RESUMO
INTRODUCTION AND OBJECTIVES: Whether the guidelines on infant nutrition, food allergy and atopic dermatitis confer real health benefits in practice at the population level has not been deeply studied. We aimed here to characterize the knowledge, attitudes, and perceptions regarding these issues among primary health care professionals. In addition, we surveyed available parent-reported information sources and the incidence of food-related symptoms, dietary restrictions, food allergy, and atopic dermatitis among one-year-old children in the general population. MATERIALS AND METHODS: An online questionnaire was designed for public health nurses and general practitioners. In addition, parents of one-year-old children were recruited to a separate survey at the time of their regular check-up visit. RESULTS: Altogether, 80 professionals took part. The median overall knowledge score was 77% and significantly higher among the general practitioners than among the nurses (p=0.004). However, only 35% of all the professionals recognized either severe airway or cardiovascular symptoms as potential food allergy-related symptoms. Moisturizers and emollients were thought to be adequate treatment for atopic dermatitis by 56%. Among 248 one-year-old children, the incidence of food allergy was 4% and atopic dermatitis 13%. During this period, parents intentionally avoided giving at least one food to 23% of the children, yet more than 80% of these restrictions can be regarded as unnecessary. CONCLUSION: The knowledge, attitudes and beliefs regarding infant feeding, food allergy, and atopic dermatitis varied significantly among the primary care professionals. This will likely result in heterogeneous guidance practices and confusion among the families at the population level.
Assuntos
Dermatite Atópica , Hipersensibilidade Alimentar , Conhecimentos, Atitudes e Prática em Saúde , Pais , Médicos de Atenção Primária , Dieta , Feminino , Humanos , Lactente , Masculino , Enfermeiros de Saúde Pública , Educação de Pacientes como Assunto , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Children whose 11th fetal week falls in pollen season (spring) reportedly have an increased risk of sensitization to food allergens. No such finding has been reported for pet allergens. OBJECTIVE: The aim of the study was to (i) evaluate the incidence of pet (dog and cat) sensitization according to the season of the 11th fetal week and (ii) whether the association between pet exposure and respective sensitization is modified by the coincidence of the 11th fetal week with pollen season. METHODS: The study population comprised all children (born between 2001 and 2006) in the province of South Karelia, Finland (N = 5920). Their data of immunoglobulin E antibodies and skin prick tests to pet allergens (N = 538) were collected from patient records and linked with questionnaire data on pet exposure. RESULTS: The seasonal incidence peak of cat sensitization was observed in children whose 11th fetal week occurred in June (7.4%) and that of dog sensitization in April (3.8%) and June (4.7%). The relative rate (RR) for cat sensitization was 2.92 (95% CI 1.40-6.08) in children with cat exposure alone, 8.53 (4.07-17.86) in children with cat and fetal pollen exposures and 0.61 (0.20-1.83) in children exposed to pollen alone, compared with children without these exposures. The respective RRs for dog sensitization were 2.17 (1.13-4.19), 4.40 (2.19-8.83) and 1.65 (0.77-3.53). CONCLUSIONS AND CLINICAL RELEVANCE: Coincidence of the first fetal trimester with pollen season strengthens the association between pet exposure and respective sensitization. Pollen exposure at early pregnancy may deviate immune system towards Th2-type reactivity promoting development of specific allergy in case allergen exposure occurred. Therefore, primary prevention of allergic diseases may need to begin during early pregnancy.
Assuntos
Hipersensibilidade/epidemiologia , Pólen/imunologia , Primeiro Trimestre da Gravidez/imunologia , Estações do Ano , Alérgenos/imunologia , Animais , Gatos , Pré-Escolar , Cães , Feminino , Finlândia , Humanos , Incidência , Lactente , Masculino , Exposição Materna/efeitos adversos , Gravidez , Inquéritos e QuestionáriosRESUMO
Our aim was to study whether the aberrant amount or function of regulatory T cells is related to the development of type 1 diabetes (T1D) in children. We also set out to investigate the balance of different T cell subtype markers during the T1D autoimmune process. Treg cells were quantified with flow cytometric assay, and the suppression capacity was analysed with a carboxyfluorescein succinimidyl ester (CFSE)-based T cell suppression assay in children in various phases of T1D disease process and in healthy autoantibody-negative control children. The mRNA expression of different T cell subpopulation markers was analysed with real-time qPCR method. The proportion and suppression capacity of regulatory T cells were similar in seroconverted children at an early stage of beta cell autoimmunity and also in children with T1D when compared to healthy and autoantibody-negative children. Significant differences were observed in the mRNA expression of different T cell subpopulation markers in prediabetic children with multiple (≥ 2) autoantibodies and in children with newly diagnosed T1D when compared to the control children. In conclusion, there were no quantitative or functional differences in regulatory T cells between the case and control groups in any phase of the autoimmune process. Decreased mRNA expression levels of T cell subtype markers were observed in children with multiple islet autoantibodies and in those with newly diagnosed T1D, probably reflecting an exhaustion of the immune system after the strong immune activation during the autoimmune process or a generally aberrant immune response related to the progression of the disease.
