Long-term effects of weaning habits: type-1 diabetes.
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Animals↗
Biomedical subjects
Outi Vaarala
Publications and source records attributed to Outi Vaarala.
IgA antibodies, TGF-beta1 and -beta2, and soluble CD14 in the colostrum and development of atopy by age 4.
Specific defense factors in breast milk together with length of breast-feeding and genetic predisposition may modulate the development of allergy. We studied whether IgA, soluble CD14 (sCD14), or transforming growth factor (TGF)-beta in colostrum could affect the development of atopy in children up to age 4. From a cohort of 4676, we selected four groups of children with either long or short exclusive breast-feeding (>3.5 or <0.5 mo); these groups further differed in the presence or absence of atopic heredity. In colostrum from mothers, we measured total IgA, IgA antibodies to cow's milk (CM) and casein, sCD14, and TGF-beta1 and -beta2. The children were divided into three groups: those with no atopic symptoms or IgE, those with allergic symptoms, and those with both outcomes. Mothers of infants later showing atopic symptoms or, in addition, having IgE sensitization (verified atopy) had a lower concentration of IgA casein antibodies in their colostrum than did mothers of infants with no indication of atopy at age 4. Low concentration of IgA casein antibodies was a significant risk for verified atopy. sCD14 levels were lower in colostrum of mothers with infants developing atopic symptoms and IgE sensitization than of those of infants with no atopy. Specific IgA antibodies to CM antigens and sCD14 in colostrum significantly associated with the appearance of both symptomatic and verified atopy by age 4.
Animals↗
Environmental triggers and determinants of type 1 diabetes.
Type 1 diabetes is perceived as a chronic immune-mediated disease with a subclinical prodromal period characterized by selective loss of insulin-producing beta-cells in the pancreatic islets in genetically susceptible subjects. A series of evidence supports a critical role of exogenous factors in the development of type 1 diabetes, such as 1) the fact that <10% of individuals with HLA-conferred diabetes susceptibility do progress to clinical disease, 2) a pairwise concordance of type 1 diabetes of <40% among monozygotic twins, 3) a more than 10-fold difference in the disease incidence among Caucasians living in Europe, 4) a several-fold increase in the incidence over the last 50 years, and 5) migration studies indicating that the disease incidence has increased in population groups who have moved from a low-incidence to a high-incidence region. This article discusses the trigger-booster hypothesis claiming that the diabetic disease process is triggered by an exogenous factor with definite seasonal variation and driven by one or several other environmental determinants. In addition, there are a series of modifying factors affecting the fate and pace of the process. Accordingly, progression to clinical type 1 diabetes typically requires the unfortunate combination of genetic disease susceptibility, a diabetogenic trigger, and a high exposure to a driving antigen.
Aging↗
Psychological stress may induce diabetes-related autoimmunity in infancy.
OBJECTIVE: In retrospective studies, a number of disparate environmental factors (including experiences of serious life events) have been proposed as trigger mechanisms for type 1 diabetes or the autoimmune process behind the disease. Psychosocial stress in families may affect children negatively due to a link to hormonal levels and nervous signals that in turn influence both insulin sensitivity/insulin need and the immune system. Our aim was to investigate whether psychological stress, measured as psychosocial strain in families, is associated with diabetes-related autoimmunity during infancy. RESEARCH DESIGN AND METHODS: The first 4,400 consecutive 1-year-old children from a large prospective population-based project participated in the study. Parents completed questionnaires at birth and at 1 year, including various measures of psychosocial stress (e.g., parenting stress) and sociodemographic background. Blood samples drawn from the children at 1 year were analyzed for type 1 diabetes-associated autoantibodies toward tyrosine phosphatase and GAD. Antibodies toward tetanus toxoid were used as non-diabetes-related control antibodies. RESULTS: Psychosocial factors, i.e., high parenting stress (odds ratio 1.8 [95% CI 1.2-2.9], P < 0.01), experiences of a serious life event (2.3 [1.3-4.0], P < 0.01), foreign origin of the mother (2.1 [1.3-3.3], P < 0.001), and low paternal education (1.6 [1.1-2.3], P < 0.01) were associated with diabetes-related autoimmunity in the child, independent of family history of diabetes. CONCLUSIONS: Psychological stress, measured as psychosocial strain in the family, seems to be involved in the induction, or progression, of diabetes-related autoimmunity in the child during the 1st year of life.
Adult↗
No difference in platelet activation or inflammation markers after diets rich or poor in vegetables, berries and apple in healthy subjects.
