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1.
Nat Immunol ; 18(5): 552-562, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28346408

RESUMO

Gut dysbiosis might underlie the pathogenesis of type 1 diabetes. In mice of the non-obese diabetic (NOD) strain, we found that key features of disease correlated inversely with blood and fecal concentrations of the microbial metabolites acetate and butyrate. We therefore fed NOD mice specialized diets designed to release large amounts of acetate or butyrate after bacterial fermentation in the colon. Each diet provided a high degree of protection from diabetes, even when administered after breakdown of immunotolerance. Feeding mice a combined acetate- and butyrate-yielding diet provided complete protection, which suggested that acetate and butyrate might operate through distinct mechanisms. Acetate markedly decreased the frequency of autoreactive T cells in lymphoid tissues, through effects on B cells and their ability to expand populations of autoreactive T cells. A diet containing butyrate boosted the number and function of regulatory T cells, whereas acetate- and butyrate-yielding diets enhanced gut integrity and decreased serum concentration of diabetogenic cytokines such as IL-21. Medicinal foods or metabolites might represent an effective and natural approach for countering the numerous immunological defects that contribute to T cell-dependent autoimmune diseases.


Assuntos
Acetatos/metabolismo , Linfócitos B/imunologia , Butiratos/metabolismo , Colo/metabolismo , Diabetes Mellitus Tipo 1/dietoterapia , Disbiose/dietoterapia , Linfócitos T Reguladores/imunologia , Animais , Autoimunidade , Linfócitos B/microbiologia , Células Cultivadas , Colo/patologia , Dietoterapia , Microbioma Gastrointestinal , Interleucinas/sangue , Camundongos , Camundongos Endogâmicos NOD , Linfócitos T Reguladores/microbiologia
3.
N Engl J Med ; 389(23): 2140-2150, 2023 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-38055252

RESUMO

BACKGROUND: Janus kinase (JAK) inhibitors, including baricitinib, block cytokine signaling and are effective disease-modifying treatments for several autoimmune diseases. Whether baricitinib preserves ß-cell function in type 1 diabetes is unclear. METHODS: In this phase 2, double-blind, randomized, placebo-controlled trial, we assigned patients with type 1 diabetes diagnosed during the previous 100 days to receive baricitinib (4 mg once per day) or matched placebo orally for 48 weeks. The primary outcome was the mean C-peptide level, determined from the area under the concentration-time curve, during a 2-hour mixed-meal tolerance test at week 48. Secondary outcomes included the change from baseline in the glycated hemoglobin level, the daily insulin dose, and measures of glycemic control assessed with the use of continuous glucose monitoring. RESULTS: A total of 91 patients received baricitinib (60 patients) or placebo (31 patients). The median of the mixed-meal-stimulated mean C-peptide level at week 48 was 0.65 nmol per liter per minute (interquartile range, 0.31 to 0.82) in the baricitinib group and 0.43 nmol per liter per minute (interquartile range, 0.13 to 0.63) in the placebo group (P = 0.001). The mean daily insulin dose at 48 weeks was 0.41 U per kilogram of body weight per day (95% confidence interval [CI], 0.35 to 0.48) in the baricitinib group and 0.52 U per kilogram per day (95% CI, 0.44 to 0.60) in the placebo group. The levels of glycated hemoglobin were similar in the two trial groups. However, the mean coefficient of variation of the glucose level at 48 weeks, as measured by continuous glucose monitoring, was 29.6% (95% CI, 27.8 to 31.3) in the baricitinib group and 33.8% (95% CI, 31.5 to 36.2) in the placebo group. The frequency and severity of adverse events were similar in the two trial groups, and no serious adverse events were attributed to baricitinib or placebo. CONCLUSIONS: In patients with type 1 diabetes of recent onset, daily treatment with baricitinib over 48 weeks appeared to preserve ß-cell function as estimated by the mixed-meal-stimulated mean C-peptide level. (Funded by JDRF International and others; BANDIT Australian New Zealand Clinical Trials Registry number, ACTRN12620000239965.).


