| 1. |
- Knip, Mikael, et al.
(författare)
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Hydrolyzed infant formula and early β-cell autoimmunity : a randomized clinical trial.
- 2014
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Ingår i: Journal of the American Medical Association (JAMA). - : American Medical Association (AMA). - 0098-7484 .- 1538-3598. ; 311:22, s. 2279-2287
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE: The disease process leading to clinical type 1 diabetes often starts during the first years of life. Early exposure to complex dietary proteins may increase the risk of β-cell autoimmunity in children at genetic risk for type 1 diabetes. Extensively hydrolyzed formulas do not contain intact proteins.OBJECTIVE: To test the hypothesis that weaning to an extensively hydrolyzed formula decreases the cumulative incidence of diabetes-associated autoantibodies in young children.DESIGN, SETTING, AND PARTICIPANTS: A double-blind randomized clinical trial of 2159 infants with HLA-conferred disease susceptibility and a first-degree relative with type 1 diabetes recruited from May 2002 to January 2007 in 78 study centers in 15 countries; 1078 were randomized to be weaned to the extensively hydrolyzed casein formula and 1081 were randomized to be weaned to a conventional cows' milk-based formula. The participants were observed to April 16, 2013.INTERVENTIONS: The participants received either a casein hydrolysate or a conventional cows' milk formula supplemented with 20% of the casein hydrolysate.MAIN OUTCOMES: AND MEASURES: Primary outcome was positivity for at least 2 diabetes-associated autoantibodies out of 4 analyzed. Autoantibodies to insulin, glutamic acid decarboxylase, and the insulinoma-associated-2 (IA-2) molecule were analyzed using radiobinding assays and islet cell antibodies with immunofluorescence during a median observation period of 7.0 years (mean, 6.3 years).RESULTS: The absolute risk of positivity for 2 or more islet autoantibodies was 13.4% among those randomized to the casein hydrolysate formula (n = 139) vs 11.4% among those randomized to the conventional formula (n = 117). The unadjusted hazard ratio for positivity for 2 or more autoantibodies among those randomized to be weaned to the casein hydrolysate was 1.21 (95% CI, 0.94-1.54), compared with those randomized to the conventional formula, while the hazard ratio adjusted for HLA risk, duration of breastfeeding, vitamin D use, study formula duration and consumption, and region was 1.23 (95% CI, 0.96-1.58). There were no clinically significant differences in the rate of reported adverse events between the 2 groups.CONCLUSIONS AND RELEVANCE: Among infants at risk for type 1 diabetes, the use of a hydrolyzed formula, when compared with a conventional formula, did not reduce the incidence of diabetes-associated autoantibodies after 7 years. These findings do not support a benefit from hydrolyzed formula. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00179777.
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| 2. |
- Lahdenperä, Anne, et al.
(författare)
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Expression pattern of T-helper 17 cell signaling pathway and mucosal inflammation in celiac disease
- 2014
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Ingår i: Scandinavian Journal of Gastroenterology. - : Informa Healthcare. - 0036-5521 .- 1502-7708. ; 49:2, s. 145-156
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Tidskriftsartikel (refereegranskat)abstract
- Objective. The aim was to investigate the mucosal activation of a broad range of genes associated with the T-helper 17 cell (Th17) signaling pathway in children at different stages of celiac disease (CD), including children with increased risk for CD and children with untreated and gluten-free diet (GFD)-treated CD. Material and methods. Small intestinal biopsies were taken from children with untreated and GFD-treated CD, transglutaminase antibody (TGA)-positive children with potential CD, and reference children. Real-time polymerase chain reaction (PCR) arrays were used to study the gene expression pattern of Th17-related genes, and quantitative PCR was used to study the interleukin (IL)-17A expression. Results. The mucosal expression of CD8A was elevated at all stages of CD. Children with untreated CD had diminished levels of IL-17RE, IL-23R, RORc, STAT6, CCL22, NFATC2, IL-18, CD4, CD247, and matrix metalloproteinase (MMP)9 but had elevated levels of MMP3, IL-17, interferon-gamma (IFN-gamma) and CD8A, compared to references. The majority of the aforementioned genes, being differentially expressed in untreated CD, displayed similar expression in GFD-treated children and references. Children with untreated and GFD-treated CD had elevated expression of IFN-gamma but had reduced expression of CD247. Interestingly, children with potential CD displayed reduced FOXP3, IL-21, and IL-17A levels. Conclusion. Mucosal upregulation of Th17 immunity occurs at the late stage of disease and is downregulated with dietary treatment, thus indicating that IL-17 immunity is not a fundamental feature of CD as Th1 immunity, which is not fully downregulated by GFD.
