/or NADPH pathway blockade. Furthermore, the elevated levels of NETs from BP patients boosted autoantibody production by inducing B-cell differentiation into plasma cells, mediated by MAPK P38 cascade activation. Together, our findings provide strong evidence that NETs are involved in a pathogenic loop, causing excessive differentiation of B cells and promotion of autoantibody production. Hence, targeting aberrant neutrophil responses will provide novel potential targets for the treatment of BP.


Assuntos
Formação de Anticorpos/imunologia , Linfócitos B/imunologia , Diferenciação Celular/imunologia , Armadilhas Extracelulares/imunologia , Neutrófilos/imunologia , Penfigoide Bolhoso/imunologia , Autoanticorpos/imunologia , Autoantígenos/imunologia , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Linfócitos B/metabolismo , Biomarcadores/metabolismo , Vesícula/imunologia , Vesícula/metabolismo , Armadilhas Extracelulares/metabolismo , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Neutrófilos/metabolismo , Penfigoide Bolhoso/metabolismo , Plasmócitos/imunologia , Plasmócitos/metabolismo , Receptores de IgG/imunologia , Transdução de Sinais/imunologia , Pele/imunologia , Pele/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
3.
JCI Insight ; 6(13)2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34081630

RESUMO

BACKGROUNDThe role of humoral immunity in COVID-19 is not fully understood, owing, in large part, to the complexity of antibodies produced in response to the SARS-CoV-2 infection. There is a pressing need for serology tests to assess patient-specific antibody response and predict clinical outcome.METHODSUsing SARS-CoV-2 proteome and peptide microarrays, we screened 146 COVID-19 patients' plasma samples to identify antigens and epitopes. This enabled us to develop a master epitope array and an epitope-specific agglutination assay to gauge antibody responses systematically and with high resolution.RESULTSWe identified linear epitopes from the spike (S) and nucleocapsid (N) proteins and showed that the epitopes enabled higher resolution antibody profiling than the S or N protein antigen. Specifically, we found that antibody responses to the S-811-825, S-881-895, and N-156-170 epitopes negatively or positively correlated with clinical severity or patient survival. Moreover, we found that the P681H and S235F mutations associated with the coronavirus variant of concern B.1.1.7 altered the specificity of the corresponding epitopes.CONCLUSIONEpitope-resolved antibody testing not only affords a high-resolution alternative to conventional immunoassays to delineate the complex humoral immunity to SARS-CoV-2 and differentiate between neutralizing and non-neutralizing antibodies, but it also may potentially be used to predict clinical outcome. The epitope peptides can be readily modified to detect antibodies against variants of concern in both the peptide array and latex agglutination formats.FUNDINGOntario Research Fund (ORF) COVID-19 Rapid Research Fund, Toronto COVID-19 Action Fund, Western University, Lawson Health Research Institute, London Health Sciences Foundation, and Academic Medical Organization of Southwestern Ontario (AMOSO) Innovation Fund.


Assuntos
Testes de Aglutinação/métodos , Formação de Anticorpos/imunologia , Teste Sorológico para COVID-19/métodos , COVID-19/imunologia , Epitopos de Linfócito B/imunologia , SARS-CoV-2/imunologia , Sequência de Aminoácidos , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Especificidade de Anticorpos/imunologia , COVID-19/sangue , COVID-19/mortalidade , Epitopos/imunologia , Epitopos de Linfócito B/química , Epitopos de Linfócito B/genética , Humanos , Imunidade Humoral , Análise em Microsséries/métodos , Nucleocapsídeo/química , Nucleocapsídeo/genética , Nucleocapsídeo/imunologia , Peptídeos/imunologia , SARS-CoV-2/genética , Índice de Gravidade de Doença , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia
4.
Nat Commun ; 12(1): 3587, 2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-34117252

