Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 62
Filtrar
1.
Immunity ; 43(5): 884-95, 2015 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-26546282

RESUMO

Activation-induced cytidine deaminase (AID), the enzyme-mediating class-switch recombination (CSR) and somatic hypermutation (SHM) of immunoglobulin genes, is essential for the removal of developing autoreactive B cells. How AID mediates central B cell tolerance remains unknown. We report that AID enzymes were produced in a discrete population of immature B cells that expressed recombination-activating gene 2 (RAG2), suggesting that they undergo secondary recombination to edit autoreactive antibodies. However, most AID+ immature B cells lacked anti-apoptotic MCL-1 and were deleted by apoptosis. AID inhibition using lentiviral-encoded short hairpin (sh)RNA in B cells developing in humanized mice resulted in a failure to remove autoreactive clones. Hence, B cell intrinsic AID expression mediates central B cell tolerance potentially through its RAG-coupled genotoxic activity in self-reactive immature B cells.


Assuntos
Tolerância Central/genética , Tolerância Central/imunologia , Citidina Desaminase/genética , Ativação Linfocitária/imunologia , Células Precursoras de Linfócitos B/imunologia , Adolescente , Adulto , Idoso , Animais , Apoptose/genética , Apoptose/imunologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Proteínas de Ligação a DNA/genética , Feminino , Genes de Imunoglobulinas/genética , Genes de Imunoglobulinas/imunologia , Humanos , Ativação Linfocitária/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Recombinação Genética/genética , Recombinação Genética/imunologia , Hipermutação Somática de Imunoglobulina/genética , Hipermutação Somática de Imunoglobulina/imunologia , Adulto Jovem
2.
Clin Infect Dis ; 77(6): 910-916, 2023 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-37337899

RESUMO

All World Health Organization (WHO) pre-qualified rabies vaccines for humans are inactivated tissue culture rabies virus formulations produced for intramuscular (IM) administration. Due to costs and vaccine shortage, dose-saving intradermal (ID) administration of rabies post-exposure prophylaxis (PEP) is encouraged by WHO. This study compared the immunogenicity of the ID 2-site, 3-visit Institut Pasteur Cambodge (IPC) PEP regimen to the IM 1-site, 4-visit 4-dose Essen regimen using Verorab vaccine (Sanofi). The development of neutralizing antibodies (nAbs) and T cell response was assessed in 210 patients with a category II or III animal exposure in a rabies-endemic country. At day 28, all participants developed nAbs (≥0.5 IU/mL), irrespective of PEP scheme, age, or administration of rabies immunoglobulin. T cell response and nAb titers were similar for both PEP schemes. This study demonstrated that the 1-week ID IPC regimen is as effective as the 2-week IM 4-dose Essen regimen in inducing an anti-rabies immune response under real-life PEP.


Assuntos
Vacina Antirrábica , Vírus da Raiva , Raiva , Animais , Humanos , Profilaxia Pós-Exposição , Injeções Intramusculares , Raiva/prevenção & controle , Anticorpos Neutralizantes , Injeções Intradérmicas , Anticorpos Antivirais
3.
PLoS Pathog ; 17(7): e1009708, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34293057

RESUMO

The humoral immune response and antibody-mediated functions of B cells during viral infections are well described. However, we have limited understanding of antibody-independent B cell functions, such as cytokine production and antigen presentation, in acute and chronic viral infections and their role in protection and/or immunopathogenesis. Here, we summarize the current literature on these antibody-independent B cell functions and identify remaining knowledge gaps. B cell subsets produce anti- and pro-inflammatory cytokines, which can have both beneficial and detrimental effects during viral clearance. As professional antigen presenting cells, B cells also play an important role in immune regulation/shaping of the developing adaptive immune responses. Since B cells primarily express TLR7 and TLR9, we specifically discuss the role of Toll-like receptor (TLR)-mediated B cell responses to viral infections and their role in augmenting adaptive immunity through enhanced cytokine production and antigen presentation. However, viruses have evolved strategies to subvert TLR signaling and additional stimulation via B cell receptor (BCR) may be required to overcome the defective TLR response in B cells. To conclude, antibody-independent B cell functions seem to have an important role in regulating both acute and chronic viral infections and may form the basis for novel therapeutic approaches in treatment of viral infections in the future.