Assuntos
Diabetes Mellitus Tipo 1 , Células Secretoras de Insulina , Inibidores de Janus Quinases , Humanos , Austrália , Glicemia/análise , Automonitorização da Glicemia , Peptídeo C/sangue , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hemoglobinas Glicadas/análise , Insulina/uso terapêutico , Inibidores de Janus Quinases/efeitos adversos , Inibidores de Janus Quinases/farmacologia , Inibidores de Janus Quinases/uso terapêutico , Células Secretoras de Insulina/efeitos dos fármacos , Método Duplo-Cego
4.
Nat Immunol ; 14(7): 741-8, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23685786

RESUMO

Functionally diverse T cell populations interact to maintain homeostasis of the immune system. We found that human and mouse antigen-activated T cells with high expression of the lymphocyte surface marker CD52 suppressed other T cells. CD52(hi)CD4(+) T cells were distinct from CD4(+)CD25(+)Foxp3(+) regulatory T cells. Their suppression was mediated by soluble CD52 released by phospholipase C. Soluble CD52 bound to the inhibitory receptor Siglec-10 and impaired phosphorylation of the T cell receptor-associated kinases Lck and Zap70 and T cell activation. Humans with type 1 diabetes had a lower frequency and diminished function of CD52(hi)CD4(+) T cells responsive to the autoantigen GAD65. In diabetes-prone mice of the nonobese diabetic (NOD) strain, transfer of lymphocyte populations depleted of CD52(hi) cells resulted in a substantially accelerated onset of diabetes. Our studies identify a ligand-receptor mechanism of T cell regulation that may protect humans and mice from autoimmune disease.


Assuntos
Antígenos CD/imunologia , Antígenos de Neoplasias/imunologia , Linfócitos T CD4-Positivos/imunologia , Diabetes Mellitus Tipo 1/imunologia , Glicoproteínas/imunologia , Ativação Linfocitária/imunologia , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/imunologia , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Animais , Antígenos CD/genética , Antígenos de Neoplasias/genética , Autoantígenos/imunologia , Antígeno CD52 , Feminino , Citometria de Fluxo , Glicoproteínas/genética , Homeostase/imunologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Fosforilação/imunologia , RNA Mensageiro/química , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína-Tirosina Quinase ZAP-70/imunologia
5.
Diabetologia ; 2024 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-39222156

RESUMO

AIMS/HYPOTHESIS: Dietary patterns characterised by high intakes of vegetables may lower the risk of pre-eclampsia and premature birth in the general population. The effect of dietary patterns in women with type 1 diabetes, who have an increased risk of complications in pregnancy, is not known. The aim of this study was to investigate the relationship between dietary patterns and physical activity during pregnancy and maternal complications and birth outcomes in women with type 1 diabetes. We also compared dietary patterns in women with and without type 1 diabetes. METHODS: Diet was assessed in the third trimester using a validated food frequency questionnaire in participants followed prospectively in the multi-centre Environmental Determinants of Islet Autoimmunity (ENDIA) study. Dietary patterns were characterised by principal component analysis. The Pregnancy Physical Activity Questionnaire was completed in each trimester. Data for maternal and birth outcomes were collected prospectively. RESULTS: Questionnaires were completed by 973 participants during 1124 pregnancies. Women with type 1 diabetes (n=615 pregnancies with dietary data) were more likely to have a 'fresh food' dietary pattern than women without type 1 diabetes (OR 1.19, 95% CI 1.07, 1.31; p=0.001). In women with type 1 diabetes, an increase equivalent to a change from quartile 1 to 3 in 'fresh food' dietary pattern score was associated with a lower risk of pre-eclampsia (OR 0.37, 95% CI 0.17, 0.78; p=0.01) and premature birth (OR 0.35, 95% CI 0.20, 0.62, p<0.001). These associations were mediated in part by BMI and HbA1c. The 'processed food' dietary pattern was associated with an increased birthweight (ß coefficient 56.8 g, 95% CI 2.8, 110.8; p=0.04). Physical activity did not relate to outcomes. CONCLUSIONS/INTERPRETATION: A dietary pattern higher in fresh foods during pregnancy was associated with sizeable reductions in risk of pre-eclampsia and premature birth in women with type 1 diabetes.

