Publications by authors named "Aleksandr Peet"

29 Publications

  • Page 1 of 1

Immunomodulatory Effects of Rhinovirus and Enterovirus Infections During the First Year of Life.

Front Immunol 2020 11;11:567046. Epub 2021 Feb 11.

Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.

Early childhood infections have been implicated in the development of immune-mediated diseases, such as allergies, asthma, and type 1 diabetes. We set out to investigate the immunomodulatory effects of early viral infections experienced before the age of one year on the peripheral regulatory T cell population (Treg) and circulating cytokines in a birth-cohort study of Estonian and Finnish infants. We show here a temporal association of virus infection with the expression of FOXP3 in regulatory T cells. Infants with rhinovirus infection during the preceding 30 days had a higher FOXP3 expression in Treg cells and decreased levels of several cytokines related to Th1 and Th2 responses in comparison to the children without infections. In contrast, FOXP3 expression was significantly decreased in highly activated (CD4+CD127-/loCD25+FOXP3high) regulatory T cells (TregFOXP3high) in the infants who had enterovirus infection during the preceding 30 or 60 days. After enterovirus infections, the cytokine profile showed an upregulation of Th1- and Th17-related cytokines and a decreased activation of CCL22, which is a chemokine derived from dendritic cells and associated with Th2 deviation. Our results reveal that immunoregulatory mechanisms are up-regulated after rhinovirus infections, while enterovirus infections are associated with activation of proinflammatory pathways and decreased immune regulation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2020.567046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905218PMC
February 2021

Thyroid peroxidase antibodies are common in children with HLA-conferred susceptibility to type 1 diabetes, but are weakly associated with thyroid function.

J Pediatr Endocrinol Metab 2020 Jul 7. Epub 2020 Jul 7.

Department of Paediatrics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.

Background The need for screening for autoimmune thyroid disease in children who have HLA-conferred susceptibility to type 1 diabetes (T1D), but have not yet been diagnosed with T1D, has not been thoroughly studied. The aim of this study was to describe the prevalence of positive thyroid peroxidase antibodies and its effect on thyroid function in children with genetic susceptibility to T1D as well as to describe the association between thyroid autoimmunity and HLA-DQ genotypes. Methods Cross-sectional study in 223 children (112 boys) aged 7.4-10.5 years with HLA-conferred susceptibility to T1D. TPOAb were measured in all children; thyroglobulin antibodies (TGAb) and thyroid function in TPOAb positive subjects. Results Girls had a significantly higher median TPOAb concentration than boys (12 vs 11 kU/L; p=0.001). Positive TPOAb occurred in 13.9% and positive TGAb in 4% of subjects. Only two children had mild changes in thyroid function. There was no association between HLA risk groups and the prevalence of TPOAb. Conclusions TPOAb are common in children with HLA-conferred susceptibility to T1D, yet are weakly associated with thyroid function, suggesting limited value of thyroid screening in this cohort.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1515/jpem-2019-0512DOI Listing
July 2020

Contrasting microbiotas between Finnish and Estonian infants: Exposure to Acinetobacter may contribute to the allergy gap.

Allergy 2020 09 17;75(9):2342-2351. Epub 2020 Mar 17.

Pediatric Research Center, Children's Hospital, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.

Background: Allergic diseases are more common in Finland than in Estonia, which-according to the biodiversity hypothesis-could relate to differences in early microbial exposures.

Methods: We aimed at defining possible microbial perturbations preceding early atopic sensitization. Stool, nasal and skin samples of 6-month-old DIABIMMUNE study participants with HLA susceptibility to type 1 diabetes were collected. We compared microbiotas of sensitized (determined by specific IgE results at 18 months of age) and unsensitized Estonian and Finnish children.

Results: Sensitization was differentially targeted between populations, as egg-specific and birch pollen-specific IgE was more common in Finland. Microbial diversity and community composition also differed; the genus Acinetobacter was more abundant in Estonian skin and nasal samples. Particularly, the strain-level profile of Acinetobacter lwoffii was more diverse in Estonian samples. Early microbiota was not generally associated with later sensitization. Microbial composition tended to differ between children with or without IgE-related sensitization, but only in Finland. While land-use pattern (ie green areas vs. urban landscapes around the children's homes) was not associated with microbiota as a whole, it associated with the composition of the genus Acinetobacter. Breastfeeding affected gut microbial composition and seemed to protect from sensitization.

Conclusions: In accordance with the biodiversity hypothesis, our results support disparate early exposure to environmental microbes between Finnish and Estonian children and suggest a significant role of the genus Acinetobacter in the allergy gap between the two populations. The significance of the observed differences for later allergic sensitization remains open.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/all.14250DOI Listing
September 2020

Maturation of Gut Microbiota and Circulating Regulatory T Cells and Development of IgE Sensitization in Early Life.

Front Immunol 2019 23;10:2494. Epub 2019 Oct 23.

Clinicum, University of Helsinki, Helsinki, Finland.

