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2.
Autoimmun Rev ; 19(5): 102513, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32173515

RESUMO

BACKGROUND: The clinical presentation of celiac disease (CD) varies between children. The objective of this study was to document the pre-test probability for CD based on symptoms and routine laboratory test and to evaluate the performance of two IgA anti-tissue transglutaminase (tTG) assays. We critically reviewed the concept of using multiples of the manufacturer's upper limit of normal (ULN), as proposed in the ESPGHAN guidelines (if IgA tTG is >10 times ULN, no biopsy is needed). METHODS: The retrospective study included 91 children with newly diagnosed CD and 605 controls (<16 years). All underwent upper endoscopy with small bowel biopsies. Four laboratory parameters and 16 symptoms were registered. All patients were tested for IgA anti-tTG antibodies with assays from Inova Diagnostics and Thermo Fisher Scientific. RESULTS: Some combinations of clinical symptoms and laboratory parameters had a high pre-test probability for CD, such as (combinations of) anorexia, failure to thrive, low ferritin level and elevated AST. The diagnostic performance of both IgA anti-tTG assays was excellent and comparable (no difference in ROC curve area under the curve). At a threshold that corresponds to a specificity of 100% (5 times ULN for Inova Diagnostics and 2 times ULN for Thermo Fisher), the sensitivity was 82% for both assays. At the 10 times ULN threshold, the sensitivity differed between the assays (77% vs. 57%), indicating that such threshold does not completely align interpretation across companies. CONCLUSIONS: Our study showed that some combinations of symptoms and aberrant laboratory parameters had a high pre-test probability. The use of the ESPGHAN non-biopsy approach could reduce small bowel biopsies, but thresholds for IgA-tTG levels are not aligned across assays and should be based on predefined likelihood ratios or specificity.


Assuntos
Doença Celíaca/sangue , Doença Celíaca/diagnóstico , Adolescente , Autoanticorpos/sangue , Autoanticorpos/imunologia , Biópsia , Criança , Pré-Escolar , Feminino , Humanos , Imunoglobulina A/sangue , Imunoglobulina A/imunologia , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos , Sensibilidade e Especificidade , Transglutaminases/imunologia
3.
Cell Host Microbe ; 27(3): 467-475.e6, 2020 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-32075742

RESUMO

Fecal IgA production depends on colonization by a gut microbiota. However, the bacterial strains that drive gut IgA production remain largely unknown. Here, we assessed the IgA-inducing capacity of a diverse set of human gut microbial strains by monocolonizing mice with each strain. We identified Bacteroides ovatus as the species that best induced gut IgA production. However, this induction varied bimodally across different B. ovatus strains. The high IgA-inducing B. ovatus strains preferentially elicited more IgA production in the large intestine through the T cell-dependent B cell-activation pathway. Remarkably, a low-IgA phenotype in mice could be robustly and consistently converted into a high-IgA phenotype by transplanting a multiplex cocktail of high IgA-inducing B. ovatus strains but not individual ones. Our results highlight the critical importance of microbial strains in driving phenotype variation in the mucosal immune system and provide a strategy to robustly modify a gut immune phenotype, including IgA production.


Assuntos
Bacteroides/classificação , Fezes , Microbioma Gastrointestinal , Imunoglobulina A/imunologia , Intestino Grosso/imunologia , Animais , Linfócitos B/imunologia , Bacteroides/imunologia , Linfócitos T CD4-Positivos/imunologia , Vida Livre de Germes , Humanos , Intestino Grosso/microbiologia , Camundongos , Camundongos Endogâmicos C57BL
4.
Nat Commun ; 11(1): 120, 2020 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-31913287

RESUMO

Monomeric serum immunoglobulin A (IgA) can contribute to the development of various autoimmune diseases, but the regulation of serum IgA effector functions is not well defined. Here, we show that the two IgA subclasses (IgA1 and IgA2) differ in their effect on immune cells due to distinct binding and signaling properties. Whereas IgA2 acts pro-inflammatory on neutrophils and macrophages, IgA1 does not have pronounced effects. Moreover, IgA1 and IgA2 have different glycosylation profiles, with IgA1 possessing more sialic acid than IgA2. Removal of sialic acid increases the pro-inflammatory capacity of IgA1, making it comparable to IgA2. Of note, disease-specific autoantibodies in patients with rheumatoid arthritis display a shift toward the pro-inflammatory IgA2 subclass, which is associated with higher disease activity. Taken together, these data demonstrate that IgA effector functions depend on subclass and glycosylation, and that disturbances in subclass balance are associated with autoimmune disease.