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| 3. |
- Lahdenperä, Anne, et al.
(författare)
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Probiotics and innate immune response in infants
- 2014
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- We studied the effects of probiotic treatment on the innate immune system during infancy. The study included a subgroup of infants recruited to the pilot study testing the feasibility of probiotics intervention in infants with genetic risk of type 1 diabetes (T1D). A mixture of Lactobacillus rhamnosus GG (5 x 109 cfu), Lactobacillus rhamnosus LC705 (5 x 109 cfu), Bifidobacterium breve Bbi99 (2 x 108 cfu) and Propionibacterium freudenreichii ssp. Shermani JS (2 x 109 cfu) was given to the infants beginning one to three weeks after birth until the age of 6 months. Blood samples were drawn at the age of 6, 12 and 24 months for the analyses of beta-cell autoantibodies and the phenotype and stimulation response of monocytes with flow-cytometry, including surface markers on circulating CD14+ monocytes and expression of co-stimulatory markers on CD14+ monocytes as response to stimulation with lipoteichoic acid (LTA) and lipopolysaccharide (LPS). Also gene expression of toll-like receptor (TLR) signalling molecules was studied in the peripheral blood mononuclear cell (PBMC) population.In the children who received probiotics the number of circulating CD14+ monocytes expressing CD58 was reduced at the age of 6 months, and a tendency for a decreased induction of CCR5, CD80 and CD58 expressing monocytes as response to LTA was seen when compared to the children who received placebo. At the age of 12 months, the number of monocytes expressing CCR5 was decreased in the probiotic group, and a decreased spontaneous expression of TNFRSF1A and an increased spontaneous expression of TLR9 was observed in the PBMC from the children treated with probiotics. In the whole study group, the numbers of circulating monocytes expressing CD80 increased with age as well as the induction of CCR5, CD80 and CD58 on monocytes as response to stimulation. By the age of 24 months one child in both groups developed multiple autoantibodies.We demonstrated that probiotics modulated the activation stage and stimulation response of monocytes, and that prolonged effects of the treatment were seen at the age of 12 months. The findings suggest that early microbial exposure may program the function of the innate immune system for later life.
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| 4. |
- Lahdenperä, Anne, 1974-
(författare)
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Studies of Mucosal Immune Regulation in Celiac Disease and Type 1 Diabetes
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Celiac disease (CD) and type 1 diabetes (T1D) are two chronic autoimmune diseases with increasing incidence worldwide. A combination of genetic, environmental and immunological factors is considered to be involved in development of the diseases, even though the exact disease mechanisms still are unknown. CD and T1D are both believed to be associated with type 1 like immune responses. However, there is limited knowledge about the complex network of intestinal and peripheral immune responses associated with the diseases.Aims: The aim of this thesis was to explore intestinal and peripheral immune responses in children at different stages of CD and in children with T1D. Further, we studied peripheral immune responses in children at risk for T1D supplemented with probiotics during their first 6 months of life (PRODIA study).Results & Discussion: Children with untreated CD had up-regulated T-helper (Th)1, T-cytotoxic (Tc)1, Th17 and T-regulatory (Treg) responses, but down-regulated Th2 and Th3 responses in the small intestine. The type 1 response (Th1 and Tc1) seemed to remain elevated in CD children under gluten free diet (GFD)-treatment and thus seemed to be related to the disease itself rather than the gluten intake. The Th2, Th3, Th17 and Treg responses seemed to be gluten dependent, since they normalized upon GFD-treatment. The alterations in the intestinal biopsies did not seem to correlate with the alterations seen in the blood Children with potential CD had diminished levels