Assuntos
Linfócitos B/imunologia , Viroses/imunologia , Animais , Humanos
4.
J Clin Immunol ; 42(4): 771-782, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35246784

RESUMO

Hyper-IgM syndrome type 2 (HIGM2) is a B cell intrinsic primary immunodeficiency caused by mutations in AICDA encoding activation-induced cytidine deaminase (AID) which impair immunoglobulin class switch recombination (CSR) and somatic hypermutation (SHM). Whereas autosomal-recessive AID-deficiency (AR-AID) affects both CSR and SHM, the autosomal-dominant form (AD-AID) due to C-terminal heterozygous variants completely abolishes CSR but only partially affects SHM. AR-AID patients display enhanced germinal center (GC) reactions and autoimmune manifestations, which are not present in AD-AID, suggesting that SHM but not CSR regulates GC reactions and peripheral B cell tolerance. Herein, we describe two siblings with HIGM2 due to a novel homozygous AICDA mutation (c.428-1G > T) which disrupts the splice acceptor site of exon 4 and results in the sole expression of a truncated AID variant that lacks 10 highly conserved amino acids encoded by exon 4 (AID-ΔE4a). AID-ΔE4a patients suffered from defective CSR and enhanced GC reactions and were therefore indistinguishable from other AR-AID patients. However, the AID-ΔE4a variant only partially affected SHM as observed in AD-AID patients. In addition, AID-ΔE4a but not AD-AID patients revealed impaired targeting of mutational hotspot motives and distorted mutational patterns. Hence, qualitative defects in AID function and altered SHM rather than global decreased SHM activity may account for the disease phenotype in these patients.


Assuntos
Síndrome de Imunodeficiência com Hiper-IgM , Citidina Desaminase/genética , Citidina Desaminase/metabolismo , Humanos , Síndrome de Imunodeficiência com Hiper-IgM/genética , Switching de Imunoglobulina/genética , Mutação/genética , Fenótipo , Irmãos , Hipermutação Somática de Imunoglobulina/genética
5.
Cytokine ; 144: 155533, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33941444

RESUMO

Type I interferons are essential for host response to viral infections, while dysregulation of their response can result in autoinflammation or autoimmunity. Among IFNα (alpha) responses, 13 subtypes exist that signal through the same receptor, but have been reported to have different effector functions. However, the lack of available tools for discriminating these closely related subtypes, in particular at the protein level, has restricted the study of their differential roles in disease. We developed a digital ELISA with specificity and high sensitivity for the IFNα2 subtype. Application of this assay, in parallel with our previously described pan-IFNα assay, allowed us to study different IFNα protein responses following cellular stimulation and in diverse patient cohorts. We observed different ratios of IFNα protein responses between viral infection and autoimmune patients. This analysis also revealed a small percentage of autoimmune patients with high IFNα2 protein measurements but low pan-IFNα measurements. Correlation with an ISG score and functional activity showed that in this small sub group of patients, IFNα2 protein measurements did not reflect its biological activity. This unusual phenotype was partly explained by the presence of anti-IFNα auto-antibodies in a subset of autoimmune patients. This study reports ultrasensitive assays for the study of IFNα proteins in patient samples and highlights the insights that can be obtained from the use of multiple phenotypic readouts in translational and clinical studies.


Assuntos
Antivirais/imunologia , Autoimunidade/imunologia , Interferon-alfa/imunologia , Viroses/imunologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Adulto Jovem
6.
J Infect Dis ; 217(11): 1690-1698, 2018 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-29490079

RESUMO

Background: Early detection of severe dengue can improve patient care and survival. To date, no reliable single-gene biomarker exists. We hypothesized that robust multigene signatures exist. Methods: We performed a prospective study on Cambodian dengue patients aged 4 to 22 years. Peripheral blood mononuclear cells (PBMCs) were obtained at hospital admission. We analyzed 42 transcriptomic profiles of patients with secondary dengue infected with dengue serotype 1. Our novel signature discovery approach controls the number of included genes and captures nonlinear relationships between transcript concentrations and severity. We evaluated the signature on secondary cases infected with different serotypes using 2 datasets: 22 PBMC samples from additional patients in our cohort and 32 whole blood samples from an independent cohort. Results: We identified an 18-gene signature for detecting severe dengue in patients with secondary infection upon hospital admission with a sensitivity of 0.93 (95% confidence interval [CI], .82-.98), specificity of 0.67 (95% CI, .53-.80), and area under the receiver operating characteristic curve (AUC) of 0.86 (95% CI, .75-.97). At validation, the signature had empirical AUCs of 0.85 (95% CI, .69-1.00) and 0.83 (95% CI, .68-.98) for the PBMCs and whole blood datasets, respectively. Conclusions: The signature could detect severe dengue in secondary-infected patients upon hospital admission. Its genes offer new insights into the pathogenesis of severe dengue.