RESUMO

There is a great need for the development of vaccines that induce potent and long-lasting protective immunity against SARS-CoV-2. Multimeric display of the antigen combined with potent adjuvant can enhance the potency and longevity of the antibody response. The receptor binding domain (RBD) of the spike protein is a primary target of neutralizing antibodies. Here, we developed a trimeric form of the RBD and show that it induces a potent neutralizing antibody response against live virus with diverse effector functions and provides protection against SARS-CoV-2 challenge in mice and rhesus macaques. The trimeric form induces higher neutralizing antibody titer compared to monomer with as low as 1µg antigen dose. In mice, adjuvanting the protein with a TLR7/8 agonist formulation alum-3M-052 induces 100-fold higher neutralizing antibody titer and superior protection from infection compared to alum. SARS-CoV-2 infection causes significant loss of innate cells and pathology in the lung, and vaccination protects from changes in innate cells and lung pathology. These results demonstrate RBD trimer protein as a suitable candidate for vaccine against SARS-CoV-2.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Vacinas contra COVID-19/imunologia , COVID-19/imunologia , COVID-19/prevenção & controle , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Ácidos Esteáricos/administração & dosagem , Compostos de Alúmen/administração & dosagem , Enzima de Conversão de Angiotensina 2/imunologia , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Formação de Anticorpos/imunologia , Vacinas contra COVID-19/administração & dosagem , Modelos Animais de Doenças , Compostos Heterocíclicos com 3 Anéis/imunologia , Humanos , Macaca mulatta , Camundongos , Ligação Proteica , SARS-CoV-2/isolamento & purificação , Glicoproteína da Espícula de Coronavírus/imunologia , Ácidos Esteáricos/imunologia
5.
Immunity ; 54(6): 1290-1303.e7, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34022127

RESUMO

Dissecting the evolution of memory B cells (MBCs) against SARS-CoV-2 is critical for understanding antibody recall upon secondary exposure. Here, we used single-cell sequencing to profile SARS-CoV-2-reactive B cells in 38 COVID-19 patients. Using oligo-tagged antigen baits, we isolated B cells specific to the SARS-CoV-2 spike, nucleoprotein (NP), open reading frame 8 (ORF8), and endemic human coronavirus (HCoV) spike proteins. SARS-CoV-2 spike-specific cells were enriched in the memory compartment of acutely infected and convalescent patients several months post symptom onset. With severe acute infection, substantial populations of endemic HCoV-reactive antibody-secreting cells were identified and possessed highly mutated variable genes, signifying preexisting immunity. Finally, MBCs exhibited pronounced maturation to NP and ORF8 over time, especially in older patients. Monoclonal antibodies against these targets were non-neutralizing and non-protective in vivo. These findings reveal antibody adaptation to non-neutralizing intracellular antigens during infection, emphasizing the importance of vaccination for inducing neutralizing spike-specific MBCs.


Assuntos
Anticorpos Antivirais/imunologia , Formação de Anticorpos/imunologia , Linfócitos B/imunologia , COVID-19/imunologia , Interações Hospedeiro-Patógeno/imunologia , Epitopos Imunodominantes/imunologia , SARS-CoV-2/imunologia , Anticorpos Neutralizantes/imunologia , Formação de Anticorpos/genética , Linfócitos B/metabolismo , Biologia Computacional/métodos , Reações Cruzadas/imunologia , Mapeamento de Epitopos , Feminino , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Interações Hospedeiro-Patógeno/genética , Humanos , Epitopos Imunodominantes/genética , Memória Imunológica , Masculino , Testes de Neutralização , Análise de Célula Única/métodos , Glicoproteína da Espícula de Coronavírus/imunologia , Transcriptoma
6.
Nat Commun ; 12(1): 2691, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976217

RESUMO

How innate and adaptive immune responses work in concert to resolve influenza disease is yet to be fully investigated in one single study. Here, we utilize longitudinal samples from patients hospitalized with acute influenza to understand these immune responses. We report the dynamics of 18 important immune parameters, related to clinical, genetic and virological factors, in influenza patients across different severity levels. Influenza disease correlates with increases in IL-6/IL-8/MIP-1α/ß cytokines and lower antibody responses. Robust activation of circulating T follicular helper cells correlates with peak antibody-secreting cells and influenza heamaglutinin-specific memory B-cell numbers, which phenotypically differs from vaccination-induced B-cell responses. Numbers of influenza-specific CD8+ or CD4+ T cells increase early in disease and retain an activated phenotype during patient recovery. We report the characterisation of immune cellular networks underlying recovery from influenza infection which are highly relevant to other infectious diseases.