of the Th17 cytokine IL-17, whereas children with untreated CD had elevated levels of IL-17, indicating that IL-17 immunity develops in the late phase of CD when villous atrophy has developed. Furthermore, stimulation of intestinal epithelial cells with IL-17 induced anti-apoptotic mechanisms. The low intestinal expression of Th1, Th17 and Treg markers was normal in children with T1D, whereas children with T1D and CD had the same pattern as children with untreated CD: high intestinal secretion of pro-inflammatory and Th17 cytokines. The immune responses in children with T1D were generally influenced by the degree of villous atrophy.As expected, the number of children in the PRODIA study developing T1D related autoantibodies during their first two years of life was low. No difference in the autoantibody emergence was seen between infants given probiotics compared to placebo. In the probiotic group, the number of circulating CD58+ monocytes was lower at 6 months of age. At 12 months of age the number of circulating CCR5+ monocytes was lower in the probiotic group, whereas the spontaneous expression of TLR9 on PBMCs was higher.Conclusion: Most of the intestinal T-cell associated immune alterations were generally gluten dependent, since they normalized on a GFD treatment, but the type 1 response seemed to be related to the disease itself, since it was still seen in GFD treated individuals. IL-17 immunity seemed to be induced in the late stage of CD, when villous atrophy has developed and it seemed to be involved in protection from tissue damage in the inflamed intestinal mucosa. The intestinal immune responses were generally not reflected in peripheral blood.Probiotic supplementation in infancy modulated the activation stage and stimulation response of monocytes. Thus, early exposure to microbes seemed to influence the function of the innate immune system in later life.
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| 5. |
- Lahdenperä, Anne, et al.
(författare)
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The effect of gluten-free diet on Th1--Th2--Th3-associated intestinal immune responses in celiac disease
- 2011
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Ingår i: SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY. - : Informa Healthcare. - 0036-5521 .- 1502-7708. ; 46:5, s. 538-549
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Tidskriftsartikel (refereegranskat)abstract
- Objective. To study T-helper (Th)1--Th2--Th3 gene activation profile in the small intestine and peripheral blood of children with celiac disease (CD) with special interest in the response to the gluten-free diet (GFD) treatment in order to elucidate an immune dysregulation not triggered by gluten. Material and methods. Small intestinal biopsies and venous blood were taken from seven children with CD (mean age: 8 years, four girls) at presentation and after 1 year of strict GFD. The Th1--Th2--Th3 gene expression profile was examined by real-time PCR arrays. The findings were compared with the corresponding expressions in peripheral blood and small intestinal biopsies from six reference children without CD (mean age: 6 years, four girls). Results. The Th1 gene expression profile including interferon (IFN)-gamma gamma, signal transducer and activator of transcription (STAT) 1 and interferon regulatory factor (IRF) 1 together with reduced interleukin (IL)-2 expression was pronounced in small intestinal biopsies from children with untreated CD. A downregulation of IFN-gamma gamma transcripts was seen after 1 year of GFD, but there was still increased expression of STAT1 and IRF1 in association with low IL-2 expression in spite of eliminated exposure to wheat gluten. By contrast, the decreased intestinal expression of Th2 gene markers observed at presentation was normalized with GFD. The alterations in the mucosal gene expression profile were not reflected in peripheral blood. Conclusion. The GFD did not correct the increased activation of the IFN-gamma gamma signaling pathway related markers and reduced IL-2 expression, suggesting that they represent an immune dysregulation not dependent on gluten exposure.
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| 6. |
- Simonen-Tikka, Marja-Leena, et al.
