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1.
J Immunol ; 196(8): 3253-63, 2016 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-26944932

RESUMEN

Identifying T cell epitopes of islet autoantigens is important for understanding type 1 diabetes (T1D) immunopathogenesis and to design immune monitoring and intervention strategies in relationship to disease progression. Naturally processed T cell epitopes have been discovered by elution from HLA-DR4 of pulsed B lymphocytes. The designated professional APC directing immune responses is the dendritic cell (DC). To identify naturally processed epitopes, monocyte-derived DC were pulsed with preproinsulin (PPI), glutamic acid decarboxylase (65-kDa isoform; GAD65), and insulinoma-associated Ag-2 (IA-2), and peptides were eluted of HLA-DR3 and -DR4, which are associated with highest risk for T1D development. Proteome analysis confirmed uptake and processing of islet Ags by DC. PPI peptides generated by DC differed from those processed by B lymphocytes; PPI signal-sequence peptides were eluted from HLA-DR4 and -DR3/4 that proved completely identical to a primary target epitope of diabetogenic HLA-A2-restricted CD8 T cells. HLA-DR4 binding was confirmed. GAD65 peptides, eluted from HLA-DR3 and -DR4, encompassed two core regions overlapping the two most immunodominant and frequently studied CD4 T cell targets. GAD65 peptides bound to HLA-DR3. Strikingly, the IA-2 ligandome of HLA-DR was exclusively generated from the extracellular part of IA-2, whereas most previous immune studies have focused on intracellular IA-2 epitopes. The newly identified IA-2 peptides bound to HLA-DR3 and -DR4. Differential T cell responses were detected against the newly identified IA-2 epitopes in blood from T1D patients. The core regions to which DC may draw attention from autoreactive T cells are largely distinct and more restricted than are those of B cells. GAD65 peptides presented by DC focus on highly immunogenic T cell targets, whereas HLA-DR-binding peptides derived from IA-2 are distinct from the target regions of IA-2 autoantibodies.


Asunto(s)
Autoinmunidad/inmunología , Células Dendríticas/inmunología , Diabetes Mellitus Tipo 1/inmunología , Antígeno HLA-DR3/inmunología , Antígeno HLA-DR4/inmunología , Islotes Pancreáticos/inmunología , Autoantígenos/inmunología , Linfocitos B/inmunología , Linfocitos T CD8-positivos/inmunología , Células Cultivadas , Epítopos de Linfocito T/inmunología , Glutamato Descarboxilasa/metabolismo , Humanos , Insulina/metabolismo , Activación de Linfocitos/inmunología , Unión Proteica/inmunología , Precursores de Proteínas/metabolismo , Proteínas Tirosina Fosfatasas Clase 8 Similares a Receptores/metabolismo
2.
Pediatr Diabetes ; 14(6): 422-8, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22957743

RESUMEN

OBJECTIVE: To investigate whether center differences in glycemic control are present in prepubertal children <11 yr with type 1 diabetes mellitus. RESEARCH DESIGN AND METHODS: This cross-sectional study involved 18 pediatric centers worldwide. All children, <11 y with a diabetes duration ≥12 months were invited to participate. Case Record Forms included information on clinical characteristics, insulin regimens, diabetic ketoacidosis (DKA), severe hypoglycemia, language difficulties, and comorbidities. Hemoglobin A1c (HbA1c) was measured centrally by liquid chromatography (DCCT aligned, range: 4.4-6.3%; IFFC: 25-45 mmol/mol). RESULTS: A total of 1133 children participated (mean age: 8.0 ± 2.1 y; females: 47.5%, mean diabetes duration: 3.8 ± 2.1 y). HbA1c (overall mean: 8.0 ± 1.0%; range: 7.3-8.9%) and severe hypoglycemia frequency (mean 21.7 events per 100 patient-years), but not DKA, differed significantly between centers (p < 0.001 resp. p = 0.179). Language difficulties showed a negative relationship with HbA1c (8.3 ± 1.2% vs. 8.0 ± 1.0%; p = 0.036). Frequency of blood glucose monitoring demonstrated a significant but weak association with HbA1c (r = -0.17; p < 0.0001). Although significant different HbA1c levels were obtained with diverse insulin regimens (range: 7.3-8.5%; p < 0.001), center differences remained after adjusting for insulin regimen (p < 0.001). Differences between insulin regimens were no longer significant after adjusting for center effect (p = 0.199). CONCLUSIONS: Center differences in metabolic outcomes are present in children <11 yr, irrespective of diabetes duration, age, or gender. The incidence of severe hypoglycemia is lower than in adolescents despite achieving better glycemic control. Insulin regimens show a significant relationship with HbA1c but do not explain center differences. Each center's effectiveness in using specific treatment strategies remains the key factor for outcome.