Assuntos
Formação de Anticorpos/imunologia , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Citocinas/imunologia , Influenza Humana/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Estudos de Coortes , Citocinas/metabolismo , Hospitalização/estatística & dados numéricos , Humanos , Vírus da Influenza A/classificação , Vírus da Influenza A/genética , Vírus da Influenza A/fisiologia , Vacinas contra Influenza/imunologia , Influenza Humana/virologia , Pessoa de Meia-Idade , Filogenia , Vacinação/métodos
7.
Front Immunol ; 12: 620437, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33936036

RESUMO

T Follicular helper (Tfh) cells promote germinal center (GC) B cell responses to develop effective humoral immunity against pathogens. However, dysregulated Tfh cells can also trigger autoantibody production and the development of autoimmune diseases. We report here that Tsc1, a regulator for mTOR signaling, plays differential roles in Tfh cell/GC B cell responses in the steady state and in immune responses to antigen immunization. In the steady state, Tsc1 in T cells intrinsically suppresses spontaneous GC-Tfh cell differentiation and subsequent GC-B cell formation and autoantibody production. In immune responses to antigen immunization, Tsc1 in T cells is required for efficient GC-Tfh cell expansion, GC-B cell induction, and antigen-specific antibody responses, at least in part via promoting GC-Tfh cell mitochondrial integrity and survival. Interestingly, in mixed bone marrow chimeric mice reconstituted with both wild-type and T cell-specific Tsc1-deficient bone marrow cells, Tsc1 deficiency leads to enhanced GC-Tfh cell differentiation of wild-type CD4 T cells and increased accumulation of wild-type T regulatory cells and T follicular regulatory cells. Such bystander GC-Tfh cell differentiation suggests a potential mechanism that could trigger self-reactive GC-Tfh cell/GC responses and autoimmunity via neighboring GC-Tfh cells.


Assuntos
Autoimunidade , Diferenciação Celular/imunologia , Imunomodulação/genética , Células T Auxiliares Foliculares/imunologia , Células T Auxiliares Foliculares/metabolismo , Proteína 1 do Complexo Esclerose Tuberosa/genética , Animais , Formação de Anticorpos/genética , Formação de Anticorpos/imunologia , Autoanticorpos/sangue , Autoanticorpos/imunologia , Autoimunidade/genética , Autoimunidade/imunologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Diferenciação Celular/genética , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Proteína 1 do Complexo Esclerose Tuberosa/metabolismo
8.
Nat Commun ; 12(1): 3073, 2021 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-34031386

RESUMO

Follicular helper T (TFH) cells control antibody responses by supporting antibody affinity maturation and memory formation. Inadequate TFH function has been found in individuals with ineffective responses to vaccines, but the mechanism underlying TFH regulation in vaccination is not understood. Here, we report that lower serum levels of the metabolic hormone leptin associate with reduced vaccine responses to influenza or hepatitis B virus vaccines in healthy populations. Leptin promotes mouse and human TFH differentiation and IL-21 production via STAT3 and mTOR pathways. Leptin receptor deficiency impairs TFH generation and antibody responses in immunisation and infection. Similarly, leptin deficiency induced by fasting reduces influenza vaccination-mediated protection for the subsequent infection challenge, which is mostly rescued by leptin replacement. Our results identify leptin as a regulator of TFH cell differentiation and function and indicate low levels of leptin as a risk factor for vaccine failure.


Assuntos
Formação de Anticorpos/imunologia , Vacinas contra Influenza/imunologia , Leptina/metabolismo , Animais , Anticorpos Antivirais/imunologia , Diferenciação Celular , Feminino , Homeostase , Humanos , Imunização , Influenza Humana/prevenção & controle , Leptina/deficiência , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Vacinação/métodos
9.
Front Immunol ; 12: 620427, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33868238

RESUMO

The positive coreceptor function of complement receptor type 2 [CR2 (CD21)] on B cells is generally accepted, although its role in the enhancement of antibody production had only been proven in mice. The importance of this phenomenon prompted reinvestigation of the functional consequences of coclustering CD21 and the B cell receptor (BCR) on primary human cells. We found that, at non-stimulatory concentrations of anti-IgG/A/M, coclustering the BCR and CR2 enhanced the Ca2+ response, while activation marker expression, cytokine production, proliferation, and antibody production were all inhibited upon the coengagement of CR2 and BCR on human B cells. Thus, the "textbook dogma" claiming that C3d acts as an adjuvant to enhance humoral immunity is relevant only to mice and not to humans.