Assuntos
RNA/sangue , Dengue Grave/sangue , Dengue Grave/diagnóstico , Adolescente , Adulto , Criança , Pré-Escolar , Coinfecção/sangue , Coinfecção/diagnóstico , Coinfecção/virologia , Vírus da Dengue/genética , Feminino , Marcadores Genéticos/genética , Hospitalização , Hospitais , Humanos , Leucócitos Mononucleares/virologia , Masculino , Estudos Prospectivos , Curva ROC , Sensibilidade e Especificidade , Sorogrupo , Transcriptoma/genética , Adulto Jovem
7.
Mamm Genome ; 29(7-8): 384-407, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30167843

RESUMO

Flaviviruses are arthropod-borne viruses, several of which represent emerging or re-emerging pathogens responsible for widespread infections with consequences ranging from asymptomatic seroconversion to severe clinical diseases and congenital developmental deficits. This variability is due to multiple factors including host genetic determinants, the role of which has been investigated in mouse models and human genetic studies. In this review, we provide an overview of the host genes and variants which modify susceptibility or resistance to major mosquito-borne flaviviruses infections in mice and humans.


Assuntos
Culicidae/virologia , Infecções por Flavivirus/genética , Infecções por Flavivirus/virologia , Flavivirus/fisiologia , Predisposição Genética para Doença , Interações Hospedeiro-Patógeno/genética , Animais , Biomarcadores , Modelos Animais de Doenças , Suscetibilidade a Doenças , Infecções por Flavivirus/imunologia , Infecções por Flavivirus/transmissão , Estudo de Associação Genômica Ampla , Interações Hospedeiro-Patógeno/imunologia , Humanos , Camundongos
8.
J Allergy Clin Immunol ; 136(5): 1315-25, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26100089

RESUMO

BACKGROUND: Heterozygous C104R or A181E TNF receptor superfamily member 13b (TNFRSF13B) mutations impair removal of autoreactive B cells, weaken B-cell activation, and convey to patients with common variable immune deficiency (CVID) an increased risk for autoimmunity. How mutant transmembrane activator and CAML interactor (TACI) influences wild-type TACI function is unclear; different models suggest either a dominant negative effect or haploinsufficiency. OBJECTIVE: We investigated potential TACI haploinsufficiency by analyzing patients with antibody-deficient Smith-Magenis syndrome (SMS) who possess only 1 TNFRSF13B allele and antibody-deficient patients carrying one c.204insA TNFRSF13B null mutation. METHODS: We tested the reactivity of antibodies isolated from single B cells from patients with SMS and patients with a c.204insA TNFRSF13B mutation and compared them with counterparts from patients with CVID with heterozygous C104R or A181E TNFRSF13B missense mutations. We also assessed whether loss of a TNFRSF13B allele induced haploinsufficiency in naive and memory B cells and recapitulated abnormal immunologic features typical of patients with CVID with heterozygous TNFRSF13B missense mutations. RESULTS: We found that loss of a TNFRSF13B allele does not affect TACI expression, activation responses, or establishment of central B-cell tolerance in naive B cells. Additionally, patients with SMS and those with a c.204insA TNFRSF13B mutation display normal regulatory T-cell function and peripheral B-cell tolerance. The lack of a TNFRSF13B allele did result in decreased TACI expression on memory B cells, resulting in impaired activation and antibody secretion. CONCLUSION: TNFRSF13B hemizygosity does not recapitulate autoimmune features of CVID-associated C104R and A181E TNFRSF13B mutations, which likely encode dominant negative products, but instead reveals selective TACI haploinsufficiency at later stages of B-cell development.


Assuntos
Linfócitos B/imunologia , Imunodeficiência de Variável Comum/imunologia , Síndrome de Smith-Magenis/imunologia , Linfócitos T Reguladores/imunologia , Proteína Transmembrana Ativadora e Interagente do CAML/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Formação de Anticorpos/genética , Autoimunidade , Criança , Feminino , Haploinsuficiência , Hemizigoto , Humanos , Memória Imunológica , Ativação Linfocitária/genética , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto/genética , Proteína Transmembrana Ativadora e Interagente do CAML/genética , Adulto Jovem
9.
J Allergy Clin Immunol ; 133(4): 1149-61, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24373350