Assuntos
Autoimunidade/imunologia , Diabetes Mellitus Tipo 1/etiologia , Diabetes Mellitus Tipo 1/imunologia , Estado Pré-Diabético/imunologia , Linfócitos T Reguladores/imunologia , Adolescente , Autoanticorpos/imunologia , Antígenos CD4/metabolismo , Criança , Pré-Escolar , Feminino , Citometria de Fluxo , Fatores de Transcrição Forkhead/metabolismo , Humanos , Tolerância Imunológica/imunologia , Lactente , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Masculino , RNA Mensageiro/biossínteseRESUMO
We observed 42 initially non-diabetic siblings of affected children to characterize the humoral immune response to the 65 kDa isoform of glutamic acid decarboxylase (GAD65) in preclinical type I diabetes. During the observation period with a mean duration of 9.6 years 21 siblings progressed to type I diabetes. The humoral immune response to GAD65 was observed initially as a simultaneous response to the middle (M) and carboxy (C)-terminal regions of the GAD65 molecule in most cases, and if the response was restricted initially to the middle region, it spread rapidly to the C-terminal domain and in a few cases later to the amino (N)-terminal domain. There was some heterogeneity in the GAD65 isotype response, but it was composed mainly of antibodies of immunoglobulin (Ig) G1 subclass. Responses of IgG2-, IgG4-, IgM- and IgA-GAD65Ab were observed frequently, whereas IgE- and IgG3-GAD65Ab responses were seen more rarely. Initially, the non-progressors tended more often to have IgG2- and IgG4-GAD65Ab than the progressors. As a sign of a dynamic process a significant isotype spreading was seen for IgG2-GAD65Ab (P < 0.05) and close to significant for IgM (P = 0.06) among progressors and for IgM-GAD65Ab (P < 0.05) among non-progressors during the observation period. This study failed to identify any GAD65 epitope- or isotype-specific antibody reactivity that could be used as a marker for progression to disease, as such progression was not associated with any specific changes in reactivity over time. Our findings indicate that epitope- and isotype-specific GAD65 antibodies are hardly capable of separating progressors from non-progressors among GAD65Ab-positive first-degree relatives of children with type I diabetes.
Assuntos
Autoanticorpos/sangue , Diabetes Mellitus Tipo 1/imunologia , Glutamato Descarboxilase/imunologia , Estado Pré-Diabético/imunologia , Adolescente , Biomarcadores/sangue , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/genética , Progressão da Doença , Epitopos/imunologia , Feminino , Seguimentos , Humanos , Imunoglobulina G/sangue , Isotipos de Imunoglobulinas/sangue , Masculino , Estado Pré-Diabético/genéticaRESUMO
We set out to study the association between human leukocyte antigen-defined genetic disease susceptibility and the stage of preclinical type 1 diabetes and whether genetic predisposition affects the natural course of preclinical diabetes in initially nondiabetic siblings of affected children. A total of 701 initially unaffected siblings were graded into four stages of preclinical type 1 diabetes based on the initial number of disease-associated autoantibodies detectable close to the time of diagnosis of the index case: no prediabetes (no antibodies), early (one antibody specificity), advanced (two antibodies), and late prediabetes (three or more antibodies). Another classification system covering 659 siblings was based on a combination of the initial number of antibodies and the first-phase insulin response (FPIR) to iv glucose: no prediabetes (no antibodies), early (one antibody specificity, normal FPIR), advanced (two or more antibodies, normal FPIR), and late prediabetes (at least one antibody, reduced FPIR). Genetic susceptibility to type 1 diabetes was defined by human leukocyte antigen identity and DR and DQ genotypes. There was a higher proportion of siblings with late prediabetes initially among those with strong genetic disease susceptibility than among those with decreased genetic predisposition (16.7% vs. 0.5%; P < 0.001 for DQB1 genotypes according to the first classification), whereas there was a higher proportion of siblings with no signs of prediabetes among those with genotypes conferring decreased risk (91.2% vs. 70.4% among those with high-risk DQB1 genotypes; P < 0.001 according to the first classification). Autoantibodies alone were more sensitive in the prediction of future diabetes in siblings than when combined with genetic susceptibility. Genetic susceptibility played a role in whether the initial prediabetic stage progressed (progression in 29.6% of the high-risk siblings compared with 6.6% of the siblings with DQB1 genotypes conferring decreased risk; P < 0.001 according to the first classification) and whether overt type 1 diabetes became manifest or not. Genetic susceptibility has an impact on both the initiation and progression of the autoimmune process leading to clinical diabetes in siblings of affected children.