Assuntos
Formação de Anticorpos/imunologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Ativação Linfocitária/imunologia , Receptores de Antígenos de Linfócitos B/metabolismo , Receptores de Complemento 3d/metabolismo , Formação de Anticorpos/genética , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Biomarcadores , Células Cultivadas , Citocinas/metabolismo , Humanos , Lectinas Tipo C/metabolismo , Ativação Linfocitária/genética , Ligação Proteica
10.
Scand J Immunol ; 94(2): e13045, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33891354

RESUMO

There is limited knowledge of influenza-specific immune responses and their kinetics in critically ill patients. We investigated humoral and cellular immune responses after critical influenza A/H1N1 infection and hypothesized that dysfunctionality or absence of immune responses could contribute to more severe illness. We followed 12 patients hospitalized with severe influenza infection; the majority admitted to intensive care unit (ICU). Blood samples were collected at days 10 and 19 and at 5 months. Antibody responses to surface glycoproteins haemagglutinin (HA) and neuraminidase (NA) of A/H1N1pdm09 were quantified by haemagglutination inhibition (HAI), microneutralization (MN), Enzyme-linked immunosorbent assay (ELISA) and Enzyme-linked lectin assay (ELLA). Influenza-specific antibody levels and avidity were measured separately for head and stalk domains of H1. Cytokine secreting CD4+ and CD8+ T cell responses to conserved influenza epitopes (M1, NP and PB1) were analysed by FluoroSpot. Overall, the patients retained a high level of functional HA- and NA-specific antibodies over the study period. During the acute phase (up to 3 weeks from symptom onset), antibodies specific to H1 stalk increased earlier and were present in higher amount compared with H1 head-specific antibodies. The NA-specific antibodies and the non-neutralizing HA-specific antibody response for H1 head and H1 full-length showed a significant decline from acute to convalescent phase. Despite high total IgG concentrations, avidity to H1 head and H1 full-length protein remained low at all time points. Similarly, CD8+ T cell responses were continuously measured at low levels. In conclusion, our study found that critically ill patients were characterized by low HA-specific antibody avidity and CD8+ T cell response.


Assuntos
Imunidade Celular/imunologia , Imunidade Humoral/imunologia , Vírus da Influenza A Subtipo H1N1/imunologia , Influenza Humana/imunologia , Adulto , Idoso , Anticorpos Antivirais/imunologia , Formação de Anticorpos/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Estado Terminal , Feminino , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Humanos , Vacinas contra Influenza/imunologia , Masculino , Pessoa de Meia-Idade
11.
Arch Virol ; 166(7): 1977-1984, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33871696

RESUMO

To enhance the potency of a foot-and-mouth disease (FMD) vaccine, saponin was included in the vaccine formula. In this study, the combined effect of Montanide ISA 50 and saponin was evaluated. Two experiments were performed in guinea pigs and one in cattle to determine the optimal antigen and saponin doses. Only serotype O of foot-and-mouth disease virus (O/PanAsia-2 of ME-SA topotype) was employed in preparation of the monovalent vaccine. All animals were immunized twice with a four-week interval, except for the negative controls. Blood was collected 10 days after the second booster, and the immune response was evaluated using a serum neutralization test. Oil-based FMD vaccines containing saponin induced higher neutralizing antibody levels than formulations lacking saponin. The addition of saponin to formulations with low antigen payload (2.5 µg of inactivated whole virus particles [146S particles] per dose) gave significantly higher neutralizing antibody levels (p < 0.005) than 5 µg of 146S without saponin, suggesting that it can be used to improve FMD vaccine potency in susceptible animals. No adverse effects were observed in vaccinated cattle or guinea pigs.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Anticorpos Antivirais/imunologia , Formação de Anticorpos/imunologia , Vírus da Febre Aftosa/imunologia , Febre Aftosa/imunologia , Saponinas/imunologia , Vacinas Virais/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Bovinos , Doenças dos Bovinos/imunologia , Doenças dos Bovinos/virologia , Febre Aftosa/virologia , Cobaias , Testes de Neutralização/métodos , Sorogrupo , Vacinação/métodos
12.
Int J Mol Sci ; 22(7)2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33917390