RESUMO

BACKGROUND: Signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) can mediate the function of SLAM molecules, which have been proposed to be involved in the development of autoimmunity in mice. OBJECTIVE: We sought to determine whether the SLAM/SAP pathway regulates the establishment of human B-cell tolerance and what mechanisms of B-cell tolerance could be affected by SAP deficiency. METHODS: We tested the reactivity of antibodies isolated from single B cells from SAP-deficient patients with X-linked lymphoproliferative disease (XLP). The expressions of SAP and SLAM family members were assessed in human bone marrow-developing B cells. We also analyzed regulatory T (Treg) cell function in patients with XLP and healthy control subjects. RESULTS: We found that new emigrant/transitional B cells from patients with XLP were enriched in autoreactive clones, revealing a defective central B-cell tolerance checkpoint in the absence of functional SAP. In agreement with a B cell-intrinsic regulation of central tolerance, we identified SAP expression in a discrete subset of bone marrow immature B cells. SAP colocalized with SLAMF6 only in association with clustered B-cell receptors likely recognizing self-antigens, suggesting that SLAM/SAP regulate B-cell receptor-mediated central tolerance. In addition, patients with XLP displayed defective peripheral B-cell tolerance, which is normally controlled by Treg cells. Treg cells in patients with XLP seem functional, but SAP-deficient T cells were resistant to Treg cell-mediated suppression. Indeed, SAP-deficient T cells were hyperresponsive to T-cell receptor stimulation, which resulted in increased secretion of IL-2, IFN-γ, and TNF-α. CONCLUSIONS: SAP expression is required for the counterselection of developing autoreactive B cells and prevents their T cell-dependent accumulation in the periphery.


Assuntos
Antígenos CD/metabolismo , Linfócitos B/imunologia , Linfócitos B/metabolismo , Tolerância Imunológica , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Receptores de Superfície Celular/metabolismo , Transdução de Sinais , Autoimunidade/genética , Autoimunidade/imunologia , Fator Ativador de Células B/sangue , Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Peptídeos e Proteínas de Sinalização Intracelular/genética , Ativação Linfocitária/imunologia , Transtornos Linfoproliferativos/genética , Transtornos Linfoproliferativos/imunologia , Transtornos Linfoproliferativos/metabolismo , Ligação Proteica , Transporte Proteico , Receptores de Antígenos de Linfócitos B/metabolismo , Proteína Associada à Molécula de Sinalização da Ativação Linfocitária , Família de Moléculas de Sinalização da Ativação Linfocitária , Membro 1 da Família de Moléculas de Sinalização da Ativação Linfocitária , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
10.
Rheumatology (Oxford) ; 53(3): 438-47, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24287514

RESUMO

OBJECTIVE: Melanoma inhibitory activity (MIA) is a small chondrocyte-specific protein with unknown function. MIA knockout mice (MIA(-/-)) have a normal phenotype with minor microarchitectural alterations of cartilage. Our previous study demonstrated that immunodominant epitopes of MIA are actively presented in an HLA-DR4-restricted manner in the inflamed RA joint. The objective of this study was to investigate the potential role of MIA as an autoantigen. METHODS: Collagen-induced arthritis (CIA) and anti-collagen antibody-induced arthritis (CAIA) were induced in MIA(-/-) mice. Anti-type II collagen (anti-CII) antibodies were measured by ELISA. T cell proliferation and cytokine production were assessed by flow cytometry. RESULTS: MIA(-/-) mice had a markedly reduced incidence and severity of CIA and CAIA compared with wild-type (WT) mice. Attenuation of disease was not related to defective binding of anti-CII antibodies to cartilage in the absence of MIA. However, MIA(-/-) mice had significantly reduced anti-CII IgG1 and IgG2a antibody levels accompanied by an increase in FoxP3-expressing CD25(+)CD4(+) regulatory T cells. This was paralleled by a significant reduction in CII-specific IFN-γ production by T cells in MIA(-/-) but not WT animals, suggesting a qualitative impact of MIA on the collagen-induced Th1 response. Furthermore, Ag-specific proliferation of T cells after restimulation with MIA in WT but not MIA(-/-) mice indicated the existence of MIA-specific T cells in the context of CIA. CONCLUSION: These data support a role for MIA as an autoantigen during arthritis development. Whether MIA can influence the balance of pathogenic vs regulatory responses in human RA remains to be investigated.


Assuntos
Artrite Experimental/imunologia , Artrite Experimental/metabolismo , Autoantígenos/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Animais , Anticorpos Anti-Idiotípicos/efeitos adversos , Artrite Experimental/patologia , Autoantígenos/imunologia , Proliferação de Células , Colágeno/efeitos adversos , Colágeno/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Proteínas da Matriz Extracelular/deficiência , Proteínas da Matriz Extracelular/genética , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Índice de Gravidade de Doença , Linfócitos T/patologia
11.
Arthritis Rheum ; 65(4): 939-48, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23280233