7.
Proc Natl Acad Sci U S A ; 118(10)2021 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-33658363

RESUMO

Blood pH is tightly maintained between 7.35 and 7.45, and acidosis (pH <7.3) indicates poor prognosis in sepsis, wherein lactic acid from anoxic tissues overwhelms the buffering capacity of blood. Poor sepsis prognosis is also associated with low zinc levels and the release of High mobility group box 1 (HMGB1) from activated and/or necrotic cells. HMGB1 added to whole blood at physiological pH did not bind leukocyte receptors, but lowering pH with lactic acid to mimic sepsis conditions allowed binding, implying the presence of natural inhibitor(s) preventing binding at normal pH. Testing micromolar concentrations of divalent cations showed that zinc supported the robust binding of sialylated glycoproteins with HMGB1. Further characterizing HMGB1 as a sialic acid-binding lectin, we found that optimal binding takes place at normal blood pH and is markedly reduced when pH is adjusted with lactic acid to levels found in sepsis. Glycan array studies confirmed the binding of HMGB1 to sialylated glycan sequences typically found on plasma glycoproteins, with binding again being dependent on zinc and normal blood pH. Thus, HMGB1-mediated hyperactivation of innate immunity in sepsis requires acidosis, and micromolar zinc concentrations are protective. We suggest that the potent inflammatory effects of HMGB1 are kept in check via sequestration by plasma sialoglycoproteins at physiological pH and triggered when pH and zinc levels fall in late stages of sepsis. Current clinical trials independently studying zinc supplementation, HMGB1 inhibition, or pH normalization may be more successful if these approaches are combined and perhaps supplemented by infusions of heavily sialylated molecules.


Assuntos
Acidose/sangue , Proteína HMGB1/sangue , Sepse/sangue , Sialoglicoproteínas/sangue , Zinco/sangue , Acidose/imunologia , Acidose/metabolismo , Acidose/patologia , Proteínas de Transporte , Proteína HMGB1/farmacologia , Humanos , Concentração de Íons de Hidrogênio , Imunidade Inata , Lipopolissacarídeos/farmacologia , Polissacarídeos/química , Sepse/imunologia , Sepse/patologia , Ácidos Siálicos/química , Sialoglicoproteínas/química , Zinco/metabolismo
8.
J Allergy Clin Immunol ; 152(3): 667-675, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37150361

RESUMO

BACKGROUND: The mechanisms underlying the protective effect of older siblings on allergic disease remain unclear but may relate to the infant gut microbiota. OBJECTIVE: We sought to investigate whether having older siblings decreases the risk of IgE-mediated food allergy by accelerating the maturation of the infant gut microbiota. METHODS: In a birth cohort assembled using an unselected antenatal sampling frame (n = 1074), fecal samples were collected at 1 month, 6 months, and 1 year, and food allergy status at 1 year was determined by skin prick test and in-hospital food challenge. We used 16S rRNA gene amplicon sequencing to derive amplicon sequence variants. Among a random subcohort (n = 323), microbiota-by-age z scores at each time point were calculated using fecal amplicon sequence variants to represent the gut microbiota maturation over the first year of life. RESULTS: A greater number of siblings was associated with a higher microbiota-by-age z score at age 1 year (ß  = 0.15 per an additional sibling; 95% CI, 0.05-0.24; P = .003), which was in turn associated with decreased odds of food allergy (odds ratio, 0.45; 95% CI, 0.33-0.61; P < .001). Microbiota-by-age z scores mediated 63% of the protective effect of siblings. Analogous associations were not observed at younger ages. CONCLUSIONS: The protective effect of older siblings on the risk of developing IgE-mediated food allergy during infancy is substantially mediated by advanced maturation of the gut microbiota at age 1 year.


Assuntos
Hipersensibilidade Alimentar , Microbioma Gastrointestinal , Gravidez , Lactente , Humanos , Feminino , Irmãos , RNA Ribossômico 16S/genética , Hipersensibilidade Alimentar/prevenção & controle , Imunoglobulina E
9.
Immunol Cell Biol ; 101(10): 923-935, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37721869

RESUMO

The emergence of large language models (LLMs) and assisted artificial intelligence (AI) technologies have revolutionized the way in which we interact with technology. A recent symposium at the Walter and Eliza Hall Institute explored the current practical applications of LLMs in medical research and canvassed the emerging ethical, legal and social implications for the use of AI-assisted technologies in the sciences. This paper provides an overview of the symposium's key themes and discussions delivered by diverse speakers, including early career researchers, group leaders, educators and policy-makers highlighting the opportunities and challenges that lie ahead for scientific researchers and educators as we continue to explore the potential of this cutting-edge and emerging technology.