RESUMO

Glycosphingolipids (GSLs) are composed of a mono-, di-, or oligosaccharide and a ceramide and function as constituents of cell membranes. Various molecular species of GSLs have been identified in mammalian cells due to differences in the structures of oligosaccharides. The oligosaccharide structure can vary depending on cell lineage, differentiation stage, and pathology; this property can be used as a cell identification marker. Furthermore, GSLs are involved in various aspects of the immune response, such as cytokine production, immune signaling, migration of immune cells, and antibody production. GSLs containing certain structures exhibit strong immunogenicity in immunized animals and promote the production of anti-GSL antibodies. By exploiting this property, it is possible to generate antibodies that recognize the fine oligosaccharide structure of specific GSLs or glycoproteins. In our study using artificially synthesized GSLs (artGSLs), we found that several structural features are correlated with the antibody-inducing activity of GSLs. Based on these findings, we designed artGSLs that efficiently induce the production of antibodies accompanied by class switching and developed several antibodies that recognize not only certain glycan structures of GSLs but also those of glycoproteins. This review comprehensively introduces the immune activities of GSLs and their application as pharmaceuticals.


Assuntos
Anticorpos/imunologia , Formação de Anticorpos , Movimento Celular , Glicoesfingolipídeos/farmacologia , Switching de Imunoglobulina/efeitos dos fármacos , Transdução de Sinais , Animais , Formação de Anticorpos/efeitos dos fármacos , Formação de Anticorpos/imunologia , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Citocinas/imunologia , Glicoesfingolipídeos/química , Glicoesfingolipídeos/imunologia , Humanos , Transdução de Sinais/imunologia
13.
Int J Mol Sci ; 22(6)2021 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-33801155

RESUMO

The causes of otitis media (OM) involve bacterial and viral infection, anatomo-physiological abnormalities of the Eustachian canal and nasopharynx, allergic rhinitis, group childcare centers, second-hand smoking, obesity, immaturity and defects of the immune system, formula feeding, sex, race, and age. OM is accompanied by complex and diverse interactions among bacteria, viruses, inflammatory cells, immune cells, and epithelial cells. The present study summarizes the antibodies that contribute to immune reactions in all types of otitis media, including acute otitis media, otitis media with effusion, and chronic otitis media with or without cholesteatoma, as well as the transcription factors that induce the production of these antibodies. The types and distribution of B cells; the functions of B cells, especially in otorhinolaryngology; antibody formation in patients with otitis media; and antibodies and related transcription factors are described. B cells have important functions in host defenses, including antigen recognition, antigen presentation, antibody production, and immunomodulation. The phenotypes of B cells in the ear, nose, and throat, especially in patients with otitis media, were shown to be CD5low, CD23high, CD43low, B220high, sIgMlow, sIgDhigh, Mac-1low, CD80(B7.1)low, CD86(B7.2)low, and Syndecam-1low. Of the five major classes of immunoglobulins produced by B cells, three (IgG, IgA, and IgM) are mainly involved in otitis media. Serum concentrations of IgG, IgA, and IgM are lower in patients with OM with effusion (OME) than in subjects without otitis media. Moreover, IgG, IgA, and IgM concentrations in the middle ear cavity are increased during immune responses in patients with otitis media. B cell leukemia/lymphoma-6 (Bcl-6) and paired box gene 5 (Pax-5) suppress antibody production, whereas B lymphocyte inducer of maturation program 1 (Blimp-1) and X-box binding protein 1 (XBP-1) promote antibody production during immune responses in patients with otitis media.


Assuntos
Suscetibilidade a Doenças , Imunoglobulinas/imunologia , Otite Média/etiologia , Otite Média/metabolismo , Fatores de Transcrição/metabolismo , Animais , Formação de Anticorpos/imunologia , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Gerenciamento Clínico , Regulação da Expressão Gênica , Humanos , Imunoglobulina A/biossíntese , Imunoglobulina A/imunologia , Imunoglobulinas/genética , Otite Média/diagnóstico
14.
Nat Commun ; 12(1): 2037, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33795692