BACKGROUND: High intake of vegetables and fruits is associated with decreased risk of coronary heart disease. Part of these cardioprotective effects may be mediated via the antithrombotic effects of compounds found in vegetables and fruits, such as flavonoids. AIM OF THE STUDY: To study the effects of high and low intake of vegetables, berries and apple on platelet function and inflammatory markers. METHODS: The study was a randomised, controlled parallel human dietary intervention with healthy female and male volunteers (n = 77, 19-52 y). Nineteen healthy volunteers served as controls. The volunteers consumed one of four strictly controlled isocaloric 6-week diets containing either 810 or 196 g/10 MJ of vegetables, berries and apple and rich either in linoleic acid (11% of energy, en%) or oleic acid (12 en%). Blood and three 24-hour urine samples were collected at the beginning and at the end of the study period for analyses of various markers of platelet function and inflammation. RESULTS: No differences between the treatment groups were seen in platelet count or volume, markers of platelet activation ( ex vivo aggregation to ADP and thrombin receptor activating peptide, protein kinase C activity, urinary 2,3-dinor-thromboxane B2 excretion, plasma P-selectin), plasma intercellular adhesion molecule-1, sensitive C-reactive protein, or antiphospholipid antibodies. CONCLUSIONS: The results indicate that in healthy volunteers 6-week diets differing markedly in the amounts of vegetables, berries and apple do not differ in their effects on platelets or inflammation.
Adult↗
Lactobacillus GG effect in increasing IFN-gamma production in infants with cow's milk allergy.
BACKGROUND: Probiotic bacteria are potentially beneficial to maturation of the infant's immune system. OBJECTIVE: To examine the role of probiotic bacteria in treatment of cow's milk allergy (CMA) and IgE-associated dermatitis, we investigated the immunologic effects of Lactobacillus rhamnosus GG (LGG) and a mixture of 4 bacterial species (MIX). METHODS: In a randomized, double-blind study design, concomitantly with elimination diet and skin treatment, LGG, MIX, or placebo was given for 4 weeks to infants with suspected CMA. After anti-CD3 (OKT3) and anti-CD28 stimulation of PBMCs, IFN-gamma, IL-4, IL-5, and IL-12 levels were measured in culture supernatants by ELISA. Intracellular IFN-gamma, IL-4, and IL-5 production on CD4 lymphocytes was analyzed with fluorescence-activated cell sorting. RESULTS: Secretion of IFN-gamma by PBMCs before the treatment was significantly lower in infants with CMA (P=.016) and in infants with IgE-associated CMA (P=.003) than in non-CMA infants. Among the infants who received LGG, the level of secreted IFN-gamma increased in those with CMA (P=.006) and in those with IgE-associated dermatitis (P=.017) when compared with the placebo group. Secretion of IL-4 increased significantly in infants with CMA in the MIX (P=.034) but not in the LGG group. CONCLUSION: Deficiency in IFN-gamma response appears to be related to CMA. LGG raises IFN-gamma production of PBMC in infants with CMA and in infants with IgE-associated dermatitis and may thus provide beneficial TH1 immunomodulatory signals. MIX, although containing LGG, appears to modulate the immune responses differently.
Cytokines↗
A TLR4 polymorphism is associated with asthma and reduced lipopolysaccharide-induced interleukin-12(p70) responses in Swedish children.
BACKGROUND: Bacterial signals play an important role in the maturation of the immune system. Polymorphisms in genes coding for receptors to bacterial components can alter the immune responsiveness of the host to microbial agents and may indicate the development of aberrant immune responses that are associated with immune-mediated diseases such as atopic diseases. OBJECTIVE: The study's objective was to investigate the relationship between TLR4 and CD14 gene polymorphisms, the LPS responsiveness of PBMCs, and the presence of asthma and allergic rhinoconjunctivitis in children. METHODS: The TLR4 (Asp299Gly) and CD14/-159 polymorphisms were determined in 115 Swedish children aged 8 and 14 years. LPS-induced IL-12(p70), IL-10, and IFN-gamma responses of PBMCs from 69 of the children were analyzed by means of ELISA. The levels of soluble CD14 in serum samples were analyzed by means of ELISA, and the total IgE levels were analyzed by means of UniCAP Total IgE (Pharmacia Diagnostics, Uppsala, Sweden). RESULTS: Decreased LPS-induced IL-12(p70) and IL-10 responses were associated with the TLR4 (Asp299Gly) polymorphism and independently with asthma, especially atopic asthma. The TLR4 (Asp299Gly) polymorphism was associated with a 4-fold higher prevalence of asthma in school-aged children (adjusted odds ratio 4.5, 95% CI 1.1-17.4) but not to allergic rhinoconjunctivitis. CONCLUSION: A TLR4 polymorphism modifies innate immune responses in children and may be an important determinant for the development of asthma. This may influence the outcome of intervention studies that use microbial stimuli as immune modulators.