Assuntos
Diabetes Mellitus Tipo 1/genética , Predisposição Genética para Doença , Irmãos , Adolescente , Autoanticorpos/análise , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/fisiopatologia , Progressão da Doença , Glucose/administração & dosagem , Humanos , Lactente , Injeções Intravenosas , Insulina/sangue , Medição de Risco , Fatores de TempoRESUMO
AIMS: This prospective case-control study aimed at evaluating the time course of serum concentrations of soluble adhesion molecules; intercellular adhesion molecule-1 and L-selectin in siblings with signs of pre-clinical Type 1 diabetes in order to relate these concentrations to autoantibody status and to assess whether these markers could discriminate between those siblings who progressed to clinical diabetes and those who remained non-diabetic. METHODS: Serum levels of soluble adhesion molecules were measured with enzyme-linked immunosorbent assays in autoantibody-positive initially healthy siblings of diabetic children who progressed to clinical disease during the observation period of 10 years and in sex- and age-matched autoantibody-positive siblings who have remained unaffected. RESULTS: The intraindividual and interindividual variability in the concentrations of soluble adhesion molecules was conspicuous both among the progressors and non-progressors. Integrated concentrations (area-under-the curve) of intercellular adhesion molecule-1 over a period of 6 to 48 months before the diagnosis was higher in the progressors ( p=0.035), the difference being most evident 18 to 24 months before diagnosis ( p=0.015). The integrated concentrations of soluble L-selectin were similar in progressors and non-progressors over the total pre-clinical period. There were no differences in the integrated concentrations of soluble adhesion molecules in relation to the initial or maximal number of autoantibodies detected during the follow-up. CONCLUSION/INTERPRETATION: These observations suggest that the process of destructive insulitis could be initiated approximately 4 years before the manifestation of clinical diabetes, being most active about 1.5 years before diagnosis. Peripheral concentrations of soluble intercellular adhesion molecule-1 or L-selectin are not helpful in the identification of those prediabetic subjects who will progress to clinical disease over the next 10 years, since there is substantial overlapping in these concentrations between progressors and non-progressors.
Assuntos
Diabetes Mellitus Tipo 1/sangue , Molécula 1 de Adesão Intercelular/sangue , Selectina L/sangue , Adolescente , Autoanticorpos/sangue , Criança , Diabetes Mellitus Tipo 1/imunologia , Humanos , Estudos ProspectivosRESUMO
AIMS/HYPOTHESIS: To assess the role of HLA-defined genetic diabetes susceptibility in the appearance of signs of beta-cell autoimmunity in a series of children derived from the general population. METHODS: Tests for five HLA DQB1 alleles and four diabetes-associated autoantibodies were carried out on 1,584 older sibs of infants with an increased HLA-defined genetic risk of Type 1 diabetes. The DQB1 genotypes were classified into those conferring high (* 02/0302), moderate (* 0302/x; where x indicates * 0302 or a non-defined allele), low (* 0301/0302, * 02/0301, * 02/x, * 0302/0602, * 0302/0603; where x indicates * 02 or a non-defined allele) or decreased risk (other genotypes). RESULTS: Both islet cell antibodies (ICA) and GAD65 antibodies (GADA) were more frequent among the sibs with the high-risk genotype than among those with a low or decreased risk. Insulin autoantibodies and IA-2 antibodies (IA-2A) were more prevalent in the high-risk than low-risk sibs. Sibs with moderate-risk genotypes tested positive for ICA, GADA and IA-2A more often than sibs with genotypes conferring decreased risk. Autoantibody titres were also dependent on the genetic risk with high risk sibs having the highest values. Sibs carrying high-risk or moderate-risk genotypes tested positive for multiple antibodies (> or =2) more often than did the sibs with low or decreased genetic risk. CONCLUSIONS/INTERPRETATION: The data show that HLA-defined susceptibility to Type 1 diabetes has an effect on both the quality and quantity of humoral beta-cell autoimmunity in unaffected children derived from the general population.
Assuntos
Autoimunidade , Diabetes Mellitus Tipo 1/genética , Predisposição Genética para Doença , Antígenos HLA/genética , Ilhotas Pancreáticas/imunologia , Anticorpos/análise , Autoanticorpos/análise , Estudos de Coortes , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/prevenção & controle , Feminino , Finlândia , Genótipo , Glutamato Descarboxilase/imunologia , Humanos , Insulina/imunologia , Isoenzimas/imunologia , Masculino , PrognósticoRESUMO
AIM: To define the dynamics of preclinical type 1 diabetes in siblings of affected children and to characterize the siblings experiencing a progressive process. METHODS: From 801 families taking part in the "Childhood Diabetes in Finland" (DiMe) Study, 715 initially unaffected siblings were graded into four stages of preclinical type 1 diabetes based on the initial number of disease-associated autoantibodies detectable close to the time of diagnosis of the index case, while another classification system covering 641 of the siblings was based on a combination of the initial number of antibodies and the first-phase insulin response (FPIR) to intravenous glucose. RESULTS: Based on the first classification, there was a total of 95 siblings with initial signs of prediabetes, out of whom 34 (36%) progressed, 26 (27%) remained stable and 35 (37%) regressed during prospective observation for a median of 3.6 y (range 0.01-9.8 y). The siblings who progressed were younger, had a higher initial number of detectable autoantibodies, higher initial levels of various antibodies, with the exception of insulin autoantibodies, lower FPIR and a retarded glucose elimination rate in the first intravenous glucose tolerance test as compared with those that regressed. According to the second classification there were 41 siblings with initial signs of prediabetes, among whom 23 (56%) progressed, 14 (34%) remained stable and 4 (10%) regressed during the observation period. CONCLUSION: These data show that almost half of the siblings with signs of prediabetes at the time of diagnosis of the index case progressed further in their preclinical disease process during prospective observation. Young age, a strong humoral immune response to beta-cell antigens and reduced insulin secretory capacity appeared to be characteristic of those with a progressive process. Advanced and late prediabetes seem to represent a point of no return, as regression from these stages to no prediabetes was extremely rare.