RESUMO

The hallmarks of COVID-19 are higher pathogenicity and mortality in the elderly compared to children. Examining baseline SARS-CoV-2 cross-reactive immunological responses, induced by circulating human coronaviruses (hCoVs), is needed to understand such divergent clinical outcomes. Here we show analysis of coronavirus antibody responses of pre-pandemic healthy children (n = 89), adults (n = 98), elderly (n = 57), and COVID-19 patients (n = 50) by systems serology. Moderate levels of cross-reactive, but non-neutralizing, SARS-CoV-2 antibodies are detected in pre-pandemic healthy individuals. SARS-CoV-2 antigen-specific Fcγ receptor binding accurately distinguishes COVID-19 patients from healthy individuals, suggesting that SARS-CoV-2 infection induces qualitative changes to antibody Fc, enhancing Fcγ receptor engagement. Higher cross-reactive SARS-CoV-2 IgA and IgG are observed in healthy elderly, while healthy children display elevated SARS-CoV-2 IgM, suggesting that children have fewer hCoV exposures, resulting in less-experienced but more polyreactive humoral immunity. Age-dependent analysis of COVID-19 patients, confirms elevated class-switched antibodies in elderly, while children have stronger Fc responses which we demonstrate are functionally different. These insights will inform COVID-19 vaccination strategies, improved serological diagnostics and therapeutics.


Assuntos
Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Formação de Anticorpos/imunologia , SARS-CoV-2/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19/imunologia , Vacinas contra COVID-19/imunologia , Criança , Pré-Escolar , Reações Cruzadas/imunologia , Humanos , Imunoglobulina A/sangue , Imunoglobulina A/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Imunoglobulina M/sangue , Imunoglobulina M/imunologia , Pessoa de Meia-Idade , Receptores de IgG/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Adulto Jovem
15.
16.
Front Immunol ; 12: 615102, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33732238

RESUMO

The re-emergence of Zika virus (ZIKV) caused widespread infections that were linked to Guillain-Barré syndrome in adults and congenital malformation in fetuses, and epidemiological data suggest that ZIKV infection can induce protective antibody responses. A more detailed understanding of anti-ZIKV antibody responses may lead to enhanced antibody discovery and improved vaccine designs against ZIKV and related flaviviruses. Here, we applied recently-invented library-scale antibody screening technologies to determine comprehensive functional molecular and genetic profiles of naturally elicited human anti-ZIKV antibodies in three convalescent individuals. We leveraged natively paired antibody yeast display and NGS to predict antibody cross-reactivities and coarse-grain antibody affinities, to perform in-depth immune profiling of IgM, IgG, and IgA antibody repertoires in peripheral blood, and to reveal virus maturation state-dependent antibody interactions. Repertoire-scale comparison of ZIKV VLP-specific and non-specific antibodies in the same individuals also showed that mean antibody somatic hypermutation levels were substantially influenced by donor-intrinsic characteristics. These data provide insights into antiviral antibody responses to ZIKV disease and outline systems-level strategies to track human antibody immune responses to emergent viral infections.


Assuntos
Anticorpos Antivirais/imunologia , Formação de Anticorpos/imunologia , Interações Hospedeiro-Patógeno/imunologia , Infecção por Zika virus/imunologia , Infecção por Zika virus/virologia , Zika virus/imunologia , Anticorpos Neutralizantes/genética , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/genética , Formação de Anticorpos/genética , Linfócitos B/imunologia , Linfócitos B/metabolismo , Biologia Computacional/métodos , Citometria de Fluxo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Testes de Neutralização , Biblioteca de Peptídeos
17.
Front Immunol ; 12: 614115, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33717097