RESUMO

OBJECTIVE: Anti-citrullinated protein antibodies (ACPAs) are the serologic hallmark of rheumatoid arthritis. Functional studies on the role of ACPAs in experimental arthritis have yielded conflicting results, and therefore the present study was undertaken to assess systematically whether citrullinated proteins can really induce ACPAs and modulate arthritis in mice. METHODS: Balb/c, SJL, and DBA/1 mice were immunized with either native or citrullinated fibrinogen, myelin basic protein (MBP), and type II collagen (CII). ACPAs were detected with a peptide-based enzyme-linked immunosorbent assay (ELISA) and with Western blotting using fibrinogen as substrate. Arthritis was induced in mice by immunization with CII in Freund's complete adjuvant or by injection of anticollagen antibodies. RESULTS: Analysis of the sera of mice immunized with citrullinated proteins revealed false-positive results with the citrulline peptide-based ELISA. In contrast, Western blot analysis using either citrullinated or native fibrinogen as substrate reliably detected ACPAs in Balb/c mice immunized with citrullinated fibrinogen, MBP, and CII. However, these ACPAs failed to induce or aggravate disease in Balb/c mice in the anticollagen antibody-induced arthritis model. Immunization with citrullinated fibrinogen induced ACPAs but did not lead to arthritis development in SJL and DBA/1 mice. In contrast, immunization with citrullinated CII failed to induce ACPAs or enhance disease in these strains in the collagen-induced arthritis model. CONCLUSION: Mice can develop genuine ACPAs, but detection of ACPAs is highly dependent on strain, immunogen, immunization protocol, and detection assay. Murine ACPAs are not overtly pathogenic, since neither preexisting ACPAs nor the use of citrullinated collagen as immunogen modulates the clinical course of arthritis.


Assuntos
Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Autoanticorpos/imunologia , Citrulina , Proteínas , Adjuvantes Imunológicos , Animais , Artrite Experimental/terapia , Artrite Reumatoide/terapia , Autoanticorpos/genética , Autoantígenos/imunologia , Colágeno Tipo II/imunologia , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Reações Falso-Positivas , Fibrinogênio/imunologia , Adjuvante de Freund/imunologia , Predisposição Genética para Doença , Imunoterapia Ativa , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos DBA , Proteína Básica da Mielina/imunologia , Processamento de Proteína Pós-Traducional , Proteínas/imunologia
12.
Arthritis Rheum ; 65(1): 174-85, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22972410

RESUMO

OBJECTIVE: The molecular processes driving the distinct patterns of synovial inflammation and tissue remodeling in spondylarthritis (SpA) as compared to rheumatoid arthritis (RA) remain largely unknown. Therefore, we aimed to identify novel and unsuspected disease-specific pathways in SpA by a systematic and unbiased synovial gene expression analysis. METHODS: Differentially expressed genes were identified by pan-genomic microarray and confirmed by quantitative polymerase chain reaction and immunohistochemical analyses of synovial tissue biopsy samples from patients with SpA (n=63), RA (n=28), and gout (n=9). The effect of inflammation on gene expression was assessed by stimulating fibroblast-like synoviocytes (FLS) with synovial fluid and by analysis of synovial tissue samples at weeks 0 and 12 of etanercept treatment. RESULTS: Using very stringent statistical thresholds, microarray analysis identified 64 up-regulated transcripts in patients with SpA synovitis as compared to those with RA synovitis. Pathway analysis revealed a robust myogene signature in this gene set. The myogene signature was technically and biologically reproducible, was specific for SpA, and was independent of disease duration, treatment, and SpA subtype (nonpsoriatic versus psoriatic). Synovial tissue staining identified the myogene expressing cells as vimentin-positive, prolyl 4-hydroxylase ß-positive, CD90+, and CD146+ mesenchymal cells that were significantly overrepresented in the intimal lining layer and synovial sublining of inflamed SpA synovium. Neither in vitro exposure to synovial fluid from inflamed SpA joints nor in vivo blockade of tumor necrosis factor modulated the SpA-specific myogene signature. CONCLUSION: These data identify a novel and disease-specific myogene signature in SpA synovitis. The fact that this stromal alteration appeared not to be downstream of local inflammation warrants further analysis of its functional role in the pathogenesis of the disease.


