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1.
Life Sci Alliance ; 7(4)2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38316462

RESUMO

Bidirectional interactions between the immune system and the gut microbiota are key contributors to various physiological functions. Immune-associated diseases such as cancer and autoimmunity, and efficacy of immunomodulatory therapies, have been linked to microbiome variation. Although COVID-19 infection has been shown to cause microbial dysbiosis, it remains understudied whether the inflammatory response associated with vaccination also impacts the microbiota. Here, we investigate the temporal impact of COVID-19 vaccination on the gut microbiome in healthy and immuno-compromised individuals; the latter included patients with primary immunodeficiency and cancer patients on immunomodulating therapies. We find that the gut microbiome remained remarkably stable post-vaccination irrespective of diverse immune status, vaccine response, and microbial composition spanned by the cohort. The stability is evident at all evaluated levels including diversity, phylum, species, and functional capacity. Our results indicate the resilience of the gut microbiome to host immune changes triggered by COVID-19 vaccination and suggest minimal, if any, impact on microbiome-mediated processes. These findings encourage vaccine acceptance, particularly when contrasted with the significant microbiome shifts observed during COVID-19 infection.


Assuntos
COVID-19 , Microbioma Gastrointestinal , Neoplasias , Humanos , Vacinas contra COVID-19 , COVID-19/prevenção & controle , Vacinação
2.
Nat Commun ; 14(1): 3292, 2023 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-37369658

RESUMO

Age-associated B cells (ABC) accumulate with age and in individuals with different immunological disorders, including cancer patients treated with immune checkpoint blockade and those with inborn errors of immunity. Here, we investigate whether ABCs from different conditions are similar and how they impact the longitudinal level of the COVID-19 vaccine response. Single-cell RNA sequencing indicates that ABCs with distinct aetiologies have common transcriptional profiles and can be categorised according to their expression of immune genes, such as the autoimmune regulator (AIRE). Furthermore, higher baseline ABC frequency correlates with decreased levels of antigen-specific memory B cells and reduced neutralising capacity against SARS-CoV-2. ABCs express high levels of the inhibitory FcγRIIB receptor and are distinctive in their ability to bind immune complexes, which could contribute to diminish vaccine responses either directly, or indirectly via enhanced clearance of immune complexed-antigen. Expansion of ABCs may, therefore, serve as a biomarker identifying individuals at risk of suboptimal responses to vaccination.


Assuntos
COVID-19 , Imunidade Humoral , Humanos , Inibidores de Checkpoint Imunológico , Vacinas contra COVID-19 , COVID-19/prevenção & controle , SARS-CoV-2 , Vacinação , Complexo Antígeno-Anticorpo , Anticorpos Antivirais
4.
Nature ; 583(7814): 90-95, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32499645

RESUMO

Primary immunodeficiency (PID) is characterized by recurrent and often life-threatening infections, autoimmunity and cancer, and it poses major diagnostic and therapeutic challenges. Although the most severe forms of PID are identified in early childhood, most patients present in adulthood, typically with no apparent family history and a variable clinical phenotype of widespread immune dysregulation: about 25% of patients have autoimmune disease, allergy is prevalent and up to 10% develop lymphoid malignancies1-3. Consequently, in sporadic (or non-familial) PID genetic diagnosis is difficult and the role of genetics is not well defined. Here we address these challenges by performing whole-genome sequencing in a large PID cohort of 1,318 participants. An analysis of the coding regions of the genome in 886 index cases of PID found that disease-causing mutations in known genes that are implicated in monogenic PID occurred in 10.3% of these patients, and a Bayesian approach (BeviMed4) identified multiple new candidate PID-associated genes, including IVNS1ABP. We also examined the noncoding genome, and found deletions in regulatory regions that contribute to disease causation. In addition, we used a genome-wide association study to identify loci that are associated with PID, and found evidence for the colocalization of-and interplay between-novel high-penetrance monogenic variants and common variants (at the PTPN2 and SOCS1 loci). This begins to explain the contribution of common variants to the variable penetrance and phenotypic complexity that are observed in PID. Thus, using a cohort-based whole-genome-sequencing approach in the diagnosis of PID can increase diagnostic yield and further our understanding of the key pathways that influence immune responsiveness in humans.