RESUMO

Mucosal immune responses are crucial in protecting against pathogens entering through mucosal surfaces. However, due to poor T-cell responsiveness upon mucosal antigenic stimulation, mucosal immunity remains difficult to obtain through vaccines and requires appropriate adjuvants. We previously demonstrated that administered systemically to healthy macaques or locally expressed in the intestinal mucosa of acutely SIV-infected macaques, interleukin-7 (IL-7) triggers chemokine expression and immune cell homing into mucosae, suggesting its important role in the development of mucosal immune responses. We therefore examined whether local delivery of recombinant glycosylated simian IL-7 (rs-IL-7gly) to the vaginal mucosa of rhesus macaques could prepare the lower female genital tract (FGT) for subsequent immunization and act as an efficient mucosal adjuvant. First, we showed that local administration of rs-IL-7gly triggers vaginal overexpression of chemokines and infiltration of mDCs, macrophages, NKs, B- and T-cells in the lamina propria while MamuLa-DR+ APCs accumulated in the epithelium. Subsequent mucosal anti-DT immunization in macaques resulted in a faster, stronger, and more persistent mucosal antibody response compared to DT-immunization alone. Indeed, we detected robust productions of DT-specific IgAs and IgGs in their vaginal secretions and identified cells secreting DT-specific IgAs in their vaginal mucosa and IgGs in draining lymph nodes. Finally, the expression of chemokines involved in the organization of tertiary lymphoid structures (TLS) was only increased in the vaginal mucosa of IL-7-adjuvanted immunized macaques. Interestingly, TLSs developed around PNAd+ high endothelial venules in their lower FGT sampled 2 weeks after the last immunization. Non-traumatic vaginal administration of rs-IL-7gly prepares the mucosa to respond to subsequent local immunization and allows the development of a strong mucosal immune response in macaques, through the chemokine-dependent recruitment of immune cells, the activation of mDCs and the formation of TLSs. The localization of DT-specific IgA+ plasma cells in the upper vaginal mucosa argues for their contribution to the production of specific immunoglobulins in the vaginal secretions. Our results highlight the potential of IL-7 as a potent mucosal adjuvant to stimulate the FGT immune system and elicit vaginal antibody responses to local immunization, which is the most promising way to confer protection against many sexually transmitted diseases.


Assuntos
Adjuvantes Imunológicos , Imunidade nas Mucosas , Interleucina-7/imunologia , Membrana Mucosa/imunologia , Vacinas/imunologia , Vagina/imunologia , Animais , Anticorpos Antivirais/imunologia , Formação de Anticorpos/imunologia , Biomarcadores , Quimiocinas/metabolismo , Feminino , Hepevirus/imunologia , Interações Hospedeiro-Patógeno/imunologia , Imunização , Macaca mulatta , Membrana Mucosa/metabolismo , Vírus da Imunodeficiência Símia/imunologia , Vacinas/administração & dosagem
18.
J Food Sci ; 86(4): 1410-1417, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33768522

RESUMO

Immunosenescence can negatively affect cytokine production in elderly and may impair poor antibody responses to influenza vaccination and infection. Herein, the effects of Banafine® administration on influenza vaccine antibody titer in elderly patients (average age ∼80 years) receiving gastrostomy tube feeding were examined. In the double-blind, single-center, randomized clinical studies, 30 elderly bedridden patients were administered Banafine® or placebo for 8 weeks. At week 4, all patients received influenza vaccination against H1N1, H3N2, B/Yamagata, or B/Victoria. Blood biochemical indices and serum antibody titers were assessed. Banafine® administration significantly increased hemagglutination inhibition titers in response to vaccination against H1N1, H3N2, and B/Yamagata in the elderly patients (P < 0.05). Moreover, the seroconversion rate against H1N1 (47.1%) and H3N2 (29.4%) and seroprotection rate against H1N1 (71.4%) and both B strains (31.3% and 12.5%, respectively) were increased for the Banafine® group. These results suggest that Banafine® administration can increase antibody responses to influenza vaccination in bedridden hospitalized patients, and potentially modulate immune function in the elderly. PRACTICAL APPLICATION: Literature review suggested that most of the synbiotics are based on innate immunity, strain specific (probiotics), and are not consistently observed. Herein, in clinical studies we demonstrate that administration of Banafine® , a plant-based glycoconjugate, can increase antibody levels in bedridden hospitalized elderly patients following influenza vaccination.


Assuntos
Anticorpos Antivirais/sangue , Formação de Anticorpos/imunologia , Nutrição Enteral/métodos , Glicoconjugados/administração & dosagem , Vacinas contra Influenza/imunologia , Influenza Humana/prevenção & controle , Musa/imunologia , Idoso , Idoso de 80 Anos ou mais , Formação de Anticorpos/efeitos dos fármacos , Método Duplo-Cego , Feminino , Fermentação , Gastrostomia , Glicoconjugados/imunologia , Testes de Inibição da Hemaglutinação , Humanos , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H3N2/imunologia , Vírus da Influenza B/imunologia , Vacinas contra Influenza/administração & dosagem , Influenza Humana/imunologia , Masculino , Musa/química , Probióticos/administração & dosagem
19.
Gut ; 70(5): 865-875, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33753421