Assuntos
Imunoglobulina A/imunologia , Polissacarídeos/metabolismo , Adulto , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Autoanticorpos/química , Autoanticorpos/imunologia , Autoanticorpos/metabolismo , Feminino , Glicosilação , Humanos , Imunoglobulina A/química , Imunoglobulina A/metabolismo , Macrófagos/imunologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia
6.
PLoS Genet ; 15(11): e1008461, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31697674

RESUMO

Much of our knowledge of the drivers of immune variation, and how these responses vary over time, comes from humans, domesticated livestock or laboratory organisms. While the genetic basis of variation in immune responses have been investigated in these systems, there is a poor understanding of how genetic variation influences immunity in natural, untreated populations living in complex environments. Here, we examine the genetic architecture of variation in immune traits in the Soay sheep of St Kilda, an unmanaged population of sheep infected with strongyle gastrointestinal nematodes. We assayed IgA, IgE and IgG antibodies against the prevalent nematode Teladorsagia circumcincta in the blood plasma of > 3,000 sheep collected over 26 years. Antibody levels were significantly heritable (h2 = 0.21 to 0.57) and highly stable over an individual's lifespan. IgA levels were strongly associated with a region on chromosome 24 explaining 21.1% and 24.5% of heritable variation in lambs and adults, respectively. This region was adjacent to two candidate loci, Class II Major Histocompatibility Complex Transactivator (CIITA) and C-Type Lectin Domain Containing 16A (CLEC16A). Lamb IgA levels were also associated with the immunoglobulin heavy constant loci (IGH) complex, and adult IgE levels and lamb IgA and IgG levels were associated with the major histocompatibility complex (MHC). This study provides evidence of high heritability of a complex immunological trait under natural conditions and provides the first evidence from a genome-wide study that large effect genes located outside the MHC region exist for immune traits in the wild.


Assuntos
Animais Selvagens/imunologia , Imunidade Inata , Ovinos/imunologia , Infecções por Strongylida/imunologia , Animais , Animais Selvagens/sangue , Anticorpos/sangue , Anticorpos/imunologia , Helmintos/imunologia , Helmintos/patogenicidade , Imunoglobulina A/sangue , Imunoglobulina A/imunologia , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Ovinos/sangue , Infecções por Strongylida/sangue
7.
BMC Immunol ; 20(1): 36, 2019 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-31623558

RESUMO

BACKGROUND: A previous study demonstrated pleural fluid (PF) IgA immunodominance for the fused MT10.3:MPT64 protein in pleural tuberculosis (PLTB) cases. However, no clue on the role of IgA and IgG against this and other antigens in PF and serum concerning improved diagnosis is available. Thus, the aim of the present study was to validate PF IgA-MT10.3:MPT64 and evaluate PF and serum IgA and IgG reactivity against this protein, its peptides (F2) and single MPT64, MT10.3 and the PPE59 mycobacterial specific antigens. IgA and IgG ELISA were measured against the antigen in PLTB (n = 29) and other non-TB pleurisy (n = 39) patient samples. RESULTS: The immunodominance of PF IgA-MT10.3:MPT64 was confirmed in PLTB (86.2%) followed by PPE59 (62%), while serum IgA-F2 exhibited 51.7% sensitivity. PF and serum IgG-MT10.3:MPT64 led to 65.5 and 51.7% sensitivity, respectively. However, MT10.3 and MPT64 displayed overall lower sensitivity (≤34.5) for both antibodies. All results at 95% fixed specificity. Combinatory results indicated 93.1% sensitivity for PF IgA-MT10.3:MPT64/-PPE59 and IgA/IgG-MT10.3:MPT64 at 92.3% specificity, followed by IgA-MT10.3:MPT64/-MPT64 or /-F2 (89.6%) without jeopardizing specificity (94.9%). The combinatory results of the PF adenosine deaminase test (ADA) and IgA-MT10.3:MPT64/-F2 demonstrated the highest sensitivity (96.6%), with a specificity of 92.3%. CONCLUSIONS: The PF IgA-MT10:MPT64 immune dominance was validated in PLTB, and its combinatory results with PPE59 or MPT64 or F2 antigens as well as with IgG, are reported herein for the first time, improving their potential to assist diagnosis. Combining PF-ADA and IgA-MT10.3:MPT64/-F2 results achieved better accuracy. Moreover, serum IgG, although less accurate, displays potential beyond microbiological tests.