Assuntos
Diabetes Mellitus Tipo 1/genética , Estado Pré-Diabético/fisiopatologia , Adolescente , Fatores Etários , Autoanticorpos/sangue , Criança , Pré-Escolar , Progressão da Doença , Feminino , Teste de Tolerância a Glucose , Humanos , Masculino , Estudos ProspectivosRESUMO
The aim of this study was to evaluate the frequency and predictive value of diabetes-associated autoantibodies, such as islet cell antibodies (ICA) and autoantibodies to insulin (IAA), GAD65 (GADA), and the IA-2 molecule (IA-2A) in genetically susceptible children from the general population during the first 2 yr of life. Of 12,170 newborn infants, 1,005 with increased genetic risk of type 1 diabetes (high risk, human leukocyte antigen DQB1*02/*0302; moderate risk, DQB1*0302/x, where x = other than *02, *0301, or *0602) were monitored for ICA, IAA, GADA, and IA-2A at 3- to 6-month intervals from birth up to a minimum age of 2 yr. In addition, all 15 genetically susceptible children from the general population who had participated in regular immunological follow-up and developed clinical type 1 diabetes by the end of April 2000 were analyzed for the development of autoantibodies. Among 1,005 children, 63 (6.3%) tested positive for at least one autoantibody, 31 for ICA (3.1%), 48 for IAA (4.8%), 23 for GADA (2.3%), and 13 for IA-2A (1.3%) at least once by the age of 2 yr. Both ICA and IAA identified 95% [95% confidence interval (CI), 77.2-99.9%] of those who tested persistently positive for multiple (> or = 2) antibodies at the age of 2 yr, GADA identified 86% (CI, 65.1-97.1%), and IA-2A identified 55% (CI, 32.2-75.6%). Close to half of the antibody-positive children (29 of 63) reverted back to antibody negativity. Autoantibodies disappeared more often among those who tested positive for IAA than among those who tested positive for other autoantibodies (P < or = 0.021). Among the 15 children who developed type 1 diabetes, the disease sensitivity of ICA was 80% (CI, 51.9-95.7%), that of IAA was 93% (CI, 68.0-99.8%), that of GADA was 60% (CI, 32.3-83.7%), and that of IA-2A was 40% (CI, 16.3-67.7%). These results suggest that IAA are characterized by high sensitivity, early appearance, and high frequency of transient antibody positivity, whereas ICA detected with a thoroughly standardized assay appear to be more specific for the screening of beta-cell autoimmunity in young children with increased genetic susceptibility to type 1 diabetes in the Finnish population, which has the highest incidence of type 1 diabetes in the world.
Assuntos
Autoimunidade/genética , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Predisposição Genética para Doença , Ilhotas Pancreáticas/imunologia , Envelhecimento , Autoanticorpos/sangue , Glutamato Descarboxilase/imunologia , Humanos , Lactente , Anticorpos Anti-Insulina/sangue , Isoenzimas/imunologiaRESUMO
We studied the pattern of type 1 diabetes-associated autoantibodies during pregnancy and the transplacental transfer of these autoantibodies to the fetal circulation and searched for possible signs of prenatal induction of beta-cell autoimmunity in newborn infants. The population comprised 208 mothers and their newborn infants. Seventy-four of the mothers (36%) had type 1 diabetes and 134 (64%) of the infants had an affected father or sibling. Blood samples were obtained from the mother at the end of the first trimester and at delivery, and from the cord blood of the newborn infant. Close to 40% of the mothers with type 1 diabetes had antibodies to islet cells (ICA), 55% to glutamic acid decarboxylase (GADA) and 54% to the IA-2 protein (IA-2A) in early pregnancy, whereas the corresponding frequencies in the nonaffected mothers were 5.2%, 5.2% and 3.0%. No significant changes could be seen in autoantibody levels during pregnancy, and there was a close correlation between the two maternal samples. One third of the infants of mothers with type 1 diabetes tested positive for ICA, 50% for GADA and 51% for IA-2A. Six percent of the infants of nondiabetic mothers had ICA, 2.2% GADA and none had IA-2A. None of the infants of the antibody negative mothers had antibodies in their cord blood. These observations indicate that the immunomodulatory effect of pregnancy on signs of beta-cell autoimmunity is weak, but if diabetes-associated autoantibodies are present in the mother, most of them are transferred to the fetal circulation. Our data do not provide any support for fetal induction of beta-cell autoimmunity.