Assuntos
Inteligência Artificial , Pesquisa Biomédica , Tecnologia
10.
Blood ; 135(23): 2049-2058, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32305044

RESUMO

Loss of heterochromatin has been proposed as a universal mechanism of aging across different species and cell types. However, a comprehensive analysis of hematopoietic changes caused by heterochromatin loss is lacking. Moreover, there is conflict in the literature around the role of the major heterochromatic histone methyltransferase Suv39h1 in the aging process. Here, we use individual and dual deletion of Suv39h1 and Suv39h2 enzymes to examine the causal role of heterochromatin loss in hematopoietic cell development. Loss of neither Suv39h1 nor Suv39h2 individually had any effect on hematopoietic stem cell function or the development of mature lymphoid or myeloid lineages. However, deletion of both enzymes resulted in characteristic changes associated with aging such as reduced hematopoietic stem cell function, thymic involution and decreased lymphoid output with a skewing toward myeloid development, and increased memory T cells at the expense of naive T cells. These cellular changes were accompanied by molecular changes consistent with aging, including alterations in nuclear shape and increased nucleolar size. Together, our results indicate that the hematopoietic system has a remarkable tolerance for major disruptions in chromatin structure and reveal a role for Suv39h2 in depositing sufficient H3K9me3 to protect the entire hematopoietic system from changes associated with premature aging.


Assuntos
Senilidade Prematura/patologia , Diferenciação Celular , Hematopoese , Células-Tronco Hematopoéticas/patologia , Heterocromatina/metabolismo , Histona-Lisina N-Metiltransferase/fisiologia , Metiltransferases/fisiologia , Proteínas Repressoras/fisiologia , Idoso , Senilidade Prematura/metabolismo , Animais , Núcleo Celular/genética , Feminino , Células-Tronco Hematopoéticas/metabolismo , Heterocromatina/genética , Humanos , Masculino , Camundongos , Camundongos Knockout , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/patologia
11.
Pediatr Allergy Immunol ; 33(6): e13810, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35754137

RESUMO

BACKGROUND: Children born to larger households have less allergic disease. T regulatory cell (Treg) development may be a relevant mechanism, but this has not been studied longitudinally. OBJECTIVE: We aim to (i) describe how prenatal and postnatal environmental factors are associated with Treg development and (ii) investigate whether serial Treg measures predict allergic outcomes at 1 year of age. METHODS: A birth cohort (n = 1074) with information on prenatal and postnatal early life factors. Both naïve Treg (nTreg) and activated Treg (aTreg) cell populations (as a proportion of CD4+ T cells) were available in 463 infants at birth (cord blood), 600 at 6 months, and 675 at 12 months. 191 infants had serial measures. Measures of allergic status at 12 months were polysensitization (sensitization to 2 or more allergens), clinically proven food allergy, atopic eczema, and atopic wheeze. RESULTS: Infants born to larger households (3 or more residents) had higher longitudinal nTreg proportions over the first postnatal year with a mean difference (MD) of 0.67 (95% CI 0.30-1.04)%. Higher nTreg proportions at birth were associated with a reduced risk of infant allergic outcomes. Childcare attendance and breastfeeding were associated with higher longitudinal nTreg proportions (MD 0.48 (95% CI 0.08-0.80)%. CONCLUSION: Multiple prenatal and postnatal microbial factors are associated with nTreg and aTreg development. Larger household size was associated with higher nTreg at birth which in turn was associated with reduced allergic sensitization and disease at 12 months of age.


Assuntos
Dermatite Atópica , Hipersensibilidade Alimentar , Coorte de Nascimento , Criança , Estudos de Coortes , Feminino , Humanos , Lactente , Recém-Nascido , Gravidez , Linfócitos T Reguladores
12.
Pediatr Diabetes ; 23(8): 1594-1601, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36175392

RESUMO

AIMS: Islet autoantibody screening of infants and young children in the Northern Hemisphere, together with semi-annual metabolic monitoring, is associated with a lower risk of ketoacidosis (DKA) and improved glucose control after diagnosis of clinical (stage 3) type 1 diabetes (T1D). We aimed to determine if similar benefits applied to older Australians and New Zealanders monitored less rigorously. METHODS: DKA occurrence and metabolic control were compared between T1D relatives screened and monitored for T1D and unscreened individuals diagnosed in the general population, ascertained from the Australasian Diabetes Data Network. RESULTS: Between 2005 and 2019, 17,105 relatives (mean (SD) age 15.7 (10.8) years; 52% female) were screened for autoantibodies against insulin, glutamic acid decarboxylase, and insulinoma-associated protein 2. Of these, 652 screened positive to a single and 306 to multiple autoantibody specificities, of whom 201 and 215, respectively, underwent metabolic monitoring. Of 178 relatives diagnosed with stage 3 T1D, 9 (5%) had DKA, 7 of whom had not undertaken metabolic monitoring. The frequency of DKA in the general population was 31%. After correction for age, sex and T1D family history, the frequency of DKA in screened relatives was >80% lower than in the general population. HbA1c and insulin requirements following diagnosis were also lower in screened relatives, consistent with greater beta cell reserve. CONCLUSIONS: T1D autoantibody screening and metabolic monitoring of older children and young adults in Australia and New Zealand, by enabling pre-clinical diagnosis when beta cell reserve is greater, confers protection from DKA. These clinical benefits support ongoing efforts to increase screening activity in the region and should facilitate the application of emerging immunotherapies.