Assuntos
Anticorpos Antibacterianos/imunologia , Antígenos de Bactérias/imunologia , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Mycobacterium tuberculosis/imunologia , Derrame Pleural/imunologia , Tuberculose Pleural/imunologia , Biomarcadores , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Derrame Pleural/patologia , Curva ROC , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Tuberculose Pleural/sangue , Tuberculose Pleural/diagnóstico
8.
Vet Microbiol ; 237: 108401, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31585639

RESUMO

Influenza results in significant economic loss in the swine industry each year. A broadly protective swine influenza vaccine would have the dual benefit of protecting pigs from influenza A viruses (IAVs) and limiting their possible zoonotic transmission to humans. In this study, we developed polyanhydride nanoparticles-based swine influenza vaccine (KAg + CpG-nanovaccine) co-encapsulating inacticated/killed soluble antigen (KAg) and Toll-like receptor (TLR)-9 agonist (CpG-ODN). The immunogenicity and protective efficacy of KAg + CpG-nanovaccine was compared with KAg vaccine containing five-times greater quantity of antigens following heterologous virus challenge. Prime-boost intranasally delivered KAg + CpG-nanovaccine induced significantly higher levels of cross-reactive antigen-specific IgA antibody responses in the nasal cavity, greater lymphoproliferative response in peripheral blood mononuclear cells (PBMCs), and higher IFN-γ secretion during antigen-induced recall responses of PBMCs and tracheobronchial lymph nodes cells compared to those immunized with KAg alone. Importantly, KAg + CpG-nanovaccine provided better protective efficacy through a significant reduction in influenza-induced fever, 16-fold reduction of nasal virus shedding and 80-fold reduction in lung virus titers compared to those immunized with soluble KAg. Our results indicated that CpG-ODN-adjuvanted polyanhydride nanovaccine can induce higher mucosal antibody and cellular immune responses in pigs; and provide better protection as compared with intranasally delivered soluble KAg.


Assuntos
Vacinas contra Influenza/imunologia , Oligodesoxirribonucleotídeos/farmacologia , Infecções por Orthomyxoviridae/veterinária , Doenças dos Suínos/prevenção & controle , Adjuvantes Imunológicos , Administração Intranasal , Animais , Anticorpos Antivirais , Antígenos Virais/imunologia , Feminino , Imunidade nas Mucosas , Imunoglobulina A/imunologia , Interferon gama/metabolismo , Leucócitos Mononucleares , Masculino , Nanoestruturas , Oligodesoxirribonucleotídeos/imunologia , Infecções por Orthomyxoviridae/prevenção & controle , Polianidridos , Suínos , Vacinas de Produtos Inativados/imunologia
9.
Infect Immun ; 88(1)2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31611272

RESUMO

IgA plays an important role in mucosal immunity against infectious pathogens; however, the molecular mechanism of IgA secretion in response to infection remains largely unknown, particularly in Mycoplasma spp. In this study, we found that the levels of IgA in the peripheral blood serum, bronchoalveolar lavage fluid, nasal mucosa, trachea, hilar lymph nodes, and lung tissues of pigs increased significantly after infection with Mycoplasma hyopneumoniae Furthermore, IgA and CD11c were detected in the lungs and hilar lymph nodes by immunohistochemical analysis, and colocalization of these two markers indicates that CD11c+ cells play an important role in IgA mucosal immunity induced by M. hyopneumoniae To investigate the regulatory mechanism of IgA, we separated mouse dendritic cells (DCs) from different tissues and mouse macrophages from the lungs and then cultured mouse B cells together with either DCs or macrophages in vitro In the mouse lung-DC/B (LDC/B) cell coculture, IgA secretion was increased significantly after the addition of whole-cell lysates of M. hyopneumoniae The expression of both Toll-like receptor 2 (TLR2) and TLR4 was also upregulated, as determined by mRNA and protein expression analyses, whereas no obvious change in the expression of TLR3 and TLR7 was detected. Moreover, the IgA level decreased to the same as the control group when TLR2 or TLR4 was inhibited instead of TLR8 or TLR7/9. In conclusion, M. hyopneumoniae can stimulate the response of IgA through TLR2 and TLR4 in a mouse LDC/B cell coculture model, and the coculture model is an ideal tool for studying the IgA response mechanism, particularly that with Mycoplasma spp.