Assuntos
Doenças da Imunodeficiência Primária/genética , Sequenciamento Completo do Genoma , Complexo 2-3 de Proteínas Relacionadas à Actina/genética , Teorema de Bayes , Estudos de Coortes , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Doenças da Imunodeficiência Primária/diagnóstico , Doenças da Imunodeficiência Primária/imunologia , Proteína Tirosina Fosfatase não Receptora Tipo 2/genética , Proteínas de Ligação a RNA/genética , Sequências Reguladoras de Ácido Nucleico/genética , Proteína 1 Supressora da Sinalização de Citocina/genética , Fatores de Transcrição/genética
5.
Clin Immunol ; 215: 108443, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32353633

RESUMO

A 29-year old male with recurrent respiratory and skin infections, anaemia and neutropaenia during childhood required immunoglobulin replacement for antibody deficiency from age 16. He remained relatively well until age 28 when he presented with a two-week history of fatigue, sore throat, fever and productive cough. He was found to have EBV viraemia and splenomegaly and a diagnosis of EBV-driven lymphoproliferative disease was made following bone marrow trephine. Family history was notable with three siblings: a healthy sister and two brothers with anaemia and neutropaenia; one who succumbed to septicaemia secondary to neutropaenic enterocolitis age 5 and another who developed intestinal vasculitis and antibody deficiency and had a successful haemopoetic stem cell transplant. The proband's DNA underwent targeted sequencing of 279 genes associated with immunodeficiency (GRID panel). The best candidates were two ADA2 variants, p.Arg169Gln (R169Q) and p.Asn370Lys (N370K). Sanger sequencing and co-segregation of variants in the parents, unaffected sister and all three affected brothers was fully consistent with compound heterozygous inheritance. Subsequent whole genome sequencing of the proband identified no other potential causal variants. ADA2 activity was consistent with a diagnosis of ADA2 deficiency in affected family members. This is the first description of EBV-driven lymphoproliferative disease in ADA2 deficiency. ADA2 deficiency may cause susceptibility to severe EBV-induced disease and we would recommend that EBV status and viral load is monitored in patients with this diagnosis and allogeneic SCT is considered at an early stage for patients whose ADA2 deficiency is associated with significant complications.


Assuntos
Adenosina Desaminase/deficiência , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/metabolismo , Herpesvirus Humano 4/patogenicidade , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Transtornos Linfoproliferativos/complicações , Transtornos Linfoproliferativos/metabolismo , Adulto , Humanos , Masculino
7.
J Exp Med ; 216(9): 1986-1998, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31235509

RESUMO

IL-6 excess is central to the pathogenesis of multiple inflammatory conditions and is targeted in clinical practice by immunotherapy that blocks the IL-6 receptor encoded by IL6R We describe two patients with homozygous mutations in IL6R who presented with recurrent infections, abnormal acute-phase responses, elevated IgE, eczema, and eosinophilia. This study identifies a novel primary immunodeficiency, clarifying the contribution of IL-6 to the phenotype of patients with mutations in IL6ST, STAT3, and ZNF341, genes encoding different components of the IL-6 signaling pathway, and alerts us to the potential toxicity of drugs targeting the IL-6R.


Assuntos
Síndromes de Imunodeficiência/patologia , Inflamação/patologia , Receptores de Interleucina-6/deficiência , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Células HEK293 , Humanos , Recém-Nascido , Masculino , Receptores de Interleucina-6/metabolismo
9.
J Allergy Clin Immunol ; 142(4): 1285-1296, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29477724

RESUMO

BACKGROUND: The genetic cause of primary immunodeficiency disease (PID) carries prognostic information. OBJECTIVE: We conducted a whole-genome sequencing study assessing a large proportion of the NIHR BioResource-Rare Diseases cohort. METHODS: In the predominantly European study population of principally sporadic unrelated PID cases (n = 846), a novel Bayesian method identified nuclear factor κB subunit 1 (NFKB1) as one of the genes most strongly associated with PID, and the association was explained by 16 novel heterozygous truncating, missense, and gene deletion variants. This accounted for 4% of common variable immunodeficiency (CVID) cases (n = 390) in the cohort. Amino acid substitutions predicted to be pathogenic were assessed by means of analysis of structural protein data. Immunophenotyping, immunoblotting, and ex vivo stimulation of lymphocytes determined the functional effects of these variants. Detailed clinical and pedigree information was collected for genotype-phenotype cosegregation analyses. RESULTS: Both sporadic and familial cases demonstrated evidence of the noninfective complications of CVID, including massive lymphadenopathy (24%), unexplained splenomegaly (48%), and autoimmune disease (48%), features prior studies correlated with worse clinical prognosis. Although partial penetrance of clinical symptoms was noted in certain pedigrees, all carriers have a deficiency in B-lymphocyte differentiation. Detailed assessment of B-lymphocyte numbers, phenotype, and function identifies the presence of an increased CD21low B-cell population. Combined with identification of the disease-causing variant, this distinguishes between healthy subjects, asymptomatic carriers, and clinically affected cases. CONCLUSION: We show that heterozygous loss-of-function variants in NFKB1 are the most common known monogenic cause of CVID, which results in a temporally progressive defect in the formation of immunoglobulin-producing B cells.


