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- Forsberg, Göte, 1957-
(author)
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Innate and adaptive immunity in childhood celiac disease
- 2006
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Doctoral thesis (other academic/artistic)abstract
- Celiac disease (CD) is an inflammatory small-bowel enteropathy caused by a permanent intolerance to wheat gluten and related proteins in rye and barley. Even though the disease originate from the small intestine the clinical symptoms varies in affected individuals and are often different in small children compared to adolescents and adults. Susceptibility to develop the disease is strongly associated with certain genetic factors i.e. HLADQ2/DQ8 but it is undoubtedly that additional inherited and environmental factors are involved. As specific T lymphocyte reactions are central in the pathogenesis of CD, six key cytokine messenger RNA levels in intestinal intraepithelial and lamina propria T lymphocytes (IEL, LPL), retrieved from small intestinal biopsies, were determined by using quantitative real-time reverse transcription polymerase chain reaction (RTPCR). Levels of cytokines, small secreted proteins which mediate and regulate immunity, in children with active disease were compared with that of treated children and controls. Interferon (IFN)-γ and interleukin (IL)-10 were also determined at the protein level by immunohistochemistry. Active celiac disease was characterized by distortions in cytokine expression, with highly significant increases of IFN-γ and IL-10 but no concomitant increases in tumor necrosis factor α (TNF-α), transforming growth factor β1 (TGFβ1), or IL-2 and no induction of IL-4. A marked shift of IFN-γ and IL-10 production from LPLs to IELs was characteristic of active celiac disease, and as many as one fourth of the IELs expressed IFN-γ. IELs in treated, symptom-free celiac patients still had increased IFN-γ levels compared with controls. In CD, gluten intake seems to cause an overreaction in IELs, with uncontrolled production of IFN-γ and IL-10 which may cause both recruitment of more IELs and a leaky epithelium, leading to a vicious circle with amplified immune activity and establishment of the intestinal lesion. In order to determine different IEL subsets contribution of the produced cytokines, γδIELs, CD4+αβIELs, and CD8+αβIELs as well as CD94+CD8+αβIELs and CD94CD8+αβIELs of children with active CD and children with no food-intolerance were analyzed for cytokine mRNA expression levels by RT-PCR. In active CD, CD8+αβIELs had the highest expression levels of IFN-γ- and IL-10 mRNA and constituted the cellular source for almost all IFN-γ and a large fraction of the IL-10. Expression levels of these two cytokines correlated and were higher in CD94-CD8+αβIELs than CD94+CD8+αβIELs CD4+αβIELs had the highest expression levels of TNF-α and despite the small number of this cell subset they contributed with half of the small amounts of this cytokine. Interestingly, TNF-α levels correlated with IL-10 in CD4+αβIELs. γδIELs had the lowest expression levels of IFN-γ, TNF-α, IL-10, and TGF-β1. Essentially no IL-2 mRNA was detected in the three IEL subpopulations. “Classical” CD8+CD94-αβT cells in the epithelial compartment are responsible for most of the excessive production of proinflammatory IFN-γ. The question whether an impaired extrathymic T cell maturation and/or capacity for secondary T cell receptor (TCR) gene recombination in iIELs is a contributing factor to CD was addressed. Expression levels of recombination activating gene-1 (RAG1) and the pre T α-chain (preTα) mRNAs were determined in IEL T cell lineage subsets of children with CD and controls. In controls, RAG1 was expressed in both mature (TCRγδ+ and TCRαβ+) and immature (CD2+CD7+TCR-) IELs while preTα was expressed preferentially in immature IELs. The RAG1 splice form selectively expressed outside thymus (RAG1 1A/2) as well as preTα were significantly decreased in CD patients both in active and inactive disease suggesting a deteriorated capacity of de novo TCR gene rearrangement in local T cell development and / or of secondary TCR gene rearrangement during editing or antigen-driven revision. This may lead to an imbalance between thymus- and gut derived T lymphocytes in the intestinal mucosa with consequent inefficient regulation of T cell responses against food antigens. Innate or nonspecific immunity is the first line, immediate defense against pathogens mediated by the epithelial cells in the intestine (IECs). As certain adaptive immune reaction in CD mimics that of intestinal infections, aberrant innate immune reaction could be a contributing factor to CD. Therefore jejunal biopsies were screened for bacteria and the innate immune status of the epithelium was investigated. Bacteria were freqently (40%) associated with the mucosa of children with active but also treated disease (20%) compared to controls (2%). Lack of antimicrobial factors such as mucins, proteins forming protective biofilm on the IECs, defensins and lysozym, peptides and enzymes with antibacterial effects, could not explain the presence of bacteria. If anything, mucin-2 (MUC2), α-defensins, HD-5, HD-6, and lysozyme mRNA levels were increased in epithelial cells in active CD, returning to normal levels in treated CD. Their expression levels correlated to the IFN-γ mRNA levels in IELs. Analysis of beta defensins, hBD-1 and hBD-2 as well as carcinoembryonic antigen (CEA) cell adhesion molecule 1a (CECAM1a), glycoproteins in the glycocalyx with ability to bind micro organisms, were not affected by the disease. Lectin staining by histochemistry revealed that goblet cells were stained by UEA1 in CD both active and treated but not in controls. The opposite pattern was seen for the lectin PNA where staining was seen in controls in the glycocalyx layer but not in CD. Thus altered glycocalyx/mucous layer may promote bacterial adhesion in CD.