Assuntos
Formação de Anticorpos , Imunoglobulina A/imunologia , Mycoplasma hyopneumoniae/imunologia , Pneumonia Suína Micoplasmática/imunologia , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Linfócitos B/imunologia , Células Dendríticas/imunologia , Macrófagos/imunologia , Camundongos , Modelos Teóricos , Suínos
10.
Nature ; 574(7776): 122-126, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31554970

RESUMO

B cells are important in the pathogenesis of many, and perhaps all, immune-mediated diseases. Each B cell expresses a single B cell receptor (BCR)1, and the diverse range of BCRs expressed by the total B cell population of an individual is termed the 'BCR repertoire'. Our understanding of the BCR repertoire in the context of immune-mediated diseases is incomplete, and defining this could provide new insights into pathogenesis and therapy. Here, we compared the BCR repertoire in systemic lupus erythematosus, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, Crohn's disease, Behçet's disease, eosinophilic granulomatosis with polyangiitis, and immunoglobulin A (IgA) vasculitis by analysing BCR clonality, use of immunoglobulin heavy-chain variable region (IGHV) genes and-in particular-isotype use. An increase in clonality in systemic lupus erythematosus and Crohn's disease that was dominated by the IgA isotype, together with skewed use of the IGHV genes in these and other diseases, suggested a microbial contribution to pathogenesis. Different immunosuppressive treatments had specific and distinct effects on the repertoire; B cells that persisted after treatment with rituximab were predominately isotype-switched and clonally expanded, whereas the inverse was true for B cells that persisted after treatment with mycophenolate mofetil. Our comparative analysis of the BCR repertoire in immune-mediated disease reveals a complex B cell architecture, providing a platform for understanding pathological mechanisms and designing treatment strategies.


Assuntos
Doenças do Sistema Imunitário/imunologia , Isotipos de Imunoglobulinas/análise , Isotipos de Imunoglobulinas/imunologia , Receptores de Antígenos de Linfócitos B/análise , Receptores de Antígenos de Linfócitos B/imunologia , Adulto , Idoso , Células Clonais/citologia , Células Clonais/imunologia , Humanos , Imunoglobulina A/análise , Imunoglobulina A/imunologia , Switching de Imunoglobulina/imunologia , Imunoglobulina G/análise , Imunoglobulina G/imunologia , Pessoa de Meia-Idade , Adulto Jovem
11.
Mayo Clin Proc ; 94(9): 1769-1780, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31486380

RESUMO

OBJECTIVE: To describe the differences in clinical characteristics and outcome between adult- and childhood-onset biopsy-proven IgA vasculitis (IgAV) in North America. PATIENTS AND METHODS: Patients with IgAV diagnosed from January 1, 1997, through December 31, 2016, were retrospectively identified. Data were abstracted from direct medical record review. Kaplan-Meier methods were used to estimate survival rates. RESULTS: A total of 243 patients with IgAV were included (227 [93.4%] white, 141 [58.0%] male); 174 patients were adults (≥21 years), and 69 were younger than 21 years. Compared with patients younger than 21 years, adults at baseline more frequently had ulcerative skin lesions (19 [10.9%] vs 1 [1.4%]; P=.02) and nephrotic-range proteinuria (21 of 96 [21.9%] vs 1 of 38 [2.6%]; P=.007) but less commonly had abdominal pain (59 [33.9%] vs 42 [60.9%]; P<.001), ischemic gastrointestinal tract involvement (18 [10.3%] vs 14 [20.3%]; P=.04), and arthralgias (66 [37.9%] vs 42 [60.8%]; P<.001). During 389 person-years of follow-up, 29 deaths were observed. Five-year survival rates for patients aged younger than 21, 21 to 50, and 51 years or older were 100%, 94%, and 40%, respectively. In comparison to data from the United States life tables for whites, patients 51 years or older at diagnosis had a greater than 7-fold increased risk of mortality (standardized mortality, 7.60 [95% CI, 5.01-11.06]; P<.001). CONCLUSION: IgA vasculitis in adults is associated with more severe skin/kidney involvement and poorer renal outcome. Among adults with IgAV, patients aged 51 years or older at diagnosis have significantly higher mortality (P<.001).