Assuntos
Linfócitos B/imunologia , Imunodeficiência de Variável Comum/genética , Subunidade p50 de NF-kappa B/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Europa (Continente) , Feminino , Humanos , Lactente , Recém-Nascido , Mutação com Perda de Função , Masculino , Pessoa de Meia-Idade , Fenótipo , Linfócitos T/imunologia , Adulto Jovem
11.
Front Immunol ; 7: 71, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27014260

RESUMO

Helicobacter pylori infections are usually established in early childhood and continuously stimulate immunity, including T-helper 1 (Th1), Th17, and regulatory T-cell (Treg) responses, throughout life. Although known to be the major cause of peptic ulcer disease and gastric cancer, disease occurs in a minority of those who are infected. Recently, there has been much interest in beneficial effects arising from infection with this pathogen. Published data robustly show that the infection is protective against asthma in mouse models. Epidemiological studies show that H. pylori is inversely associated with human allergy and asthma, but there is a paucity of mechanistic data to explain this. Since Th1 and Treg responses are reported to protect against allergic responses, we investigated if there were links between the human systemic Th1 and Treg response to H. pylori and allergen-specific IgE levels. The human cytokine and T-cell responses were examined using peripheral blood mononuclear cells (PBMCs) from 49 infected and 58 uninfected adult patients. Concentrations of total and allergen-specific plasma IgE were determined by ELISA and ImmunoCAP assays. These responses were analyzed according to major virulence factor genotypes of the patients' colonizing H. pylori strains. An in vitro assay was employed, using PBMCs from infected and uninfected donors, to determine the role of Treg cytokines in the suppression of IgE. Significantly higher frequencies of IL-10-secreting CD4(+)CD25(hi) Tregs, but not H. pylori-specific Th1 cells, were present in the peripheral blood of infected patients. Total and allergen-specific IgE concentrations were lower when there was a strong Treg response, and blocking IL-10 in vitro dramatically restored IgE responses. IgE concentrations were also significantly lower when patients were infected with CagA(+) strains or those expressing the more active i1 form of VacA. The systemic IL-10(+) Treg response is therefore likely to play a role in H. pylori-mediated protection against allergy in humans.

12.
Gut ; 63(10): 1550-9, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24436142

RESUMO

BACKGROUND: Helicobacter pylori-induced peptic ulceration is less likely to occur in patients with a strong gastric anti-inflammatory regulatory T cell (Treg) response. Migration of Tregs into the gastric mucosa is therefore important. OBJECTIVE: To identify the homing receptors involved in directing Tregs to the gastric mucosa, and investigate how H pylori stimulates the relevant chemokine responses. DESIGN: Gastric biopsy samples and peripheral blood were donated by 84 H pylori-infected and 46 uninfected patients. Luminex assays quantified gastric biopsy chemokine concentrations. Flow cytometry was used to characterise homing receptors on CD4(+)CD25(hi) Tregs. H pylori wild-type and isogenic mutants were used to investigate the signalling mechanisms behind CCL20 and IL-8 induction in gastric epithelial cell lines. Transwell assays were used to quantify Treg migration towards chemokines in vitro. RESULTS: CCL20, CXCL1-3 and IL-8 concentrations were significantly increased in gastric biopsy samples from H pylori-infected patients. CCR6 (CCL20 receptor), CXCR1 and CXCR2 (IL-8 and CXCL1-3 receptors) were expressed by a higher proportion of peripheral blood Tregs in infected patients. Most gastric Tregs expressed these receptors. H pylori induced CCL20 production by gastric epithelial cells via cag pathogenicity island (cagPAI)-dependent NF-κB signalling. Foxp3(+), but not Foxp3(-), CD4 cells from infected mice migrated towards recombinant CCL20 in vitro. CONCLUSIONS: As well as increasing Treg numbers, H pylori infection induces a change in their characteristics. Expression of CCR6, CXCR1 and CXCR2 probably enables their migration towards CCL20 and IL-8 in the infected gastric mucosa. Such qualitative changes may also explain how H pylori protects against some extragastric inflammatory disorders.