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| 2. |
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| 3. |
- Kristjánsson, Guðjón, 1962-
(author)
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Food Antigen Sensitivity in Coeliac Disease Assessed by the Mucosal Patch Technique
- 2005
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Doctoral thesis (other academic/artistic)abstract
- A diagnosis of coeliac disease (CD) in adults relies on the presence of a structurally abnormal intestinal mucosa, followed by a clear clinical remission on a gluten-free diet. There is a clear need for a rapid, simple, safe and sensitive method to determine the type and intensity of inflammation in the gut mucosa in clinical practice. The overall aims of our studies were to develop and evaluate a new technique, “the mucosal patch technique”, to characterize rectal local inflammatory process after rectal food challenge in patients with CD. In study 1 we evaluated the potential of the new technique. The technique was well tolerated and easily applied. Pronounced neutrophil and eosinophil involvement in ulcerative colitis (UC) was demonstrated. With the high sensitivity of the technique, low-degree mucosal neutrophil activation could also be quantified in patients with collagen colitis,UC in clinical remission and in patients with irritable bowel syndrome. In study 2 and 3 the aim was to elucidate the dynamics of the rectal inflammatory response and nitric oxide (NO) production after rectal gluten challenge. We found a pronounced neutrophil activation in coeliac patients after rectal gluten challenge. This activation was apparent 4 hours after challenge and remains for at least 48 hours. A more modest eosinophil activation started 1-2 hours later and remained at least for 48 hours. The biphasic pattern of neutrophil and eosinonphil activation after challenge suggests a biphasic inflammatory reaction. The activation of neutrophils and eosinophils precedes a pronounced enhancement of mucosal NO production. Some of our coeliac patients displayed signs of an inflammatory reaction after rectal corn gluten challenge. In study 4 the aim was to investigate the local inflammatory reaction to gluten and cow’s milk protein in CD patients in remission. The findings indicate that not only gluten sensitivity but also cow’s milk (CM) protein sensitivity is common in CD. The data support the hypothesis that CM sensitivity may contribute to persistent symptoms in coeliac patients on gluten-free diet.
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| 4. |
- Mearin, Maria Luisa, et al.
(author)
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ESPGHAN Position Paper on Management and Follow-up of Children and Adolescents with Celiac Disease
- 2022
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In: Journal of Pediatric Gastroenterology and Nutrition. - 0277-2116. ; 75:3, s. 369-386
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Journal article (peer-reviewed)abstract
- There is a need for consensus on the recommendations for follow-up of children and adolescents with celiac disease. Objectives: To gather the current evidence and to offer recommendations for follow-up and management. Methods: The Special Interest Group on Celiac Diseases of the European Society of Paediatric Gastroenterology Hepatology and Nutrition formulated ten questions considered to be essential for follow-up care. A literature search (January 2010-March 2020) was performed in PubMed or Medline. Relevant publications were identified and potentially eligible studies were assessed. Statements and recommendations were developed and discussed by all coauthors. Recommendations were voted upon: joint agreement was set as at least 85%. Results: Publications (n = 2775) were identified and 164 were included. Using evidence or expert opinion, 37 recommendations were formulated on: The need to perform follow-up, its frequency and what should be assessed, how to assess adherence to the gluten-free diet, when to expect catch-up growth, how to treat anemia, how to approach persistent high serum levels of antibodies against tissue-transglutaminase, the indication to perform biopsies, assessment of quality of life, management of children with unclear diagnosis for which a gluten-challenge is indicated, children with associated type 1 diabetes or IgA deficiency, cases of potential celiac disease, which professionals should perform follow-up, how to improve the communication to patients and their parents/caregivers and transition from pediatric to adult health care. Conclusions: We offer recommendations to improve follow-up of children and adolescents with celiac disease and highlight gaps that should be investigated to further improve management.