RESUMO

OBJECTIVE: Antitumour necrosis factor (anti-TNF) drugs impair protective immunity following pneumococcal, influenza and viral hepatitis vaccination and increase the risk of serious respiratory infections. We sought to determine whether infliximab-treated patients with IBD have attenuated serological responses to SARS-CoV-2 infections. DESIGN: Antibody responses in participants treated with infliximab were compared with a reference cohort treated with vedolizumab, a gut-selective anti-integrin α4ß7 monoclonal antibody that is not associated with impaired vaccine responses or increased susceptibility to systemic infections. 6935 patients were recruited from 92 UK hospitals between 22 September and 23 December 2020. RESULTS: Rates of symptomatic and proven SARS-CoV-2 infection were similar between groups. Seroprevalence was lower in infliximab-treated than vedolizumab-treated patients (3.4% (161/4685) vs 6.0% (134/2250), p<0.0001). Multivariable logistic regression analyses confirmed that infliximab (vs vedolizumab; OR 0.66 (95% CI 0.51 to 0.87), p=0.0027) and immunomodulator use (OR 0.70 (95% CI 0.53 to 0.92), p=0.012) were independently associated with lower seropositivity. In patients with confirmed SARS-CoV-2 infection, seroconversion was observed in fewer infliximab-treated than vedolizumab-treated patients (48% (39/81) vs 83% (30/36), p=0.00044) and the magnitude of anti-SARS-CoV-2 reactivity was lower (median 0.8 cut-off index (0.2-5.6) vs 37.0 (15.2-76.1), p<0.0001). CONCLUSIONS: Infliximab is associated with attenuated serological responses to SARS-CoV-2 that were further blunted by immunomodulators used as concomitant therapy. Impaired serological responses to SARS-CoV-2 infection might have important implications for global public health policy and individual anti-TNF-treated patients. Serological testing and virus surveillance should be considered to detect suboptimal vaccine responses, persistent infection and viral evolution to inform public health policy. TRIAL REGISTRATION NUMBER: ISRCTN45176516.


Assuntos
Anticorpos Antivirais/imunologia , Formação de Anticorpos/imunologia , Fármacos Gastrointestinais/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Infliximab/uso terapêutico , SARS-CoV-2/imunologia , Adulto , Anticorpos Monoclonais Humanizados/uso terapêutico , COVID-19/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Testes Sorológicos , Reino Unido/epidemiologia
20.
Sci Adv ; 7(10)2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33674317

RESUMO

Limited knowledge exists on immune markers associated with disease severity or recovery in patients with coronavirus disease 2019 (COVID-19). Here, we elucidated longitudinal evolution of SARS-CoV-2 antibody repertoire in patients with acute COVID-19. Differential kinetics was observed for immunoglobulin M (IgM)/IgG/IgA epitope diversity, antibody binding, and affinity maturation in "severe" versus "mild" COVID-19 patients. IgG profile demonstrated immunodominant antigenic sequences encompassing fusion peptide and receptor binding domain (RBD) in patients with mild COVID-19 who recovered early compared with "fatal" COVID-19 patients. In patients with severe COVID-19, high-titer IgA were observed, primarily against RBD, especially in patients who succumbed to SARS-CoV-2 infection. The patients with mild COVID-19 showed marked increase in antibody affinity maturation to prefusion SARS-CoV-2 spike that associated with faster recovery from COVID-19. This study revealed antibody markers associated with disease severity and resolution of clinical disease that could inform development and evaluation of effective immune-based countermeasures against COVID-19.


Assuntos
Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Antígenos Virais/imunologia , Biomarcadores/sangue , COVID-19/imunologia , COVID-19/patologia , SARS-CoV-2/fisiologia , Índice de Gravidade de Doença , Afinidade de Anticorpos/imunologia , Formação de Anticorpos/imunologia , COVID-19/sangue , COVID-19/virologia , Citocinas/sangue , Células HEK293 , Hospitalização , Humanos , Switching de Imunoglobulina , Cinética , Testes de Neutralização , Ligação Proteica , Domínios Proteicos , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/imunologia , Carga Viral
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