Adolescent↗
Environmental causes: dietary causes.
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Celiac Disease↗
Anti-insulin activity in IgG-fractions from children with newly-diagnosed type 1 diabetes and negative for insulin autoantibodies.
Insulin autoantibodies (IAA) are often detected as the first humoral sign of beta-cell autoimmunity in prospective studies in young children with increased genetic risk of type 1 diabetes. After the appearance of IAA their level typically rise but seems to decline in many cases before the clinical presentation of type 1 diabetes. We hypothesized that the reason for the sudden drops in the levels of IAA could be the formation of immune complexes caused by binding of antibodies to free insulin in plasma. We studied whether isolation of the IgG-fraction and dissociation of immune complexes by acid treatment using protein A column results in the appearance of detectable IAA in those children with newly-diagnosed type 1 diabetes whose plasma samples test negative for IAA. IAA assay was performed in IgG-fractions and corresponding plasma samples from 17 children with type 1 diabetes and 23 unaffected children all testing negative for plasma IAA. The levels of IAA measured from IgG-fractions of diabetic children were higher than the levels of IAA measured from IgG-fractions in the control children (p = 0.004 in Mann-Whitney U-test). Forty-seven percent (8 out of 17) of newly-diagnosed patients negative for plasma IAA before IgG separation had increased levels of IAA in IgG-fractions and only 13% (3 out of 23) of controls. The levels of glutamate decarboxylase autoantibodies (GADA) did not differ between patients (n = 14) and controls (n = 21) negative for plasma GADA when measured in IgG-fractions. Our results suggest that formation of immune complexes results in false negative results in tests for IAA but not for GADA.
Autoantibodies↗
Intestinal immunity and type 1 diabetes.
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Diabetes Mellitus, Type 1↗
Enterovirus infection may induce humoral immune response reacting with islet cell autoantigens in humans.
Molecular mimicry is one of the mechanisms by which enterovirus infections have been postulated to have a role in the pathogenesis of type 1 diabetes. Immunogenic epitopes in enterovirus capsid protein VP1 and procapsid protein VP0 have sequence similarities with diabetes-associated epitopes in tyrosine phosphatase IA-2/IAR and heat shock protein 60. In the present study, documented enterovirus infection was shown to induce humoral responses, that in 7% and 1% of patients cross-reacted with the known diabetes-associated epitopes in tyrosine phosphatase IAR and heat shock protein 60, respectively. In contrast, none of the children vaccinated against poliomyelitis had antibodies to the diabetes-associated epitope of tyrosine phosphatases IA-2/IAR. The antibody response studied in serum samples from six patients with coxsackievirus A9 infection was mainly targeted to capsid protein VP1. Coxsackievirus A9 infection induced antibodies cross-reacted with one epitope in heat shock protein 60, but not with epitopes derived from other autoantigens. Most diabetic children had high levels of antibodies to both coxsackievirus and poliovirus derived VP1 peptides but the pattern of reactivity did not differ from that seen in healthy children. The reactivity of linear epitopes derived from autoantigens was low in general and associated with the presence of multiple autoantibodies in the patients. Some linear auto-epitopes derived from tyrosine phosphatase IA-2, glutamic acid decarboxylase 65, preproinsulin, and heat shock protein 60 were recognized by sera from diabetic patients, but not by sera from healthy children. In conclusion, enteroviruses may induce immune responses that react with islet cell autoantigens, which is a concern when a putative inactivated enterovirus vaccine is considered.
Adolescent↗
Variation in enterovirus receptor genes.
The increased incidence of a enterovirus infections observed in patients with type 1 diabetes preceding the development of the clinical disease could be partially explained by variation in the genes coding for enterovirus receptors. We carried out sequence analysis of the most common enterovirus receptor molecules in 21 diabetic children and 20 healthy adults. DNA was isolated from the leukocytes, and gene regions known to code for virus-recognizing domains in major enterovirus receptors were amplified and sequenced. Heterozygous single-nucleotide polymorphism (SNP), Ala 67 (GCG) --> Thr (ACG), was detected in the poliovirus receptor gene in four individuals in the diabetes group, but not in the control group. However, serological studies could not confirm that this substitution would convey different susceptibility to poliovirus infection. A heterozygous SNP, Lys 29 (AAG) --> Met (ATG), was found in the intracellular adhesion molecule-1 (ICAM-1) (receptor for rhinoviruses and some coxsackie A viruses) in one individual in both groups. A silent SNP in the alpha2 integrin subunit gene (echovirus 1 receptor) was frequently found in both groups, a silent heterozygotic SNP in coxsackievirus-adenovirus receptor (coxsackie B virus receptor) gene was seen in one individual in the diabetes group, whereas no variation was found in the DAF (echovirus receptor) and beta3 integrin subunit sequences (receptor for coxsackievirus A9) studied. In conclusion, both synonymous and nonsynonymous sequence variability of genes coding for enterovirus and rhinovirus receptors was shown to occur, but no pattern directly specific for type 1 diabetes was found. =
Autoimmune Diseases↗
Enterovirus infection and activation of human umbilical vein endothelial cells.