Assuntos
Quimiocina CCL20/metabolismo , Quimiotaxia de Leucócito/fisiologia , Mucosa Gástrica/imunologia , Infecções por Helicobacter/imunologia , Úlcera Péptica/imunologia , Receptores CCR6/metabolismo , Linfócitos T Reguladores/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular , Quimiocinas/metabolismo , Feminino , Citometria de Fluxo , Infecções por Helicobacter/microbiologia , Helicobacter pylori/patogenicidade , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Úlcera Péptica/microbiologia , Reino Unido , Adulto Jovem
13.
Doc Ophthalmol ; 127(2): 165-71, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23794161

RESUMO

BACKGROUND: To present a case of melanoma-associated retinopathy (MAR) which manifested 26 months prior to a formal diagnosis of melanoma. METHODS: Case report. RESULTS: A 72-year-old female presented with bilateral continuous photopsia consistent with MAR of 7-months duration. At this point, visual function appeared normal with the exception of mildly impaired colour vision (10/17 Ishihara plates). The flash electroretinographic (ERG) revealed extinguished rod responses, a normal a-wave and reduced b-wave (electronegative ERG) on the maximal combined response, absent oscillatory potentials and broadened a-wave trough on the cone response. Multifocal ERG (mfERG) responses were delayed and demonstrated atypical morphology. Nineteen months after the initial presentation, her visual symptoms had progressed significantly with constant debilitating photopsia in combination with 13 kg weight loss. Biopsy of a now evident left axillary mass demonstrated a metastatic high-grade malignant melanoma. No primary was detected, and an axillary lymph node clearance was undertaken. Subsequently, visual symptoms resolved with corresponding improvement in the ERG over the next 18 months. Rod responses recovered such that the amplitude was at the lower limit of normal and the mfERG response delay lessened. Unfortunately, the melanoma recurred and the patient passed away 6 months later. Visual symptoms did not recur. CONCLUSION: We present a case which demonstrates MAR may precede the formal diagnosis of melanoma by up to 26 months. The potential for improvement in the rod visual function persists over a period of years with normalisation of an electronegative waveform. In this case, cytoreductive surgery resulted in complete resolution of the MAR, which did not return even with a recurrence of the tumour.


Assuntos
Melanoma/secundário , Síndromes Paraneoplásicas Oculares/diagnóstico , Neoplasias Cutâneas/patologia , Idoso , Axila , Eletrorretinografia , Evolução Fatal , Feminino , Humanos , Excisão de Linfonodo , Linfonodos/patologia , Metástase Linfática , Síndromes Paraneoplásicas Oculares/fisiopatologia , Síndromes Paraneoplásicas Oculares/cirurgia , Estimulação Luminosa , Células Fotorreceptoras Retinianas Bastonetes/fisiologia , Acuidade Visual
14.
J Immunol Methods ; 394(1-2): 1-9, 2013 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-23644159

RESUMO

Sensitive measurement of multiple cytokine profiles from small mucosal tissue biopsies, for example human gastric biopsies obtained through an endoscope, is technically challenging. Multiplex methods such as Luminex assays offer an attractive solution but standard protocols are not available for tissue samples. We assessed the utility of three commercial Luminex kits (VersaMAP, Bio-Plex and MILLIPLEX) to measure interleukin-17A (IL-17) and interferon-gamma (IFNγ) concentrations in human gastric biopsies and we optimised preparation of mucosal samples for this application. First, we assessed the technical performance, limits of sensitivity and linear dynamic ranges for each kit. Next we spiked human gastric biopsies with recombinant IL-17 and IFNγ at a range of concentrations (1.5 to 1000 pg/mL) and assessed kit accuracy for spiked cytokine recovery and intra-assay precision. We also evaluated the impact of different tissue processing methods and extraction buffers on our results. Finally we assessed recovery of endogenous cytokines in unspiked samples. In terms of sensitivity, all of the kits performed well within the manufacturers' recommended standard curve ranges but the MILLIPLEX kit provided most consistent sensitivity for low cytokine concentrations. In the spiking experiments, the MILLIPLEX kit performed most consistently over the widest range of concentrations. For tissue processing, manual disruption provided significantly improved cytokine recovery over automated methods. Our selected kit and optimised protocol were further validated by measurement of relative cytokine levels in inflamed and uninflamed gastric mucosa using Luminex and real-time polymerase chain reaction. In summary, with proper optimisation Luminex kits (and for IL-17 and IFNγ the MILLIPLEX kit in particular) can be used for the sensitive detection of cytokines in mucosal biopsies. Our results should help other researchers seeking to quantify multiple low concentration cytokines in small tissue samples.


Assuntos
Citocinas/análise , Imunoensaio/métodos , Kit de Reagentes para Diagnóstico , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
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