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| 5. |
- Szajewska, Hania, et al.
(author)
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Early diet and the risk of coeliac disease. An update 2024 position paper by the ESPGHAN special interest group on coeliac disease
- 2024
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In: Journal of Pediatric Gastroenterology and Nutrition - JPGN. - : John Wiley & Sons. - 0277-2116 .- 1536-4801.
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Journal article (peer-reviewed)abstract
- This position paper by the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Special Interest Group on Coeliac Disease (SIG-CD) presents an update to the 2016 recommendations concerning early diet and the risk of coeliac disease (CD). This update adheres to the policy that mandates reviewing guidelines every 5 years, particularly when new data emerge. The 2024 statements and recommendations are essentially similar to the 2016 recommendations. Breastfeeding, whether any amount, exclusive, or of any duration, does not reduce the risk of developing CD. Introducing gluten into an infant's diet at any time between completed 4 months (≥17 weeks) and 12 months of age does not affect the cumulative incidence of CD, although earlier introduction may lead to earlier seroconversion and CD. In observational studies involving cohorts with a known risk for CD, consuming a high amount of gluten compared to a low amount during weaning and in the subsequent childhood years—specifically the first 2–3 years, and even up to 5 years in some studies—was associated with an increased risk for CD. However, the specific optimal amounts of gluten consumption remain undetermined due to insufficient evidence on safe thresholds, and the impact of restricting gluten in the diet of healthy children of unknown risk for CD is unknown. Thus, any recommendation on the gluten amount is currently unjustifiable for the general population and infants with known HLA risk types. There is no specific guidance on the type of gluten-containing foods to be introduced at weaning.
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| 6. |
- Szajewska, Hania, et al.
(author)
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Early Feeding Practices and Celiac Disease Prevention : Protocol for an Updated and Revised Systematic Review and Meta-Analysis
- 2022
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In: Nutrients. - : MDPI. - 2072-6643. ; 14:5
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Research review (peer-reviewed)abstract
- Uncertainty remains in regard to when, how, and in what form gluten should be introduced into the diet, particularly of infants genetically predisposed to developing celiac disease (CD). MEDLINE (PubMed), EMBASE, and Cochrane Central Register of Controlled Trials databases will be searched from inception. Randomized controlled trials (RCTs) and observational studies (cohort, case-control, or cross-sectional studies) investigating the association between early feeding practices and the risk of CD and/or CD autoimmunity will be included. In prospective studies, participants will be infants regardless of the risk of developing CD. For retrospective studies, participants will be children or adults with CD or presenting with positive serology indicative of CD. Interventions will be gluten-containing products of any type. Exposures will be breastfeeding and/or the introduction of gluten-containing products of any type. In control groups, there will be no exposure, different degrees of exposure (partial vs. exclusive breastfeeding, different amounts of gluten, etc.), or a placebo. The primary outcome measure will be CD or CD autoimmunity (i.e., anti-transglutaminase or anti-endomysial antibodies). At least two reviewers will independently assess the risk of bias using a validated risk assessment tool depending on study design. Disagreements will be resolved by discussion to achieve a consensus with the involvement of one or more additional reviewers if required. If appropriate, data will be pooled. If not, a narrative synthesis will be performed. The findings will be submitted to a peer-reviewed journal.
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| 7. |
- Szajewska, Hania, et al.