Asunto(s)
Diabetes Mellitus Tipo 1/tratamiento farmacológico , Cetoacidosis Diabética/prevención & control , Hiperglucemia/prevención & control , Hipoglucemia/prevención & control , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Niño , Estudios de Cohortes , Estudios Transversales , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/fisiopatología , Cetoacidosis Diabética/inducido químicamente , Cetoacidosis Diabética/epidemiología , Cetoacidosis Diabética/fisiopatología , Femenino , Hemoglobina Glucada/análisis , Humanos , Hiperglucemia/epidemiología , Hipoglucemia/epidemiología , Hipoglucemiantes/efectos adversos , Incidencia , Insulina/efectos adversos , Masculino , Índice de Severidad de la Enfermedad , Factores de Tiempo
3.
Eur J Pediatr ; 171(3): 493-8, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21968905

RESUMEN

In the present article, we aimed to compare the cardiometabolic risk between overweight children with and without type 1 diabetes (T1DM). Therefore, data with regard to cardiometabolic risk parameters of 44 overweight Caucasian children (3-18 years) with T1DM were matched with 44 overweight peers without T1DM for sex, ethnicity, age and standard deviation score of BMI (Z-BMI). Detailed history was taken, information regarding anthropometrics and family history were collected and blood pressure was measured. Blood samples were collected for evaluation of lipid profiles (fasting in controls, non-fasting in T1DM children), alanine aminotransferase and HbA1c (in children with T1DM). It was found that overweight children with T1DM had lower median standard deviation score of waist circumference (Z-WC) as compared to the overweight control group [median, 2.0 (interquartile range, IQR, 1.5-2.3) vs. 2.6 (IQR, 2.0-2.9), P < 0.001]. After adjustment for Z-WC, in children with T1DM, median high-density lipoprotein cholesterol levels were significantly higher and median low-density lipoprotein cholesterol lower in T1DM children, as compared to their peers without T1DM [1.40 (IQR, 1.2-1.5) vs. 1.2 (IQR, 1.0-1.3) and 2.7 (IQR, 2.5-3.2) vs. 3.0 (IQR, 2.5-3.4), respectively, all P < 0.01]. When dividing children according to glycaemic status, children with suboptimal glycaemic control had higher values of triglycerides as compared to well-controlled children [1.3 (IQR, 1.0-1.8) vs. 0.96 (IQR, 0.80-1.2), P = 0.036]. In conclusion, overweight children with T1DM have a more favourable lipid profile, as compared to non-diabetic overweight controls, in spite of a higher frequency of a positive family history of CVD, T2DM and hypertension. Still, paediatricians should give extra attention to cardiometabolic risk factors within this vulnerable group, taking into account the already high cardiometabolic risk.


Asunto(s)
HDL-Colesterol/sangre , LDL-Colesterol/sangre , Diabetes Mellitus Tipo 1/sangre , Sobrepeso/sangre , Triglicéridos/sangre , Adolescente , Alanina Transaminasa/sangre , Biomarcadores/sangre , Enfermedades Cardiovasculares/etiología , Estudios de Casos y Controles , Niño , Preescolar , Estudios Transversales , Diabetes Mellitus Tipo 1/complicaciones , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Masculino , Sobrepeso/complicaciones , Factores de Riesgo , Circunferencia de la Cintura
4.
J Pediatr ; 156(6): 923-929, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20223481