Assuntos
Artrite Reumatoide/genética , Expressão Gênica , Espondilartrite/genética , Membrana Sinovial/metabolismo , Sinovite/genética , Adulto , Idoso , Artrite Reumatoide/patologia , Técnicas de Cultura de Células , Feminino , Citometria de Fluxo , Imunofluorescência , Humanos , Imuno-Histoquímica , Masculino , Análise em Microsséries , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase em Tempo Real , Espondilartrite/metabolismo , Espondilartrite/patologia , Células Estromais/patologia , Membrana Sinovial/patologia , Sinovite/metabolismo , Sinovite/patologia
13.
Emerg Microbes Infect ; 13(1): 2304061, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38192073

RESUMO

Mosquito-borne viral infections are on the rise worldwide and can lead to severe symptoms such as haemorrhage, encephalitis, arthritis or microcephaly. A protective immune response following mosquito-borne viral infections requires the generation of a controlled and balanced immune response leading to viral clearance without immunopathology. Here, regulatory T cells play a central role in restoring immune homeostasis. In current review, we aim to provide an overview and summary of the phenotypes of FOXP3+ Tregs in various mosquito-borne arboviral disease, their association with disease severity and their functional characteristics. Furthermore, we discuss the role of cytokines and Tregs in the immunopathogenesis of mosquito-borne infections. Lastly, we discuss possible novel lines of research which could provide additional insight into the role of Tregs in mosquito-borne viral infections in order to develop novel therapeutic approaches or vaccination strategies.


Assuntos
Infecções por Arbovirus , Arbovírus , Culicidae , Encefalite , Microcefalia , Viroses , Animais , Humanos , Linfócitos T Reguladores , Mosquitos Vetores
14.
Microbes Infect ; : 105313, 2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38369008

RESUMO

Single-cell genomics provide researchers with tools to assess host-pathogen interactions at a resolution previously inaccessible. Transcriptome analysis, epigenome analysis, and immune profiling techniques allow for a better comprehension of the heterogeneity underlying both the host response and infectious agents. Here, we highlight technological advancements and data analysis workflows that increase our understanding of host-pathogen interactions at the single-cell level. We review various studies that have used these tools to better understand host-pathogen dynamics in a variety of infectious disease contexts, including viral, bacterial, and parasitic diseases. We conclude by discussing how single-cell genomics can advance our understanding of host-pathogen interactions.

15.
Oxf Open Immunol ; 5(1): iqae003, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38737941

RESUMO

Dengue virus (DENV) poses a global health threat, affecting millions individuals annually with no specific therapy and limited vaccines. Mosquitoes, mainly Aedes aegypti and Aedes albopictus worldwide, transmit DENV through their saliva during blood meals. In this study, we aimed to understand how Aedes mosquito saliva modulate skin immune responses during DENV infection in individuals living in mosquito-endemic regions. To accomplish this, we dissociated skin cells from Cambodian volunteers and incubated them with salivary gland extract (SGE) from three different mosquito strains: Ae. aegypti USDA strain, Ae. aegypti and Ae. albopictus wild type (WT) in the presence/absence of DENV. We observed notable alterations in skin immune cell phenotypes subsequent to exposure to Aedes salivary gland extract (SGE). Specifically, exposure lead to an increase in the frequency of macrophages expressing chemokine receptor CCR2, and neutrophils expressing CD69. Additionally, we noted a substantial increase in the percentage of macrophages that became infected with DENV in the presence of Aedes SGE. Differences in cellular responses were observed when Aedes SGE of three distinct mosquito strains were compared. Our findings deepen the understanding of mosquito saliva's role in DENV infection and skin immune responses in individuals regularly exposed to mosquito bites. This study provides insights into skin immune cell dynamics that could guide strategies to mitigate DENV transmission and other arbovirus diseases.

16.
mBio ; 15(6): e0006324, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38752787

RESUMO

The pathogenesis of dengue involves a complex interplay between the viral factor and the host immune response. A mismatch between the infecting serotype and the adaptive memory response is hypothesized to lead to exacerbated immune responses resulting in severe dengue. Here, we aim to define in detail the phenotype and function of different regulatory T cell (Treg) subsets and their association with disease severity in a cohort of acute dengue virus (DENV)-infected Cambodian children. Treg frequencies and proliferation of Tregs are increased in dengue patients compared to age-matched controls. Tregs from dengue patients are skewed to a Th1-type Treg phenotype. Interestingly, Tregs from severe dengue patients produce more interleukin-10 after in vitro stimulation compared to Tregs from classical dengue fever patients. Functionally, Tregs from dengue patients have reduced suppressive capacity, irrespective of disease severity. Taken together, these data suggest that even though Treg frequencies are increased in the blood of acute DENV-infected patients, Tregs fail to resolve inflammation and thereby could contribute to the immunopathology of dengue. IMPORTANCE: According to the World Health Organization, dengue is the fastest-spreading, epidemic-prone infectious disease. The extent of dengue virus infections increased over the years, mainly driven by globalization-including travel and trade-and environmental changes. Dengue is an immunopathology caused by an imbalanced immune response to a secondary heterotypic infection. As regulatory T cells (Tregs) are essential in maintaining immune homeostasis and dampening excessive immune activation, this study addressed the role of Tregs in dengue immunopathology. We show that Tregs from dengue patients are highly activated, skewed to a Th1-like Treg phenotype and less suppressive compared to healthy donor Tregs. Our data suggest that Tregs fail to resolve ongoing inflammation during dengue infection and hence contribute to the immunopathology of severe dengue disease. These data clarify the role of Tregs in dengue immunopathogenesis, emphasizing the need to develop T cell-based vaccines for dengue.