Assuntos
Corticosteroides/uso terapêutico , Glomerulonefrite por IGA/epidemiologia , Imunoglobulina A/imunologia , Vasculite/epidemiologia , Vasculite/patologia , Centros Médicos Acadêmicos , Adulto , Idade de Início , Biópsia por Agulha , Criança , Estudos de Coortes , Bases de Dados Factuais , Feminino , Glomerulonefrite por IGA/tratamento farmacológico , Glomerulonefrite por IGA/patologia , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Prevalência , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença , Taxa de Sobrevida , Resultado do Tratamento , Vasculite/imunologia , Vasculite/terapia
12.
Scand J Immunol ; 90(6): e12828, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31520490

RESUMO

BACKGROUND: Immunoglobulin A deficiency (IgAD) is the most common primary immunodeficiency. Although most people with selective IgAD (sIgAD) are asymptomatic, many patients often suffer from recurrent respiratory infections and different allergic disorders. Our aim was to investigate connection between subtypes of sIgAD and incidence of respiratory and allergic disorders, as well as connection with lung function changes in children. METHODS: Children with IgAD where divided into two groups; severe IgAD in patients was defined as serum IgA level <7 mg/dL, while partial IgA deficiency diagnosis was made when serum IgA levels was higher than 7 mg/dL but at least two standard deviations (SD) below mean normal concentrations for their age. All patients were evaluated by their clinical and laboratory investigation parameters and compared to control group of children. RESULTS: Group of children with IgAD, severe as well as partial, showed higher prevalence of allergic diseases and total number of infections, compared to controls. There was a statistically significant difference in lung function for peak expiratory flow (PEF), the maximal expiratory flow at 50% of the forced vital capacity (MEF50) and fraction of exhaled nitric oxide (FENO) between group of patients with severe as well as partial IgAD and control group, where children with IgAD showed reduced lung function. CONCLUSIONS: Children with sIgAD are at increased risk for higher number of respiratory infections and developing allergic diseases, resulting in significantly lower pulmonary function which is related with the severity of sIgAD.


Assuntos
Hipersensibilidade/etiologia , Deficiência de IgA/complicações , Doenças Respiratórias/etiologia , Adolescente , Fatores Etários , Biomarcadores , Criança , Pré-Escolar , Feminino , Humanos , Hipersensibilidade/diagnóstico , Deficiência de IgA/diagnóstico , Imunoglobulina A/sangue , Imunoglobulina A/imunologia , Masculino , Testes de Função Respiratória , Doenças Respiratórias/diagnóstico , Índice de Gravidade de Doença
13.
Immunity ; 51(3): 508-521.e6, 2019 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-31471109

RESUMO

Recent experimental data and clinical, genetic, and transcriptome evidence from patients converge to suggest a key role of interleukin-1ß (IL-1ß) in the pathogenesis of Kawasaki disease (KD). However, the molecular mechanisms involved in the development of cardiovascular lesions during KD vasculitis are still unknown. Here, we investigated intestinal barrier function in KD vasculitis and observed evidence of intestinal permeability and elevated circulating secretory immunoglobulin A (sIgA) in KD patients, as well as elevated sIgA and IgA deposition in vascular tissues in a mouse model of KD vasculitis. Targeting intestinal permeability corrected gut permeability, prevented IgA deposition and ameliorated cardiovascular pathology in the mouse model. Using genetic and pharmacologic inhibition of IL-1ß signaling, we demonstrate that IL-1ß lies upstream of disrupted intestinal barrier function, subsequent IgA vasculitis development, and cardiac inflammation. Targeting mucosal barrier dysfunction and the IL-1ß pathway may also be applicable to other IgA-related diseases, including IgA vasculitis and IgA nephropathy.