Assuntos
Diabetes Mellitus Tipo 1 , Cetoacidose Diabética , Cetose , Criança , Lactente , Humanos , Feminino , Adolescente , Pré-Escolar , Masculino , Diabetes Mellitus Tipo 1/complicações , Nova Zelândia , Cetoacidose Diabética/epidemiologia , Austrália , Insulina/uso terapêutico , Autoanticorpos
13.
BMC Bioinformatics ; 22(1): 312, 2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34107881

RESUMO

BACKGROUND: Except for bacteria, the taxonomic diversity of the human fecal metagenome has not been widely studied, despite the potential importance of viruses and eukaryotes. Widely used bioinformatic tools contain limited numbers of non-bacterial species in their databases compared to available genomic sequences and their methodologies do not favour classification of rare sequences which may represent only a small fraction of their parent genome. In seeking to optimise identification of non-bacterial species, we evaluated five widely-used metagenome classifier programs (BURST, Kraken2, Centrifuge, MetaPhlAn2 and CCMetagen) for their ability to correctly assign and count simulations of bacterial, viral and eukaryotic DNA sequence reads, including the effect of taxonomic order of analysis of bacteria, viruses and eukaryotes and the effect of sequencing depth. RESULTS: We found that the precision of metagenome classifiers varied significantly between programs and between taxonomic groups. When classifying viruses and eukaryotes, ordering the analysis such that bacteria were classified first significantly improved classification precision. Increasing sequencing depth decreased classification precision and did not improve recall of rare species. CONCLUSIONS: Choice of metagenome classifier program can have a marked effect on results with respect to precision of species assignment in different taxonomic groups. The order of taxonomic classification can markedly improve precision. Increasing sequencing depth can decrease classification precision and yields diminishing returns in probability of species detection.


Assuntos
Metagenoma , Vírus , Bactérias/genética , Biologia Computacional , Humanos , Metagenômica , Análise de Sequência de DNA , Vírus/genética
14.
Diabetologia ; 64(11): 2432-2444, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34338806

RESUMO

AIMS/HYPOTHESIS: Accurate prediction of disease progression in individuals with pre-symptomatic type 1 diabetes has potential to prevent ketoacidosis and accelerate development of disease-modifying therapies. Current tools for predicting risk require multiple blood samples taken during an OGTT. Our aim was to develop and validate a simpler tool based on a single blood draw. METHODS: Models to predict disease progression using a single OGTT time point (0, 30, 60, 90 or 120 min) were developed using TrialNet data collected from relatives with type 1 diabetes and validated in independent populations at high genetic risk of type 1 diabetes (TrialNet, Diabetes Prevention Trial-Type 1, The Environmental Determinants of Diabetes in the Young [1]) and in a general population of Bavarian children who participated in Fr1da. RESULTS: Cox proportional hazards models combining plasma glucose, C-peptide, sex, age, BMI, HbA1c and insulinoma antigen-2 autoantibody status predicted disease progression in all populations. In TrialNet, the AUC for receiver operating characteristic curves for models named M60, M90 and M120, based on sampling at 60, 90 and 120 min, was 0.760, 0.761 and 0.745, respectively. These were not significantly different from the AUC of 0.760 for the gold standard Diabetes Prevention Trial Risk Score, which requires five OGTT blood samples. In TEDDY, where only 120 min blood sampling had been performed, the M120 AUC was 0.865. In Fr1da, the M120 AUC of 0.742 was significantly greater than the M60 AUC of 0.615. CONCLUSIONS/INTERPRETATION: Prediction models based on a single OGTT blood draw accurately predict disease progression from stage 1 or 2 to stage 3 type 1 diabetes. The operational simplicity of M120, its validity across different at-risk populations and the requirement for 120 min sampling to stage type 1 diabetes suggest M120 could be readily applied to decrease the cost and complexity of risk stratification.