Assuntos
Vírus da Dengue , Dengue , Fenótipo , Linfócitos T Reguladores , Células Th1 , Humanos , Linfócitos T Reguladores/imunologia , Dengue/imunologia , Criança , Masculino , Vírus da Dengue/imunologia , Células Th1/imunologia , Feminino , Interleucina-10/imunologia , Interleucina-10/genética , Pré-Escolar , Adolescente , Camboja , Ativação Linfocitária
17.
Ann Rheum Dis ; 72(6): 1037-43, 2013 06.
Artigo em Inglês | MEDLINE | ID: mdl-22968102

RESUMO

OBJECTIVE: Experimental and human data suggest that tumour necrosis factor (TNF) blockade may affect B cell responses, in particular the induction of T cell-dependent (TD) humoral immunity. This study aimed to assess this hypothesis directly in patients with arthritis by analysing longitudinally the effect of TNF blockade on B cell activation and the maturation of humoral responses against TD and T cell-independent vaccines. MATERIALS AND METHODS: Peripheral blood samples were obtained from 56 spondyloarthritis patients before and after treatment with either non-steroidal anti-inflammatory drug (NSAID) alone or TNF blockers and analysed for B cell activation, plasma cell differentiation, germinal centre versus extra-follicular B cell maturation, and somatic hypermutation. Vaccine responses to hepatitis B and Streptococcus pneumoniae were measured by ELISA. RESULTS: TNF blockade augmented B cell activation as reflected by the expression of early activation markers, CD40, and costimulatory molecules, without affecting differentiation towards plasmablasts. This was associated with a specific increase of the unswitched fraction of circulating memory B cells and a decreased level of somatic hypermutation in anti-TNF treated patients, indicating an impairment of the germinal centre-dependent B cell maturation. In agreement with these findings, TNF blockade profoundly suppressed the response to the TD vaccination against hepatitis B, whereas the T cell-independent response against pneumococcal polysaccharides was only modestly affected. CONCLUSIONS: These data indicate that TNF blockade severely impedes the induction of primary TD humoral responses, probably by interfering with the germinal centre reaction.


Assuntos
Antirreumáticos/uso terapêutico , Linfócitos B/efeitos dos fármacos , Imunidade Humoral/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Espondiloartropatias/tratamento farmacológico , Linfócitos T/efeitos dos fármacos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab , Adulto , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Linfócitos B/citologia , Diferenciação Celular/efeitos dos fármacos , Estudos de Coortes , Etanercepte , Feminino , Citometria de Fluxo , Humanos , Imunoglobulina G/uso terapêutico , Infliximab , Masculino , Pessoa de Meia-Idade , Plasmócitos/citologia , Plasmócitos/efeitos dos fármacos , Receptores do Fator de Necrose Tumoral/uso terapêutico , Espondiloartropatias/imunologia , Linfócitos T/citologia
18.
Rheumatology (Oxford) ; 52(2): 252-60, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23065315

RESUMO

OBJECTIVE: The presence of disease-specific autoantibodies in RA but not spondyloarthritis (SpA) suggests that B-cell tolerance is preserved in the latter condition despite chronic joint inflammation. Which factors control B-cell tolerance vs autoimmunity in chronic arthritis remains incompletely understood. As single nucleotide polymorphisms in the B-cell scaffold protein with ankyrin repeats (BANK1) gene have recently been associated with various autoantibody-positive autoimmune diseases including RA, we explored whether altered expression of BANK1 was associated with humoral autoimmunity in arthritis. METHODS: Peripheral B-cell subsets and inflamed synovial tissue were obtained from active SpA and RA. Quantitative PCR was used to assess the expression of full-length BANK1 and delta2 BANK1, a splice variant lacking exon 2 that counteracts BANK1 function. B-cell subsets, autoantibody titres and clinical disease were monitored upon CIA induction in Bank1 knockout (KO) mice. RESULTS: Whereas full-length BANK1 was not differentially expressed, the BANK1 delta2 splicing variant was decreased in naïve peripheral B cells as well as in synovial tissue of SpA compared with RA. However, no differences were observed in seropositive vs seronegative RA. Performing functional analysis in mice, we found no differences in B-cell subsets and anti-collagen antibodies upon CIA induction between Bank1 KO mice and littermate controls. Accordingly, the incidence and severity of clinical disease were not altered in Bank1 KO mice. CONCLUSION: This study did not reveal a major role for BANK1 in humoral autoimmunity in chronic arthritis. The decreased levels of BANK1 delta2 in SpA, however, warrant more detailed analysis of the functional consequences of an altered BANK1/BANK1 delta2 balance.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Artrite Reumatoide/imunologia , Autoimunidade/genética , Subpopulações de Linfócitos B/imunologia , Regulação da Expressão Gênica/fisiologia , Imunidade Humoral/genética , Proteínas de Membrana/genética , Espondilartrite/imunologia , Animais , Artrite Experimental/imunologia , Autoanticorpos/sangue , Estudos de Casos e Controles , Estudos de Coortes , Primers do DNA/química , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Humanos , Imunofenotipagem , Camundongos , Camundongos Knockout , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Membrana Sinovial/imunologia , Membrana Sinovial/metabolismo
19.
Arthritis Rheum ; 64(6): 1859-68, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22231660