Assuntos
Autoanticorpos/sangue , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/imunologia , Gravidez em Diabéticas/imunologia , Adolescente , Adulto , Estudos de Casos e Controles , Diabetes Mellitus Tipo 1/genética , Feminino , Sangue Fetal/imunologia , Glutamato Descarboxilase/imunologia , Humanos , Recém-Nascido , Ilhotas Pancreáticas/imunologia , Masculino , Troca Materno-Fetal/imunologia , Pessoa de Meia-Idade , Placenta/imunologia , Gravidez , Células Th1/imunologia , Células Th2/imunologiaRESUMO
To study the dynamics of disease-associated humoral immune responses, we analyzed autoantibodies to the IA-2 protein (IA-2A), glutamic acid decarboxylase (GADA), and insulin (IAA) and also islet cell antibodies (ICA) in a population-based, prospective, representative series of 710 siblings (<20 years of age) of children with type 1 diabetes. Positivity for single autoantibodies was observed in 8-13% of these siblings during an average follow-up of 4 years. The overall incidence rates per 1,000 years (number of cases/person-years in parentheses) for positive seroconversion of IA-2A were nine (19/2,123), followed by six (12/2,049) for GADA, 19 (40/2,111) for IAA, and 16 (31/1965) for ICA. Positive seroconversions seemed to be associated with a young age of the sibling, HLA DR3/DR4 heterozygosity, HLA identity, and a high initial number of detectable autoantibodies. The overall incidence rates per 1,000 years (number of cases/person-years in parentheses) for inverse seroconversion of IA-2A were 76 (12/157), followed by 42 (10/237) for GADA, 460 (32/70) for IAA, and 27 (9/331) for ICA. No consistent risk factor for inverse seroconversions was present, although seroconversions were most frequent in siblings with older age, male sex, HLA phenotypes other than DR3/DR4, a small family size, and no other autoantibodies detectable at seroconversion. Altogether, these observations indicate that beta-cell autoimmunity may be induced at any age in childhood and adolescence. HLA-conferred genetic disease susceptibility is a strong determinant of persistent beta-cell autoimmunity, but environmental factors may also contribute to such autoimmunity.
Assuntos
Autoanticorpos/análise , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Glutamato Descarboxilase/imunologia , Humanos , Lactente , Recém-Nascido , Insulina/imunologia , Ilhotas Pancreáticas/imunologia , Masculino , Estudos ProspectivosRESUMO
Little is known about the timing of the etiological events and the preclinical process of type 1 diabetes during the first years of life in the general population. In this population-based prospective birth cohort study, the appearance of diabetes-associated autoantibodies as a sign of beta-cell autoimmunity and the development of type 1 diabetes were monitored from birth. Of 25,983 newborn infants, 2,448 genetically susceptible children were monitored for islet cell antibodies (ICA) at 3- to 6-month intervals. If an infant seroconverted to ICA positivity, all his/her samples were also analyzed for insulin autoantibodies (IAA), antibodies to the 65-kDa isoform of glutamic acid decarboxylase, and antibodies to the protein tyrosine phosphatase-related IA-2 molecule. Fifteen children of those who carried the high-risk genotype (2.7%) and 23 of those who carried the moderate-risk genotype (1.2%; P = 0.019) tested positive for ICA at least once. Among those who showed positivity for at least 2 antibodies during the observation period (25 of 38), IAA appeared as the first or among the first antibodies in 22 children (88%) and emerged earlier than the other antibodies (P < 0.019 or less). The first autoantibodies appeared in the majority of the children in the fall and winter (30 of 38 vs. 8 of 38 in the spring and summer, P < 0.001). These observations suggest that young children in the general population with a strong human-leukocyte-antigen-DQ-defined genetic risk of type 1 diabetes show signs of beta-cell autoimmunity proportionally more often than those with a moderate genetic risk. IAA emerge as the first detectable antibody more commonly than any other antibody specificity, implying that insulin may be the primary antigen in most cases of human type 1 diabetes associated with the DR4-DQB1*0302 haplotype. The seasonal variation in the emergence of the first signs of beta-cell autoimmunity suggests that infectious agents may play a role in the induction of such autoimmunity.