Gastrointestinal tract associated lymphoid tissue is considered to be the main replication site for enteroviruses. In order to invade tissues to reach pancreatic islets, cardiac muscles, and other secondary replication sites, the virus has to survive circulation in the blood and find a way to get through endothelial cells. In the present study, the susceptibility of human endothelial cells to infections caused by human parechovirus 1 and several prototype strains of enteroviruses, representing different species (human poliovirus, human enterovirus B and C), and acting through different receptor families was examined. Primary endothelial cells isolated from human umbilical vein by collagenase perfusion and also an established human endothelial cell line, HUVEC, were used. Primary endothelial cells were highly susceptible to several serotypes of enteroviruses (coxsackievirus A13, echoviruses 6, 7, 11, 30, and poliovirus 1). However, coxsackievirus A 9 and echovirus 1 infected only a few individual cells while human parechovirus 1 and coxsackie B viruses did not show evidence of replication in primary endothelial cells. In general, primary endothelial cells were more sensitive to infection-induced cytolytic effect than HUVEC. Activation of endothelial cells by interleukin-1beta did not change the pattern of enterovirus infection. Immunofluorescence stainings of infected primary endothelial cells showed that expression of activation markers, E-selectin, and intercellular adhesion molecule-1, was clearly increased by several virus infections and the former molecule also by exposing cells to UV-light inactivated coxsackieviruses. In contrast, human leukocyte antigen-DR expression was not increased by virus infection.
Cell Line↗
Antibodies to human heat shock protein 60, hypertension and dyslipidemia. A study of joint effects on coronary risk.
OBJECTIVE: High IgA-class (but not IgG-class) Anti-Heat-shock-protein 60 antibody level is a predictor of coronary risk in dyslipidemic middle-aged men. In this paper we studied the joint effects of high Anti-Hsp60-antibody level and the classical coronary risk factors. METHODS: We used nested case-control design and logistic regression analyses. The cases consisted of 233 middle-aged men with myocardial infarction or coronary death during 8.5-year follow-up in Helsinki Heart Study, a coronary primary prevention study with gemfibrozil. The controls were subjects without coronary events, matched for drug treatment and the geographical area. RESULTS: The relative coronary risks (Odds Ratios (ORs); 95% confidence interval) were 1.41 (0.96-2.05) for high IgA-class Anti-Hsp60 antibody level and 1.98 (1.35-2.90) for hypertension, defined as mean arterial pressure >114 mmHg. With simultaneous occurrence of high Anti-Hsp60 antibody level and hypertension, the ORs were 2.32 (1.26-4.27) for systolic and 2.99 (1.63-5.48) for diastolic hypertension. Similar patterns of joint effects were found between high Anti-Hsp60 antibody and lipoprotein cholesterol levels as well as antibodies against oxidized low-density lipoprotein. CONCLUSIONS: Our results suggest that, while high IgA-class Anti-Hsp60 antibody level predicts coronary risk, the effect is modest without simultaneous occurrence of other classical risk factors.
Antibodies↗
Induction of diabetes-related autoantibodies below cutoff for "positivity" in young nondiabetic children.
The aim was to study the natural course of diabetes-related autoantibodies at low concentrations, below "positivity", in a nondiabetic population followed up from infancy. Blood samples were taken from 205 children at 6 weeks, 6 months, 18 months, and 5 years of age. Autoantibodies against GAD(65) (GADA), tyrosine phosphatase (IA-2A), and insulin (IAA) were determined by radioligand-binding assays. All children had detectable levels of GADA and approximately half had IA-2A, but only approximately 10% had detectable levels of IAA during the follow-up period. Many children developed IA-2A already at 6 months of age, similar concentrations were seen at 18 months, and then the levels of IA-2A decreased until 5 years of age. GADA were induced less often at 6 months of age, increased up to 18 months, and fluctuated at similar levels up to 5 years of age. IAA were detectable in so few children and at low levels, so no trend in natural course could be revealed. We conclude that there is a natural induction of humoral immune response to beta cell autoantigens early in life. Our results suggest that the mechanisms of beta cell tolerance to GAD and IA-2 differ in healthy children.