Assuntos
Doenças Cardiovasculares/imunologia , Imunoglobulina A/imunologia , Inflamação/imunologia , Intestinos/imunologia , Animais , Modelos Animais de Doenças , Humanos , Interleucina-1beta/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Síndrome de Linfonodos Mucocutâneos/imunologia , Permeabilidade , Transdução de Sinais/imunologia , Vasculite/imunologia
14.
BMC Vet Res ; 15(1): 286, 2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31399125

RESUMO

BACKGROUND: Bovine mastitis caused by Staphylococcus aureus (S. aureus) is extremely difficult to control and new methods for its prevention and management are required. Nasal vaccines may prevent initial bovine mastitis infection caused by S. aureus. However, limited information is available regarding induction of mucosal immune response through nasal immunization with antigen and its suppression of S. aureus multiplication during bovine mastitis. This study sought to investigate whether induction of immunoglobulin A (IgA) in milk by nasal immunization could suppress multiplication of S. aureus in the bovine udder. RESULTS: Nasal immunization with formalin-killed S. aureus conjugated with a cationic cholesteryl-group-bearing pullulan-nanogel was performed. Anti-S. aureus-specific IgA antibodies were significantly more abundant in the milk of immunized cows than in non-immunized animals (P < 0.05). S. aureus counts in the quarter were negative in both non-immunized and nasal-immunized cows 1 week after mock infusion. In S. aureus-infused quarters, S. aureus multiplication was significantly suppressed in immunized compared with non-immunized cows (P < 0.05). Furthermore, a significant negative correlation was found between S. aureus-specific IgA antibodies and S. aureus counts in infused quarters of both non-immunized and nasal-immunized cows (r = - 0.811, P < 0.01). CONCLUSION: In conclusion, the present study demonstrates that S. aureus-specific IgA antibodies in milk successfully suppressed the multiplication of S. aureus in infected bovine udders. Although the exact mechanism explaining such suppressive effect remains to be elucidated, nasal vaccines that can induce humoral immunity may help prevent initial infection with S. aureus and the onset of bovine mastitis.


Assuntos
Especificidade de Anticorpos , Imunoglobulina A/imunologia , Mastite Bovina/prevenção & controle , Leite/química , Infecções Estafilocócicas/veterinária , Staphylococcus aureus/imunologia , Animais , Bovinos , Feminino , Mastite Bovina/imunologia , Mastite Bovina/microbiologia , Nanoestruturas , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/prevenção & controle
15.
Nat Commun ; 10(1): 3650, 2019 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-31409776

RESUMO

The intestinal immune system is emerging as an important contributor to obesity-related insulin resistance, but the role of intestinal B cells in this context is unclear. Here, we show that high fat diet (HFD) feeding alters intestinal IgA+ immune cells and that IgA is a critical immune regulator of glucose homeostasis. Obese mice have fewer IgA+ immune cells and less secretory IgA and IgA-promoting immune mediators. HFD-fed IgA-deficient mice have dysfunctional glucose metabolism, a phenotype that can be recapitulated by adoptive transfer of intestinal-associated pan-B cells. Mechanistically, IgA is a crucial link that controls intestinal and adipose tissue inflammation, intestinal permeability, microbial encroachment and the composition of the intestinal microbiome during HFD. Current glucose-lowering therapies, including metformin, affect intestinal-related IgA+ B cell populations in mice, while bariatric surgery regimen alters the level of fecal secretory IgA in humans. These findings identify intestinal IgA+ immune cells as mucosal mediators of whole-body glucose regulation in diet-induced metabolic disease.


Assuntos
Imunoglobulina A/imunologia , Resistência à Insulina , Obesidade/imunologia , Tecido Adiposo/imunologia , Animais , Linfócitos B/imunologia , Estudos de Coortes , Fezes/microbiologia , Microbioma Gastrointestinal , Glucose/metabolismo , Humanos , Intestinos/imunologia , Masculino , Camundongos , Obesidade/metabolismo , Obesidade/microbiologia
16.
Immunology ; 158(3): 194-205, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31433857

RESUMO

The gut has the largest commensal bacterial population in the body and its composition can be impacted by host factors such as production of immunoglobulin A (IgA). Eosinophils in the gut have been implicated in the production of antibacterial factors and maintenance of IgA-secreting plasma cells. We used an eosinophil-deficient mouse (∆dblGATA-1-/- ) and littermate controls to investigate the role of eosinophils in the regulation of the microbiota, with particular emphasis on mucus-resident species in the small and large intestine. We found no differences in IgA production or IgA-expressing plasma cells between naive littermates in the small or large intestine. However, denaturing gel gradient electrophoresis revealed differences in the bacterial communities of the mucus and stools between wild-type mice and ∆dblGATA-1-/- mice, with the greatest separation between the mucus microbial communities. Mucus-resident bacteria in ∆dblGATA-1-/- mice had reduced diversity in the mucus compared with the stools. A quantitative PCR panel of selected bacteria showed that the most significant differences in the microbiota were between mucus-resident bacteria and those in stool, such as the abundance of Clostridiales and Bacteroides. Our data implicate eosinophils in the regulation of the microbiota, especially the bacteria most hyperlocal to the gut barrier. Although we see differences between host genotypes in the overall microbial communities, further work is required to establish specifically which bacteria are different between these groups. Most importantly, the data revealed that the mucus and stool microbiota are discrete communities. Stool analysis alone may be insufficient to comprehensively explore and define the role of the gut microbiota in health and disease.