Assuntos
Autoimunidade , Diabetes Mellitus Tipo 1/genética , Predisposição Genética para Doença , Ilhotas Pancreáticas/imunologia , Autoanticorpos/sangue , Pré-Escolar , Estudos de Coortes , Feminino , Finlândia , Antígenos HLA-DQ/genética , Cadeias beta de HLA-DQ , Humanos , Lactente , Masculino , Estudos ProspectivosRESUMO
We measured the concentrations of the soluble forms of the intercellular adhesion molecule-1 (sICAM-1) and L-selectin in 95 autoantibody-positive siblings of children with type 1 diabetes and 95 sex- and age-matched siblings testing negative for diabetes-associated autoantibodies to assess the possible role of soluble adhesion molecules as markers of progressive ss-cell destruction in preclinical diabetes and their ability to discriminate between those siblings who progress to clinical disease and those who remain nondiabetic. We observed an inverse correlation between age and the levels of both sICAM-1 (r = -0.31, p < 0.001) and sL-selectin (r = -0.27, p < 0.001) in the control siblings but no association with HLA-DR phenotypes. There was no difference in the circulating levels of soluble adhesion molecules between the antibody-positive and negative siblings. Among the antibody-positive siblings, those with at least three autoantibodies had higher sICAM-1 levels (p < 0.01) than those testing positive for only one, and siblings with three autoantibodies or more had higher concentrations of sL-selectin (p < 0.01) than those with two autoantibodies. Siblings with an islet cell antibody level of 20 Juvenile Diabetes Foundation units or more had higher sICAM-1 concentrations than those with a level below 20 (p < 0.001), and those testing positive for antibodies to the protein tyrosine phosphatase-related IA-2 antigen had increased levels of both sICAM-1 (p = 0.03) and sL-selectin (p = 0.02) compared with siblings who tested negative. The antibody-positive siblings who progressed to clinical type 1 diabetes were significantly younger than the nonprogressors (p < 0.001) and had higher levels of sICAM-1 initially (p < 0.001). The difference in sICAM-1 concentrations remained significant (p = 0.03) after age adjustment. Our results indicate that concentrations of soluble adhesion molecules are increased in the autoantibody-positive siblings who have the highest risk of developing clinical diabetes, suggesting that ss-cell destruction is reflected in increased circulating levels of these molecules. This is supported by the observation of elevated sICAM-1 concentrations in the 29 siblings who actually progressed to clinical type 1 diabetes. Peripheral levels of soluble adhesion molecules are not able to discriminate between progressors and nonprogressors, however, due to substantial overlapping between these two groups.
Assuntos
Moléculas de Adesão Celular/sangue , Diabetes Mellitus Tipo 1/sangue , Adolescente , Autoanticorpos/sangue , Estudos de Casos e Controles , Moléculas de Adesão Celular/imunologia , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/imunologia , Humanos , LactenteRESUMO
OBJECTIVE: To assess whether there are any differences in genetic, autoimmune, or clinical features between type 1 diabetes presenting in childhood and that diagnosed later. RESEARCH DESIGN AND METHODS: We studied 352 individuals (252 children and adolescents <20 years of age and 100 adults > or =20 years of age) manifesting clinical signs of type 1 diabetes over a period of 7.5 years at a university hospital in northern Finland with a primary catchment area population of approximately 300,000. The patients were analyzed for susceptible and protective HLA-DQB1 alleles (*02, *0302, *0301, *0602, *0603, and *0604), islet cell antibodies (ICA), insulin autoantibodies, and antibodies to GAD and IA-2 (IA-2A). Their clinical symptoms and signs were recorded at diagnosis. RESULTS: The adult patients carried the high-risk DQB1*02/0302 genotype less frequently than the children and more often had protective genotypes. They also had a decreased frequency of all 4 single autoantibody specificities and of multiple (> or =3) autoantibodies. The proportion of patients testing negative for all autoantibodies was lower among the children than among the adults. IA-2A were associated with the DQB1*0302/x genotype in both the children and adults, and the same held true for ICA among the adults. The adults were characterized by a higher proportion of males, a longer duration of symptoms, and a lower frequency of infections during the preceding 3 months. In addition, they had a higher relative body weight on admission and milder signs of metabolic decompensation (higher pH, base excess, and bicarbonate concentrations) and a lower glycated hemoglobin level at diagnosis than the children. CONCLUSIONS: Clinical manifestation of type 1 diabetes before the age of 20 years is associated with a strong HLA-defined genetic disease susceptibility, an intensive humoral immune response to various beta-cell antigens, a higher frequency of preceding infections, and a shorter duration of symptoms and more severe metabolic decompensation at diagnosis. Taken together, these observations suggest that the age at clinical onset of type 1 diabetes is determined by the intensity of the beta-cell-destructive process, which is modulated by both genetic and environmental factors.
Assuntos
Autoanticorpos/sangue , Diabetes Mellitus Tipo 1/genética , Adolescente , Adulto , Idade de Início , Alelos , Glicemia/análise , Peso Corporal , Peptídeo C/sangue , Criança , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/fisiopatologia , Feminino , Finlândia , Glutamato Descarboxilase/imunologia , Hemoglobinas Glicadas/análise , Antígenos HLA-DQ/genética , Cadeias beta de HLA-DQ , Antígenos de Histocompatibilidade Classe II/imunologia , Hospitais Universitários , Humanos , Ilhotas Pancreáticas/imunologia , MasculinoRESUMO
BACKGROUND: Autoantibodies to glutamic acid decarboxylase (GAD-A) are present in type 1 diabetes and stiff man syndrome (SMS), and have also been reported in cerebellar ataxia. Epilepsy was present in 4 of 19 patients with SMS and GAD-A, implying that epilepsy sometimes is associated with anti-GAD autoimmunity. METHODS: The authors investigated the prevalence of GAD-A in patients with therapy-resistant localization-related epilepsy (n = 51) and generalized epilepsy (n = 49) by a radiobinding assay. The positive samples were confirmed by immunohistochemistry and immunoblotting of recombinant human GAD65. RESULTS: GAD-A were found in eight patients with localization-related epilepsy, whereas none of the patients with generalized epilepsy, other neurologic disorders (n = 38), or the control subjects (n = 48) had GAD-A. Two patients had high levels of GAD-A, similar to SMS, whereas six patients had significantly lower titers, characteristic of type 1 diabetes. The two patients with high levels of GAD-A had GAD-A both in serum and CSF by immunohistochemistry and immunoblotting. Both of them had longstanding therapy-resistant temporal lobe epilepsy but did not have diabetes. One had a history of autoimmune disease, whereas the other had serologic evidence of multiple autoantibodies without any clinical signs of autoimmune disease. CONCLUSIONS: GAD autoimmunity may be associated with refractory localization-related epilepsy.