Assuntos
Doenças Assintomáticas , Autoanticorpos/sangue , Diabetes Mellitus Tipo 1/diagnóstico , Anticorpos Anti-Insulina/sangue , Proteínas Tirosina Fosfatases Classe 8 Semelhantes a Receptores/imunologia , Transportador 8 de Zinco/imunologia , Adolescente , Área Sob a Curva , Glicemia/metabolismo , Índice de Massa Corporal , Peptídeo C/sangue , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/sangue , Progressão da Doença , Feminino , Teste de Tolerância a Glucose , Hemoglobinas Glicadas/metabolismo , Humanos , Masculino , Modelos de Riscos Proporcionais , Curva ROC
15.
Pediatr Diabetes ; 22(3): 425-433, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33470492

RESUMO

AIM: We aimed to characterize associations between diet and the gut microbiome and short chain fatty acid (SCFA) products in youth with islet autoimmunity or type 1 diabetes (IA/T1D) in comparison with controls. RESEARCH DESIGN AND METHODS: Eighty participants (25 diagnosed with T1D, 17 with confirmed IA, 38 sibling or unrelated controls) from the Australian T1D Gut Study cohort were studied (median [IQR] age 11.7 [8.9, 14.0] years, 43% female). A Food Frequency Questionnaire characterized daily macronutrient intake over the preceding 6 months. Plasma and fecal SCFA were measured by gas chromatography; gut microbiome composition and diversity by 16S rRNA gene sequencing. RESULTS: A 10 g increase in daily carbohydrate intake associated with higher plasma acetate in IA/T1D (adjusted estimate +5.2 (95% CI 1.1, 9.2) µmol/L p = 0.01) and controls (adjusted estimate +4.1 [95% CI 1.7, 8.5] µmol/L p = 0.04). A 5 g increase in total fat intake associated with lower plasma acetate in IA/T1D and controls. A 5% increase in noncore (junk) food intake associated with reduced richness (adjusted estimate -4.09 [95%CI -7.83, -0.35] p = .03) and evenness (-1.25 [95% CI -2.00, -0.49] p < 0.01) of the gut microbiome in IA/T1D. Fiber intake associated with community structure of the microbiome in IA/T1D. CONCLUSIONS: Modest increments in carbohydrate and fat intake associated with plasma acetate in all youth. Increased junk food intake associated with reduced diversity of the gut microbiome in IA/T1D alone. These associations with the gut microbiome in IA/T1D support future efforts to promote SCFA by using dietary interventions.


Assuntos
Autoimunidade/fisiologia , Diabetes Mellitus Tipo 1/metabolismo , Dieta , Ácidos Graxos Voláteis/metabolismo , Microbioma Gastrointestinal , Ilhotas Pancreáticas/imunologia , Adolescente , Estudos de Casos e Controles , Criança , Estudos Transversais , Diabetes Mellitus Tipo 1/complicações , Feminino , Humanos , Masculino , Inquéritos e Questionários
16.
BMC Infect Dis ; 21(1): 9, 2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33407180

RESUMO

BACKGROUND: To determine the prevalence of enteric infections in Aboriginal children aged 0-2 years using conventional and molecular diagnostic techniques and to explore associations between the presence of pathogens and child growth. METHODS: Cross-sectional analysis of Aboriginal children (n = 62) residing in a remote community in Northern Australia, conducted from July 24th - October 30th 2017. Stool samples were analysed for organisms by microscopy (directly in the field and following fixation and storage in sodium-acetate formalin), and by qualitative PCR for viruses, bacteria and parasites and serology for Strongyloides-specific IgG. Child growth (height and weight) was measured and z scores calculated according to WHO growth standards. RESULTS: Nearly 60% of children had evidence for at least one enteric pathogen in their stool (37/62). The highest burden of infection was with adenovirus/sapovirus (22.9%), followed by astrovirus (9.8%) and Cryptosporidium hominis/parvum (8.2%). Non-pathogenic organisms were detected in 22.5% of children. Ten percent of children had diarrhea at the time of stool collection. Infection with two or more pathogens was negatively associated with height for age z scores (- 1.34, 95% CI - 2.61 to - 0.07), as was carriage of the non-pathogen Blastocystis hominis (- 2.05, 95% CI - 3.55 to - 0.54). CONCLUSIONS: Infants and toddlers living in this remote Northern Australian Aboriginal community had a high burden of enteric pathogens and non-pathogens. The association between carriage of pathogens/non-pathogens with impaired child growth in the critical first 1000 days of life has implications for healthy child growth and development and warrants further investigation. These findings have relevance for many other First Nations Communities that face many of the same challenges with regard to poverty, infections, and malnutrition.