Assuntos
Eosinófilos/imunologia , Microbioma Gastrointestinal/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Animais , Humanos , Imunoglobulina A/imunologia , Mucosa Intestinal/patologia , Camundongos , Camundongos Knockout , Plasmócitos/imunologia
17.
Mol Immunol ; 114: 243-250, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31394381

RESUMO

Age-related macular degeneration (AMD) is the most common cause of vision loss in the aged population. Aging and inflammation are thought to promote AMD pathogenesis in people with genetic predisposition. Follicular helper T (Tfh) cells play critical roles in inflammatory responses. Here, we investigated circulating Tfh cells in AMD patients. Circulating Tfh cells were defined as CXCR5+ CD4 T cells. Data showed that patients with the wet-type AMD presented significantly higher levels of Tfh cells than non-AMD controls. Interestingly, the Tfh cells from dry and wet AMD patients also presented significantly higher ICOS and PD-1 expression, together with higher IL-17 and IL-21 expression directly ex vivo and following PMA/ionomycin stimulation. The expression of IFNg and IL-10, on the other hand, was not different between Tfh cells from AMD patients and their counterparts in non-AMD controls. Functional analysis revealed that Tfh cells from AMD patients were better at inducing the production of IgG and IgA, and this effect was in an IL-21-dependent manner. Together, we demonstrated that the circulating Tfh cell responses were dysregulated in AMD patients.


Assuntos
Interleucinas/imunologia , Degeneração Macular/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Idoso , Linfócitos T CD4-Positivos/imunologia , Técnicas de Cocultura/métodos , Citocinas/imunologia , Feminino , Humanos , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Interferon gama/imunologia , Interleucina-10/imunologia , Masculino , Pessoa de Meia-Idade
18.
20.
PLoS One ; 14(7): e0220196, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31329652

RESUMO

Middle East respiratory syndrome coronavirus (MERS-CoV) causes an acute and severe lower respiratory illness as well as vomiting, diarrhea, and renal failure. Because no licensed MERS-CoV vaccines are currently available, preventive and therapeutic measures are urgently needed. The surface spike (S) glycoprotein of MERS-CoV, which binds to the cellular receptor dipeptidyl peptidase 4 (DPP4), is considered as a major target for MERS-CoV vaccine development. Here, we designed recombinant replication-deficient adenovirus-based vaccines expressing the N-terminal domain (rAd/NTD) and receptor-binding domain (rAd/RBD) of the MERS-CoV S1 subunit and full-length Spike protein (rAd/Spike). We found that immunization with candidate vaccines via intranasal route induced S1-specific IgG antibodies and neutralizing antibodies against MERS spike pseudotyped virus. Especially, rAd/Spike induced the highest neutralizing antibody titer and the strongest cytokine-induced T cell responses among the three candidate vaccines. To compare the immune responses induced by different administration routes, rAd/Spike was administered via intranasal, sublingual, or intramuscular route. All these administration routes exhibited neutralizing effects in the serum. MERS-CoV-specific neutralizing IgA antibodies in the bronchoalveolar lavage fluid were only induced by intranasal and sublingual administration but not by intramuscular administration. Intranasal administration with rAd/Spike also created resident memory CD8 T cells in the airway and lung parenchyma. Taken together, our results showed that both the humoral and cellular immune responses are highly induced by rAd/Spike administration, suggesting that rAd/Spike may confer protection against MERS-CoV infection.


Assuntos
Infecções por Coronavirus/imunologia , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinação/métodos , Adenoviridae/genética , Adenoviridae/imunologia , Administração Intranasal , Animais , Anticorpos Neutralizantes/imunologia , Células Cultivadas , Infecções por Coronavirus/prevenção & controle , Feminino , Células HEK293 , Humanos , Imunoglobulina A/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Glicoproteína da Espícula de Coronavírus/genética , Spodoptera , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia
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