RESUMEN

OBJECTIVES: To determine the prevalence of traditional cardiometabolic risk factors and to assess the effect of overweight/obesity on the occurrence of these risk factors in a cohort of children with type 1 diabetes mellitus (T1DM). STUDY DESIGN: Two hundred eighty-three consecutive patients (3 to 18 years of age) attending an outpatient clinic for T1DM care were included. The prevalence of cardiometabolic risk factors, the metabolic syndrome, and high alanine aminotransferase, were assessed before and after stratification for weight status. RESULTS: Of all children (median age, 12.8 years; interquartile range, 9.9 to 16.0; median diabetes duration, 5.3 years; interquartile range, 2.9 to 8.6), 38.5% were overweight/obese (Z-body mass index > or =1.1). Overall, median HbA1c levels were 8.2% (interquartile range, 7.4 to 9.8), and HbA1c > or =7.5% was present in 73.9%. Microalbuminuria was found in 17.7%, high triglycerides (>1.7 mmol/L) in 17.3%, high LDL-cholesterol (>2.6 mmol/L) in 28.6%, low HDL-cholesterol (<1.1 mmol/L) in 21.2%, and hypertension in 13.1% of patients. In the overweight/obese children with T1DM, versus normal-weight children, a higher prevalence of hypertension (23.9% vs 5.7%), the metabolic syndrome (25.7% vs 6.3%), and alanine aminotransferase >30 IU/L (15.6% vs 4.5%) was found (all P < .05). CONCLUSIONS: Overweight/obesity and cardiometabolic risk factors were highly prevalent in a pediatric cohort with T1DM. Hypertension, the metabolic syndrome, and high alanine aminotransferase were significantly more prevalent in overweight/obese compared with normal-weight children with T1DM.


Asunto(s)
Enfermedades Cardiovasculares/epidemiología , Diabetes Mellitus Tipo 1/epidemiología , Síndrome Metabólico/epidemiología , Sobrepeso/epidemiología , Alanina Transaminasa/sangre , LDL-Colesterol/análisis , Comorbilidad , Estudios Transversales , Femenino , Humanos , Modelos Logísticos , Masculino , Países Bajos/epidemiología , Obesidad/epidemiología , Prevalencia , Factores de Riesgo
5.
Diabetes ; 65(3): 732-41, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26718497

RESUMEN

HLA-DQ2/8 heterozygous individuals are at far greater risk for type 1 diabetes (T1D) development by expressing HLA-DQ8trans on antigen-presenting cells compared with HLA-DQ2 or -DQ8 homozygous individuals. Dendritic cells (DC) initiate and shape adaptive immune responses by presenting HLA-epitope complexes to naïve T cells. To dissect the role of HLA-DQ8trans in presenting natural islet epitopes, we analyzed the islet peptidome of HLA-DQ2, -DQ8, and -DQ2/8 by pulsing DC with preproinsulin (PPI), IA-2, and GAD65. Quality and quantity of islet epitopes presented by HLA-DQ2/8 differed from -DQ2 or -DQ8. We identified two PPI epitopes solely processed and presented by HLA-DQ2/8 DC: an HLA-DQ8trans-binding signal-sequence epitope previously identified as CD8 T-cell epitope and a second epitope that we previously identified as CD4 T-cell epitope with increased binding to HLA-DQ8trans upon posttranslational modification. IA-2 epitopes retrieved from HLA-DQ2/8 and -DQ8 DC bound to HLA-DQ8cis/trans. No GAD65 epitopes were eluted from HLA-DQ. T-cell responses were detected against the novel islet epitopes in blood from patients with T1D but scantly detected in healthy donor subjects. We report the first PPI and IA-2 natural epitopes presented by highest-risk HLA-DQ8trans. The selective processing and presentation of HLA-DQ8trans-binding islet epitopes provides insight in the mechanism of excessive genetic risk imposed by HLA-DQ2/8 heterozygosity and may assist immune monitoring of disease progression and therapeutic intervention as well as provide therapeutic targets for immunotherapy in subjects at risk for T1D.