Assuntos
Infecções por Adenovirus Humanos/epidemiologia , Adenovírus Humanos/genética , Infecções por Astroviridae/epidemiologia , Infecções por Caliciviridae/epidemiologia , Criptosporidiose/epidemiologia , Cryptosporidium/genética , Gastroenterite/epidemiologia , Mamastrovirus/genética , Sapovirus/genética , Infecções por Adenovirus Humanos/virologia , Adenovírus Humanos/isolamento & purificação , Animais , Infecções por Astroviridae/virologia , Austrália/epidemiologia , Infecções por Caliciviridae/virologia , Pré-Escolar , Estudos Transversais , Criptosporidiose/parasitologia , Cryptosporidium/isolamento & purificação , Diarreia/epidemiologia , Diarreia/parasitologia , Diarreia/virologia , Fezes/parasitologia , Fezes/virologia , Feminino , Gastroenterite/parasitologia , Gastroenterite/virologia , Humanos , Lactente , Recém-Nascido , Masculino , Mamastrovirus/isolamento & purificação , Havaiano Nativo ou Outro Ilhéu do Pacífico , Reação em Cadeia da Polimerase/métodos , Prevalência , Sapovirus/isolamento & purificação
17.
PLoS Genet ; 14(6): e1007431, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29883495

RESUMO

It has been proposed that interactions between mammalian chromosomes, or transchromosomal interactions (also known as kissing chromosomes), regulate gene expression and cell fate determination. Here we aimed to identify novel transchromosomal interactions in immune cells by high-resolution genome-wide chromosome conformation capture. Although we readily identified stable interactions in cis, and also between centromeres and telomeres on different chromosomes, surprisingly we identified no gene regulatory transchromosomal interactions in either mouse or human cells, including previously described interactions. We suggest that advances in the chromosome conformation capture technique and the unbiased nature of this approach allow more reliable capture of interactions between chromosomes than previous methods. Overall our findings suggest that stable transchromosomal interactions that regulate gene expression are not present in mammalian immune cells and that lineage identity is governed by cis, not trans chromosomal interactions.


Assuntos
Cromossomos de Mamíferos/genética , Regulação da Expressão Gênica , Imunidade Celular/genética , Mamíferos/fisiologia , Animais , Cromatina/química , Cromatina/genética , Cromatina/metabolismo , Cromossomos de Mamíferos/química , Cromossomos de Mamíferos/metabolismo , DNA/química , DNA/genética , DNA/metabolismo , Citometria de Fluxo , Genoma , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Conformação de Ácido Nucleico , Estereoisomerismo
18.
Proc Natl Acad Sci U S A ; 115(30): 7783-7788, 2018 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-29997173

RESUMO

CD52, a glycophosphatidylinositol (GPI)-anchored glycoprotein, is released in a soluble form following T cell activation and binds to the Siglec (sialic acid-binding Ig-like lectin)-10 receptor on T cells to suppress their function. We show that binding of CD52-Fc to Siglec-10 and T cell suppression requires the damage-associated molecular pattern (DAMP) protein, high-mobility group box 1 (HMGB1). CD52-Fc bound specifically to the proinflammatory Box B domain of HMGB1, and this in turn promoted binding of the CD52 N-linked glycan, in α-2,3 sialic acid linkage with galactose, to Siglec-10. Suppression of T cell function was blocked by anti-HMGB1 antibody or the antiinflammatory Box A domain of HMGB1. CD52-Fc induced tyrosine phosphorylation of Siglec-10 and was recovered from T cells complexed with HMGB1 and Siglec-10 in association with SHP1 phosphatase and the T cell receptor (TCR). Thus, soluble CD52 exerts a concerted immunosuppressive effect by first sequestering HMGB1 to nullify its proinflammatory Box B, followed by binding to the inhibitory Siglec-10 receptor, triggering recruitment of SHP1 to the intracellular immunoreceptor tyrosine-based inhibitory motif of Siglec-10 and its interaction with the TCR. This mechanism may contribute to immune-inflammatory homeostasis in pathophysiologic states and underscores the potential of soluble CD52 as a therapeutic agent.