RESUMO

OBJECTIVE: Whether and how B lymphocytes contribute to the pathogenesis of spondylarthritis (SpA), a seronegative arthritis associated with gut inflammation, remains unknown. Because innate-like CD5+ B lymphocytes with regulatory functions have been identified in colitis models, we undertook the present study to analyze the presence and function of CD5+ B cells in human SpA. METHODS: Peripheral blood B cells from patients with SpA, patients with rheumatoid arthritis (RA), and healthy controls were analyzed by flow cytometry. Synovial biopsy samples were evaluated by immunohistochemistry analysis. Sorted CD5+ and CD5- B cells were analyzed for somatic hypermutation, expression of costimulatory molecules, and cytokine production. RESULTS: The naive, marginal zone-like, and to a lesser extent memory B cell compartments in patients with SpA exhibited a clear and specific increase of CD5+ B cells, which was not found in patients with RA. This increase was not due to either B cell activation or preferential migration of CD5- B cells to the inflamed synovium. Consistent with their phenotype and the low-affinity polyreactive immunoglobulins produced by their murine counterpart cells, CD5+ B cells from patients with SpA showed low levels of somatic hypermutation. With regard to antigen presentation, CD5+ B cells expressed slightly increased HLA-DR levels but low CD80 and CD86 levels. In vitro activation failed to up-regulate these costimulatory molecules but induced significant production of interleukin-10 and interleukin-6 by CD5+ B cells. CONCLUSION: CD5+ B cells are specifically increased in SpA. Analysis of somatic hypermutation, expression of antigen-presenting and costimulatory molecules, and cytokine production indicates that this B cell subset has regulatory capacities. Further investigation of the potential role of CD5+ cells in SpA is warranted.


Assuntos
Linfócitos B Reguladores/imunologia , Antígenos CD5/metabolismo , Espondilartrite/imunologia , Adulto , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Linfócitos B Reguladores/metabolismo , Feminino , Citometria de Fluxo , Humanos , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Masculino , Pessoa de Meia-Idade , Espondilartrite/metabolismo , Membrana Sinovial/imunologia , Membrana Sinovial/metabolismo
20.
Nat Microbiol ; 8(8): 1468-1479, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37429907

RESUMO

Although dengue virus (DENV) infection typically causes asymptomatic disease, DENV-infected patients can experience severe complications. A risk factor for symptomatic disease is pre-existing anti-DENV IgG antibodies. Cellular assays suggested that these antibodies can enhance viral infection of Fcγ receptor (FcγR)-expressing myeloid cells. Recent studies, however, revealed more complex interactions between anti-DENV antibodies and specific FcγRs by demonstrating that modulation of the IgG Fc glycan correlates with disease severity. To investigate the in vivo mechanisms of antibody-mediated dengue pathogenesis, we developed a mouse model for dengue disease that recapitulates the unique complexity of human FcγRs. In in vivo mouse models of dengue disease, we discovered that the pathogenic activity of anti-DENV antibodies is exclusively mediated through engagement of FcγRIIIa on splenic macrophages, resulting in inflammatory sequelae and mortality. These findings highlight the importance of IgG-FcγRIIIa interactions in dengue, with important implications for the design of safer vaccination approaches and effective therapeutic strategies.


Assuntos
Vírus da Dengue , Dengue , Humanos , Animais , Camundongos , Receptores de IgG , Macrófagos , Imunoglobulina G
SELEÇÃO DE REFERÊNCIAS
Detalhe da pesquisa