(författare)
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Early human enterovirus infections in healthy Swedish children participating in the PRODIA pilot study
- 2012
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Ingår i: Journal of Medical Virology. - : Wiley-Blackwell. - 0146-6615 .- 1096-9071. ; 84:6, s. 923-930
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Tidskriftsartikel (refereegranskat)abstract
- Human enteroviruses (HEV) are common, especially in childhood and during the enterovirus season, causing mainly asymptomatic infections but also mild and severe illnesses. Numerous studies have shown the association between HEV infections and type 1 diabetes. Here, the prevalence of HEV infections was studied in healthy Swedish children with increased HLA-associated risk for type 1 diabetes participating in the PRODIA pilot study in which children were randomized to receive probiotics or placebo during the first 6 months of life. Stool specimens collected from 197 children in every 3 months from the age of 3 to 24 months were screened for HEV using traditional viral culturing method and identified with reverse transcriptase polymerase chain reaction (RT-PCR) and sequencing of the partial VP1 coding part of the viral genome. Altogether 4.8% (52/1,094) of the specimens were HEV-positive and 22.3% (44/197) of the children excreted HEV during the follow-up. HEV-A and HEV-B were present in 2.1 and 2.7% of the specimens, respectively. HEV-C and HEV-D viruses were not detected. In total, 17 different HEV serotypes were detected and the most common findings were CV-A9 (13.5%), CV-A16 (11.5%), and CV-A2 (9.6%). The majority of the infections (92.3%) were during the enterovirus season extending from July to December. Probiotic treatment did not affect significantly the risk of HEV infections during the 2-year follow-up although a trend for transient decrease for HEV positivity (HEV-A and/or HEV-B) by the age of 12 months was observed in children who received probiotics [OR 0.40; 95% confidence interval 0.15 to 1.08; P-value 0.071, generalized estimating (GEE) analysis]. According to the results, HEV-A findings were nearly as common as HEV-B findings among the healthy children participating in this study. Also it was shown that serotypes belonging to HEV-A species can be detected by means of viral culturing.
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| 7. |
- Skoglund, Camilla, 1977-
(författare)
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Autoantibodies related to type 1 diabetes in children
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Type 1 diabetes is an autoimmune disease resulting from destruction of the insulin producing beta cells in the pancreas. The patients need life-long heavy treatment and still complications, both acute and later in life, are common. The incidence of type 1 diabetes has increased rapidly during the last decades, especially among young children. The disease can be predicted by genes predisposing type 1 diabetes, mainly human leukocyte antigen (HLA) genes, together with presence of autoantibodies to beta-cell antigens, where multiple autoantibodies confer the highest risk. A number of immune system intervention trials are now ongoing aiming to halt the progression of the inflammatory process in the beta cells.This thesis aimed to investigate the prevalence and levels of autoantibodies in healthy children and in children with type 1 diabetes. Another aim was to study different properties of one of these autoantibodies, such as to which epitopes the antibodies bind and the distribution of immunoglobulin (Ig)-G subclasses, after immunomodulatory treatment in children with type 1 diabetes.We found that positivity to autoantibodies against glutamic acid decarboxylase (GADA) and tyrosine phosphatase like protein islet antigen-2 (IA-2A) was associated with HLA risk genotypes in 5-year old children from the general population. HLA risk genotypes seemed important for persistence of autoantibodies and for development of type 1 diabetes, while emergence of autoantibodies, especially transient autoantibodies, seemed to be more influenced by environmental factors. Improved methods for detection of autoantibodies are needed, for prediction of diabetes and for identification of high-risk individuals suitable for prevention treatments. Therefore, an assay for measurement of insulin autoantibodies (IAA), based on surface plasmon resonance (SPR), was developed. The main advantages of this method are that there is no need for labelling and that it is time-saving compared to the traditionally used radioimmunoassay (RIA), but further development of the method is needed.Treatment with GAD-alum (Diamyd) in children with type 1 diabetes has shown to preserve residual insulin secretion. This clinical effect was accompanied by an increase in GADA levels. We investigated the epitope reactivity of GADA in both GAD-alum and placebo treated children, and found that binding to one of the tested epitopes was temporarily increased after injection of GAD-alum. This result suggests that the quality of GADA was, to some extent, transiently affected by the treatment. On the other hand, no changes in binding to epitopes associated with stiff person syndrome (SPS) were observed, which together with the lack of change in GAD65 enzyme activity further strengthens the safety of the treatment. We also observed that the distribution of IgG subclasses was changed by GAD-alum treatment, with a lower proportion of IgG1 and higher IgG3 and IgG4. Lower IgG1 and higher IgG4 suggest a temporary switch towards a protective Th2 immune response, which has previously been observed in the same individuals for other immunological markers.In conclusion, measurement of autoantibodies related to type 1 diabetes is an important tool for studying the autoimmune process in pre-diabetic and type 1 diabetic children. In addition to the use as markers of disease progression, the autoantibodies may be used for studying the effects of immunomodulatory treatments on the humoral immune response.
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