Assuntos
Antígeno CD52/imunologia , Proteína HMGB1/imunologia , Lectinas/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Motivos de Aminoácidos , Anticorpos/farmacologia , Feminino , Proteína HMGB1/antagonistas & inibidores , Humanos , Masculino , Domínios Proteicos , Proteína Tirosina Fosfatase não Receptora Tipo 6/imunologia
19.
Proc Natl Acad Sci U S A ; 115(42): 10732-10737, 2018 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-30275329

RESUMO

Type 1 diabetes (T1D) is an autoimmune disease in which insulin-producing beta cells, found within the islets of Langerhans in the pancreas, are destroyed by islet-infiltrating T cells. Identifying the antigenic targets of beta-cell reactive T cells is critical to gain insight into the pathogenesis of T1D and develop antigen-specific immunotherapies. Several lines of evidence indicate that insulin is an important target of T cells in T1D. Because many human islet-infiltrating CD4+ T cells recognize C-peptide-derived epitopes, we hypothesized that full-length C-peptide (PI33-63), the peptide excised from proinsulin as it is converted to insulin, is a target of CD4+ T cells in people with T1D. CD4+ T cell responses to full-length C-peptide were detected in the blood of: 14 of 23 (>60%) people with recent-onset T1D, 2 of 15 (>13%) people with long-standing T1D, and 1 of 13 (<8%) HLA-matched people without T1D. C-peptide-specific CD4+ T cell clones, isolated from six people with T1D, recognized epitopes from the entire 31 amino acids of C-peptide. Eighty-six percent (19 of 22) of the C-peptide-specific clones were restricted by HLA-DQ8, HLA-DQ2, HLA-DQ8trans, or HLA-DQ2trans, HLA alleles strongly associated with risk of T1D. We also found that full-length C-peptide was a much more potent agonist of some CD4+ T cell clones than an 18mer peptide encompassing the cognate epitope. Collectively, our findings indicate that proinsulin C-peptide is a key target of autoreactive CD4+ T cells in T1D. Hence, full-length C-peptide is a promising candidate for antigen-specific immunotherapy in T1D.


Assuntos
Autoantígenos/imunologia , Peptídeo C/imunologia , Peptídeo C/metabolismo , Linfócitos T CD4-Positivos/imunologia , Diabetes Mellitus Tipo 1/diagnóstico , Antígenos HLA/imunologia , Ilhotas Pancreáticas/imunologia , Proinsulina/imunologia , Adolescente , Adulto , Células Cultivadas , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/metabolismo , Humanos , Pessoa de Meia-Idade , Adulto Jovem
20.
Pediatr Diabetes ; 21(6): 945-949, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32430977

RESUMO

BACKGROUNDS: We aimed to monitor pancreatic exocrine function longitudinally in relation to the development of islet autoimmunity (IA) and type 1 diabetes (T1D) in at-risk children with a first-degree relative with T1D, who were followed prospectively in the Environmental Determinants of Islet Autoimmunity (ENDIA) study. METHODS: Fecal elastase-1 (FE-1) concentration was measured longitudinally in 85 ENDIA children from median age 1.0 (IQR 0.7,1.3) year. Twenty-eight of 85 children (progressors) developed persistent islet autoantibodies at median age of 1.5 (IQR 1.1,2.5) years, of whom 11 went on to develop clinical diabetes. The other 57 islet autoantibody-negative children (non-progressors) followed similarly were age and gender-matched with the progressors. An adjusted linear mixed model compared FE-1 concentrations in progressors and non-progressors. RESULTS: Baseline FE-1 did not differ between progressors and non-progressors, or by HLA DR type or proband status. FE-1 decreased over time in progressors in comparison to non-progressors (Wald statistic 5.46, P = .02); in some progressors the fall in FE-1 preceded the onset of IA. CONCLUSIONS: Pancreatic exocrine function decreases in the majority of young at-risk children who progress to IA and T1D.


Assuntos
Autoimunidade/fisiologia , Diabetes Mellitus Tipo 1 , Ilhotas Pancreáticas/imunologia , Pâncreas Exócrino/fisiologia , Autoanticorpos/sangue , Biomarcadores/análise , Estudos de Casos e Controles , Pré-Escolar , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 1/fisiopatologia , Progressão da Doença , Meio Ambiente , Fezes/química , Feminino , Humanos , Lactente , Estudos Longitudinais , Masculino , Pâncreas Exócrino/imunologia , Elastase Pancreática/análise , Fatores de Risco
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