Assuntos
Autoanticorpos/imunologia , Resistência a Medicamentos/imunologia , Epilepsia/imunologia , Epilepsia/patologia , Glutamato Descarboxilase/imunologia , Adolescente , Adulto , Autoanticorpos/sangue , Cerebelo/efeitos dos fármacos , Cerebelo/imunologia , Cerebelo/patologia , Epilepsia/sangue , Epilepsia/tratamento farmacológico , Feminino , Glutamato Descarboxilase/sangue , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Ensaio RadioliganteRESUMO
AIMS/HYPOTHESIS: To study temporal changes in positivity for autoantibodies associated with Type I (insulin-dependent) diabetes mellitus and the relations between these antibodies, HLA-DQB1-risk markers and first-phase insulin response (FPIR) in non-diabetic schoolchildren. METHODS: The stability of the antibody status over 2 years was assessed in 104 schoolchildren initially positive for islet cell antibodies (ICA) or antibodies to the 65,000 M(r) isoform of the glutamic acid decarboxylase (GADA) or both and in 104 antibody-negative control children matched for sex, age and place of residence. All children were also studied for their first-phase insulin response and HLA-DQB1 alleles on the second occasion. RESULTS: On the second occasion 3 of the 98 initially ICA-positive children, 3/13 of those positive for antibodies to the IA-2 protein (IA-2A), 1/17 GADA-positive and 2/7 of those positive for insulin autoantibodies (IAA) tested negative for these antibodies. Children with IA-2A, GADA, IAA and multiple (> or = 2) antibodies had significantly lower first-phase insulin responses than the control children. In contrast, these responses did not differ between subjects with and without specific HLA-DQB1-risk alleles or genotypes. Of the six subjects with a considerably reduced first-phase insulin response three had multiple antibodies on both occasions but none of them had a DQB1 genotype conferring increased diabetes risk. Two subjects progressed to Type I diabetes within 3.4 years of follow-up, both of them having multiple antibodies and a considerably reduced first-phase insulin response but neither of them having a DQB1-risk genotype. CONCLUSIONS/INTERPRETATION: Positivity for diabetes-associated autoantibodies is a relatively stable phenomenon in unaffected schoolchildren, although conversion to seronegativity can occur occasionally. Our observations also indicate that DQB1 alleles associated with decreased susceptibility to Type I diabetes do not protect from impaired beta-cell function or from progression to overt disease in initially unaffected schoolchildren.
Assuntos
Autoanticorpos/sangue , Biomarcadores/sangue , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Antígenos HLA-DQ/genética , Adolescente , Autoantígenos , Criança , Feminino , Predisposição Genética para Doença , Genótipo , Teste de Tolerância a Glucose , Glutamato Descarboxilase/imunologia , Cadeias beta de HLA-DQ , Humanos , Insulina/sangue , Insulina/imunologia , Masculino , Proteínas de Membrana/imunologia , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Proteínas Tirosina Fosfatases/imunologia , Proteínas Tirosina Fosfatases Classe 8 Semelhantes a ReceptoresRESUMO
Recent prospective studies have documented serologically an increased frequency of enterovirus infections in prediabetic children, indicating that these infections may initiate and accelerate the beta-cell damaging process several years before the clinical manifestation of type 1 diabetes. The aim of the present study was to establish whether these serological findings would be supported by the detection of enterovirus RNA in a unique prospective series of sera collected from prediabetic children 0-10 years before the manifestation of clinical type 1 diabetes. Reverse transcription followed by polymerase chain reaction employing highly conserved primers among enteroviruses were used to amplify enteroviral sequences. Viral RNA was found in 22% (11/49) of follow-up samples from prediabetic children but in only 2% (2/105) of those from controls (OR 14.9, P < 0.001). Persisting RNA positivity was not observed in any of these children. The presence of enterovirus RNA was associated with concomitant increases in the levels of autoantibodies against islet cells (OR 21.7, P < 0.01) and glutamic acid decarboxylase (OR 15.4, P < 0.05), but not in the levels of antibodies against insulin or the tyrosine phosphatase-like IA-2 protein. In contrast to the prediabetic children, those with newly diagnosed type 1 diabetes were negative for enterovirus RNA. The results thus complement previous serological data, suggesting that enterovirus infections are an important risk factor underlying type 1 diabetes and associated with the induction of beta-cell autoimmunity even years before symptoms appear.