Autoantibodies↗
Immunologic activity in the small intestinal mucosa of pediatric patients with type 1 diabetes.
Involvement of gut immune system has been implicated in the pathogenesis of type 1 diabetes. However, few studies have been performed on the gut mucosa from patients with type 1 diabetes. Thus, we characterized the stage of immune activation in jejunal biopsy samples from 31 children with type 1 diabetes by immunohistochemistry, in situ hybridization, and RT-PCR. We found enhanced expressions of HLA-DR, HLA-DP, and intercellular adhesion molecule-1 by immunohistochemistry even on structurally normal intestine of patients with type 1 diabetes and no signs of celiac disease. In addition, the densities of IL-1 alpha- and IL-4-positive cells detected by immunohistochemistry and IL-4 mRNA-expressing cells evaluated by in situ hybridization were increased in the lamina propria in patients with type 1 diabetes and normal mucosa. Instead, the densities of IL-2, gamma-interferon (IFN-gamma), and tumor necrosis factor alpha-positive cells, the density of IFN-gamma mRNA positive cells, and the amounts of IFN-gamma mRNA detected by RT-PCR correlated with the degree of celiac disease in patients with type 1 diabetes. Our study supports the hypothesis that a link exists between the gut immune system and type 1 diabetes.
Adolescent↗
CCR3, CCR5, interleukin 4, and interferon-gamma expression on synovial and peripheral T cells and monocytes in patients with rheumatoid arthritis.
OBJECTIVE: To characterize cytokine and chemokine receptor profiles of T cells and monocytes in inflamed synovium and peripheral blood (PB) in patients with rheumatoid arthritis (RA) and other arthritides. METHODS: We studied PB and synovial fluid (SF) samples taken from 20 patients with RA and 9 patients with other arthritides. PB cells from 8 healthy adults were used as controls. CCR3, CCR5, and intracellular interferon-g (IFN-g) and interleukin 4 (IL-4) expression in CD8+ and CD8- T cell populations and in CD14+ cells were determined with flow cytometry. RESULTS: Expression of CCR5 and CCR3 by CD8-, CD8+ T cells and CD14+ monocytes was increased in SF compared to PB cells in patients with RA and other arthritides. The number of CD8+ T cells spontaneously expressing IL-4 and IFN-g was higher in SF than in PB in RA patients. Spontaneous CCR5 expression was associated with intracellular IFN-g expression in CD8+ T cells derived from SF in RA. In CD8- T cells the ratio of CCR5+/CCR3+ cells was increased in patients with RA compared to patients with other arthritides. The number of PB CD8- T cells expressing IFN-g after mitogen stimulation was higher in controls than in patients. In PB monocytes the ratio of CCR5+/CCR3+ cells was increased in patients with RA compared to patients with other arthritides and controls. CONCLUSION: T cells and monocytes infiltrating joints in RA and in other arthritides showed increased activation of both type 1 and type 2 immune markers. More pronounced type 1 immune response in joints, shown as an increased CCR5/CCR3 ratio, was found in the patients with RA versus those with other arthritides. Monocytes but not T cells in PB showed increased activation in RA.
Adult↗
Environmental factors in the etiology of type 1 diabetes.
Type 1 diabetes is considered to be an autoimmune disease in which T lymphocytes infiltrate the islets of pancreas and destroy the insulin producing beta cell population. Besides antigen specificity, the quality of immune reactivity against islet cell antigen(s) is an important determinant of the beta cell destruction. Much evidence indicates that the function of the gut immune system is central in the pathogenesis, as the regulation of the gut immune system may be aberrant in type 1 diabetes. The role of virus infections in the pathogenesis of type 1 diabetes has been supported by substantial new evidence suggesting that one virus group, enteroviruses, may trigger the beta-cell damaging process in a considerable proportion of patients. The latest evidence comes from studies indicating the presence of viral genome in diabetic patients and from prospective studies confirming epidemiological risk effect. If this association holds still true in ongoing large-scale studies, intervention trials should be considered to confirm causality. Of the dietary putative etiological factors, cow's milk proteins have received the main attention. Many studies indicate an association between early exposure to dietary cow's milk proteins and an increased risk of type 1 diabetes. The question will be answered by a large scale, prospective, randomized, international intervention trial. Another dietary factor in need of more studies is the deficiency of vitamin D. Among toxins, N-nitroso compounds are the main candidates. An interaction of genetic and environmental factors is important in evaluating the possible role of a certain environmental factor in the etiology of type 1 diabetes.
Animals↗