Asunto(s)
Autoantígenos/inmunología , Células Dendríticas/inmunología , Diabetes Mellitus Tipo 1/inmunología , Epítopos/inmunología , Antígenos HLA-DQ/inmunología , Linfocitos T/inmunología , Adolescente , Adulto , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Estudios de Casos y Controles , Niño , Diabetes Mellitus Tipo 1/genética , Femenino , Glutamato Descarboxilasa/inmunología , Antígenos HLA-DQ/genética , Heterocigoto , Homocigoto , Humanos , Insulina/inmunología , Masculino , Péptidos , Precursores de Proteínas/inmunología , Procesamiento Proteico-Postraduccional , Proteínas Tirosina Fosfatasas Clase 8 Similares a Receptores/inmunología , Adulto Joven
6.
Eur J Intern Med ; 24(5): 456-60, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23414771

RESUMEN

BACKGROUND: Patients with type 1 diabetes mellitus (T1DM) are more prone to develop other auto-immune diseases, including coeliac disease (CD). Paediatric patients with T1DM are screened for CD, whereas in adult T1DM patients screening programs for CD are not standardised. The aim of this study was to investigate clinical and genetic characteristics of patients with both diagnoses so as to lead to better detection of CD in adult patients with T1DM. METHODS: We studied 118 patients with both T1DM and CD identified in The Netherlands. We retrospectively collected data on sex distribution, age of onset of T1DM, age of CD diagnosis, CD complaints, duration of CD complaints before CD diagnosis, family history of CD or T1DM, comorbidity and HLA-DQ type. RESULTS: Thirty-three percent of T1DM+CD patients reported CD related complaints for at least 5 years before CD diagnosis. Two peaks in the age of CD diagnosis in T1DM patients were observed: around 10 and 45 years of age. Women were diagnosed with CD at a younger age than men (median 25 years (IQR 9-38) versus 39 (12-55) years, respectively, P<0.05). CONCLUSION: A delay of CD diagnosis is frequently found in adult T1DM patients and two peaks in the age of CD diagnosis are present in T1DM patients. This observational study emphasises that more frequent screening for CD in particularly adult T1DM patients is required, preferably by a 5 years interval.


Asunto(s)
Enfermedad Celíaca , Diagnóstico Tardío , Diabetes Mellitus Tipo 1/epidemiología , Diabetes Mellitus Tipo 1/genética , Antígenos HLA-DQ/genética , Adolescente , Adulto , Enfermedad Celíaca/diagnóstico , Enfermedad Celíaca/epidemiología , Enfermedad Celíaca/genética , Niño , Comorbilidad , Femenino , Predisposición Genética a la Enfermedad/epidemiología , Predisposición Genética a la Enfermedad/genética , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto Joven
7.
Diabetes Care ; 30(9): 2245-50, 2007 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-17540955

RESUMEN

OBJECTIVE: To reevaluate the persistence and stability of previously observed differences between pediatric diabetes centers and to investigate the influence of demography, language communication problems, and changes in insulin regimens on metabolic outcome, hypoglycemia, and ketoacidosis. RESEARCH DESIGN AND METHODS: This was an observational cross-sectional international study in 21 centers, with clinical data obtained from all participants and A1C levels assayed in one central laboratory. All individuals with diabetes aged 11-18 years (49.4% female), with duration of diabetes of at least 1 year, were invited to participate. Fourteen of the centers participated in previous Hvidoere Studies, allowing direct comparison of glycemic control across centers between 1998 and 2005. RESULTS: Mean A1C was 8.2 +/- 1.4%, with substantial variation between centers (mean A1C range 7.4-9.2%; P < 0.001). There were no significant differences between centers in rates of severe hypoglycemia or diabetic ketoacidosis. Language difficulties had a significant negative impact on metabolic outcome (A1C 8.5 +/- 2.0% vs. 8.2 +/- 1.4% for those with language difficulties vs. those without, respectively; P < 0.05). After adjustement for significant confounders of age, sex, duration of diabetes, insulin regimen, insulin dose, BMI, and language difficulties, the center differences persisted, and the effect size for center was not reduced. Relative center ranking since 1998 has remained stable, with no significant change in A1C. CONCLUSIONS: Despite many changes in diabetes management, major differences in metabolic outcome between 21 international pediatric diabetes centers persist. Different application between centers in the implementation of insulin treatment appears to be of more importance and needs further exploration.


Asunto(s)
Diabetes Mellitus/tratamiento farmacológico , Adolescente , Niño , Barreras de Comunicación , Estudios Transversales , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiología , Cetoacidosis Diabética/epidemiología , Cetoacidosis Diabética/etiología , Femenino , Hemoglobina Glucada/análisis , Humanos , Hipoglucemia/etiología , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Masculino , Reproducibilidad de los Resultados
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