(author)
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Gluten Introduction and the Risk of Coeliac Disease : A Position Paper by the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition
- 2016
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In: Journal of Pediatric Gastroenterology and Nutrition - JPGN. - 0277-2116 .- 1536-4801. ; 62:3, s. 507-513
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Journal article (peer-reviewed)abstract
- Background:The European Society for Paediatric Gastroenterology, Hepatology and Nutrition recommended in 2008, based on observational data, to avoid both early (<4 months) and late (7 months) introduction of gluten and to introduce gluten while the infant is still being breast-fed. New evidence prompted ESPGHAN to revise these recommendations.Objective:To provide updated recommendations regarding gluten introduction in infants and the risk of developing coeliac disease (CD) during childhood.Summary:The risk of inducing CD through a gluten-containing diet exclusively applies to persons carrying at least one of the CD risk alleles. Because genetic risk alleles are generally not known in an infant at the time of solid food introduction, the following recommendations apply to all infants, although they are derived from studying families with first-degree relatives with CD. Although breast-feeding should be promoted for its other well-established health benefits, neither any breast-feeding nor breast-feeding during gluten introduction has been shown to reduce the risk of CD. Gluten may be introduced into the infant's diet anytime between 4 and 12 completed months of age. In children at high risk for CD, earlier introduction of gluten (4 vs 6 months or 6 vs 12 months) is associated with earlier development of CD autoimmunity (defined as positive serology) and CD, but the cumulative incidence of each in later childhood is similar. Based on observational data pointing to the association between the amount of gluten intake and risk of CD, consumption of large quantities of gluten should be avoided during the first weeks after gluten introduction and during infancy. The optimal amounts of gluten to be introduced at weaning, however, have not been established.
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| 8. |
- Szajewska, Hania, et al.
(author)
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Systematic review : early feeding practices and the risk of coeliac disease. A 2022 update and revision
- 2022
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In: Alimentary Pharmacology and Therapeutics. - : John Wiley & Sons. - 0269-2813 .- 1365-2036. ; 57:1, s. 8-22
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Research review (peer-reviewed)abstract
- Background: The effects of early feeding practices on the risk of coeliac disease (CD) remain debated.Aims: To update evidence on these practices on the risk of CD and/or CD-related autoimmunity (CDA), defined as anti-transglutaminase or anti-endomysial antibody positivity.Methods: We searched MEDLINE, EMBASE and the Cochrane Library to May 2022 for randomised controlled trials (RCTs) and observational studies.Results: We included 36 publications (30 studies). In the population at genetic risk of developing CD (HLA DQ2/DQ8-positive), exclusive or any breastfeeding and longer breastfeeding duration did not reduce the risk of developing CD/CDA during childhood. While a meta-analysis of four case–control studies showed a decreased risk for CD when gluten was introduced during breastfeeding, this was not shown in RCTs and cohort studies. Age at gluten introduction was not associated with cumulative CD/CDA risk, although two RCTs suggested that earlier gluten introduction was associated with earlier CDA appearance. Evidence from six observational studies suggests that consumption of a higher amount of gluten at weaning and/or thereafter may increase CD risk. There is insufficient evidence to determine the amount of gluten associated with an increased CD/CDA risk. Regarding whether infant feeding practices modulate the risk conferred by different HLA genotypes results were inconsistent.Conclusions: For the population at genetic risk of CD, breastfeeding and age at gluten introduction have no effect on its cumulative incidence during childhood. There is some evidence for an effect of the amount of gluten consumed at weaning and/or thereafter on CD/CDA risk.
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| 9. |
- Terrazzano, Giuseppe, et al.
(author)
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T1D progression is associated with loss of CD3+CD56+ regulatory T cells that control CD8+ T cell effector functions
- 2020
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In: Nature Metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 2:2, s. 142-152
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Journal article (peer-reviewed)abstract
- An unresolved issue in autoimmunity is the lack of surrogate biomarkers of immunological self-tolerance for disease monitoring. Here, we show that peripheral frequency of a regulatory T cell population, characterized by the co-expression of CD3 and CD56 molecules (TR3-56), is reduced in subjects with new-onset type 1 diabetes (T1D). In three independent T1D cohorts, we find that low frequency of circulating TR3-56 cells is associated with reduced β-cell function and with the presence of diabetic ketoacidosis. As autoreactive CD8+ T cells mediate disruption of insulin-producing β-cells1-3, we demonstrate that TR3-56 cells can suppress CD8+ T cell functions in vitro by reducing levels of intracellular reactive oxygen species. The suppressive function, phenotype and transcriptional signature of TR3-56 cells are also altered in T1D children. Together, our findings indicate that TR3-56 cells constitute a regulatory cell population that controls CD8+ effector functions, whose peripheral frequency may represent a traceable biomarker for monitoring immunological self-tolerance in T1D.
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