Assuntos
Autoanticorpos/sangue , Doenças Autoimunes/virologia , Diabetes Mellitus Tipo 1/virologia , Enterovirus/isolamento & purificação , Adolescente , Alelos , Doenças Autoimunes/imunologia , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Enterovirus/genética , Feminino , Glutamato Descarboxilase/imunologia , Antígenos HLA-DQ/análise , Antígenos HLA-DQ/genética , Cadeias beta de HLA-DQ , Humanos , Ilhotas Pancreáticas/imunologia , Masculino , Núcleo Familiar , Estudos Prospectivos , RNA Viral/sangue , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de RiscoRESUMO
To evaluate the emergence of diabetes-associated autoantibodies in young children and to assess whether such antibodies can be used as surrogate markers of type 1 diabetes in young subjects at increased genetic risk, we studied 180 initially unaffected siblings (92 boys and 88 girls) of children with newly diagnosed type 1 diabetes. All siblings were younger than 6 yr of age at the initial sampling, and they were monitored for the emergence of islet cell antibodies (ICA), insulin autoantibodies (IAA), glutamate decarboxylase antibodies (GADA), and IA-2 antibodies (IA-2A) up to the age of 6 yr and for progression to clinical type 1 diabetes up to the age of 10 yr. All 160 siblings with DNA samples available were typed for susceptible (DQB1*02 and *0302) and protective (DQB1*0301 and *0602-03) HLA DQB1 alleles. Twenty-two siblings (12.2%) tested positive for ICA in their first antibody-positive sample before the age of 6 yr, 13 (7.2%) tested positive for IAA, 15 (8.3%) tested positive for GADA, and 14 (7.8%) tested positive for IA-2A. There were 16 siblings (8.9%) who had 1 detectable autoantibody, 5 (2.8%) had 2, and 12 (6.7%) had 3 or more. In the group of 82 siblings with increased human leukocyte antigen-defined genetic susceptibility [DQB1*02/*0302, *0302/x (x = other than *02 or a protective allele), *02/y (y = other than *0302 or a protective allele)], 18 (22.0%) tested positive for ICA in their first antibody-positive sample, 10 (12.2%) tested positive for IAA, 14 (17.1%) tested positive for GADA, and 12 (14.6%) tested positive for IA-2A. One antibody was detectable in 6 siblings (7.3%), 2 were detectable in 5 (6.1%), and 3 or more were detectable in 12 (14.6%). Fifteen siblings (18.3%) presented with clinical type 1 diabetes before the age of 10 yr. All of the progressors showed increased human leukocyte antigen-defined genetic susceptibility. Thirteen of those 15 siblings, who presented with clinical type 1 diabetes before the age of 10 yr, had at least 2 antibodies detectable before the age of 6 yr (disease sensitivity, 87%; 95% confidence interval, 60-98%). Thirteen of the 17 siblings who tested positive for 2 or more autoantibodies before the age of 6 yr developed type 1 diabetes before the age of 10 yr (positive predictive value, 76%; 95% confidence interval, 50-93%). These observations suggest that disease-associated autoantibodies can well be used as surrogate markers of clinical type 1 diabetes in primary prevention trials targeting young subjects with increased genetic disease susceptibility.
Assuntos
Autoanticorpos/análise , Diabetes Mellitus Tipo 1/genética , Adolescente , Adulto , Biomarcadores , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/imunologia , Feminino , Genótipo , Glutamato Descarboxilase/imunologia , Glutamato Descarboxilase/metabolismo , Antígenos HLA-DQ/análise , Humanos , Insulina/imunologia , Masculino , Reação em Cadeia da Polimerase , Reprodutibilidade dos Testes , Fatores de RiscoRESUMO
The relationships between genetic markers and disease-associated autoantibodies were studied in an unselected population of 701 siblings of children with type 1 diabetes, and the predictive characteristics of these markers over a period of 9 years were determined. Increased prevalences of all the antibodies were closely associated with HLA identity to the index case, the DR4 and DQB1*0302 alleles, and the DR3/4 phenotype and the DQB1*02/0302 genotype. Antibodies to GAD (GADA) were also associated with the DR3 and DQB1*02 alleles. Siblings carrying the protective DR2 and DQB1*0602-3 alleles were characterized by lower frequencies of islet cell antibodies (ICA), antibodies to IA-2 (IA-2A), and GADA. Higher levels of ICA were related to HLA identity, the DR4 and DQB1*0302 alleles, and the susceptible DQB1 genotypes, while no significant differences were observed in the levels of IA-2A, GADA, or insulin autoantibodies among siblings with different HLA risk markers. The DR2 or DQB1*0602-3 alleles were not related to the levels of any antibody specificity. A combination of the genetic markers and autoantibodies increased the positive predictive values of all autoantibodies substantially, which may have clinical implications when evaluating the risk of developing type 1 diabetes at the individual level or when recruiting high-risk individuals for intervention trials. However, because such combinations also resulted in reduced sensitivity, autoantibodies alone rather than in combination with genetic markers are recommended as the first-line screening in siblings. Finally, not all siblings with a broad humoral autoimmune response or high-risk genetic markers present with type 1 diabetes, while some with a low genetic risk and weak initial signs of humoral autoimmunity may progress to disease.