Recent studies suggest that the cross-talk between the gut microbiota and human immune system during the first year of life is an important regulator of the later development of atopic diseases. We explored the changes in the gut microbiota, blood regulatory T cells, and atopic sensitization in a birth-cohort of Estonian and Finnish children followed from 3 to 36 months of age. We describe here an infant Treg phenotype characterized by high Treg frequency, the maturation of Treg population characterized by a decrease in their frequency accompanied with an increase in the highly activated Treg cells. These changes in Treg population associated first with the relative abundance of Bifidobacterium longum followed by increasing colonization with butyrate producing bacteria. High bifidobacterial abundance in the neonatal microbiota appeared to be protective, while colonization with and was associated with later risk of allergy. Estonian children with lower risk of IgE mediated allergic diseases than Finnish children showed an earlier maturation of the gut microbiota, detected as earlier switch to an increasing abundance of butyrate-producing bacteria, combined with an earlier maturation of Treg cell phenotype and total IgE production. The children with established allergic diseases by age 3 showed a decreased abundance of butyrate producing . These results suggest that as well as the maintenance of a bifidobacterial dominated gut microbiota is important during the first weeks of life, the overtake by butyrate producing bacteria seems to be a beneficial shift, which should not be postponed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2019.02494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842923PMC
October 2020

Coeliac disease and HLA-conferred susceptibility to autoimmunity are associated with IgE sensitization in young children.

Allergy 2020 03 2;75(3):692-694. Epub 2019 Oct 2.

Children's Hospital, Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/all.14055DOI Listing
March 2020

Early Detection of Peripheral Blood Cell Signature in Children Developing β-Cell Autoimmunity at a Young Age.

Diabetes 2019 10 16;68(10):2024-2034. Epub 2019 Jul 16.

Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland

The appearance of type 1 diabetes (T1D)-associated autoantibodies is the first and only measurable parameter to predict progression toward T1D in genetically susceptible individuals. However, autoantibodies indicate an active autoimmune reaction, wherein the immune tolerance is already broken. Therefore, there is a clear and urgent need for new biomarkers that predict the onset of the autoimmune reaction preceding autoantibody positivity or reflect progressive β-cell destruction. Here we report the mRNA sequencing-based analysis of 306 samples including fractionated samples of CD4 and CD8 T cells as well as CD4CD8 cell fractions and unfractionated peripheral blood mononuclear cell samples longitudinally collected from seven children who developed β-cell autoimmunity (case subjects) at a young age and matched control subjects. We identified transcripts, including interleukin 32 (), that were upregulated before T1D-associated autoantibodies appeared. Single-cell RNA sequencing studies revealed that high in case samples was contributed mainly by activated T cells and NK cells. Further, we showed that expression can be induced by a virus and cytokines in pancreatic islets and β-cells, respectively. The results provide a basis for early detection of aberrations in the immune system function before T1D and suggest a potential role for IL32 in the pathogenesis of T1D.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/db19-0287DOI Listing
October 2019

A retrospective analysis of the prevalence of imprinting disorders in Estonia from 1998 to 2016.

Eur J Hum Genet 2019 11 11;27(11):1649-1658. Epub 2019 Jun 11.

Department of Clinical Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia.

Imprinting disorders (ImpDis) represent a small group of rare congenital diseases primarily affecting growth, development, and the hormonal and metabolic systems. The aim of present study was to identify the prevalence of the ImpDis in Estonia, to describe trends in the live birth prevalence of these disorders between 1998 and 2016, and to compare the results with previously published data. We retrospectively reviewed the records of all Estonian patients since 1998 with both molecularly and clinically diagnosed ImpDis. A prospective study was also conducted, in which all patients with clinical suspicion for an ImpDis were molecularly analyzed. Eighty-seven individuals with ImpDis were identified. Twenty-seven (31%) of them had Prader-Willi syndrome (PWS), 15 (17%) had Angelman syndrome (AS), 15 (17%) had Silver-Russell syndrome (SRS), 12 (14%) had Beckwith-Wiedemann syndrome (BWS), 10 (11%) had pseudo- or pseudopseudohypoparathyroidism, four had central precocious puberty, two had Temple syndrome, one had transient neonatal diabetes mellitus, and one had myoclonus-dystonia syndrome. One third of SRS and BWS cases fulfilled the diagnostic criteria for these disorders, but tested negative for genetic abnormalities. Seventy-six individuals were alive as of January 1, 2018, indicating the total prevalence of ImpDis in Estonia is 5.8/100,000 (95% CI 4.6/100,000-7.2/100,000). The minimum live birth prevalence of all ImpDis in Estonia in 2004-2016 was 1/3,462, PWS 1/13,599, AS 1/27,198, BWS 1/21,154, SRS 1/15,866, and PHP/PPHP 1/27,198. Our results are only partially consistent with previously published data. The worldwide prevalence of SRS and GNAS-gene-related ImpDis is likely underestimated and may be at least three times higher than expected.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41431-019-0446-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6871525PMC
November 2019

Early childhood infections and the use of antibiotics and antipyretic-analgesics in Finland, Estonia and Russian Karelia.

Acta Paediatr 2019 11 23;108(11):2075-2082. Epub 2019 Jun 23.

Pediatric Research Center, Children's Hospital, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.

Aim: Infections in early childhood are common reasons to seek medical attention. This study compares the prevalence of infections, and the use of antibiotics and antipyretic-analgesics, in children from Finland, Estonia and Russian Karelia.

Methods: Children with a genetically increased risk for type 1 diabetes (N = 797) were observed from birth up to 3 years of age. Illnesses and medications were reported by parents continuously. All reported infections, antibiotics and antipyretic-analgesics were compared between Finland and Estonia, and to a lesser extent with Russian Karelia, due to poor study compliance.

Results: Compared with Estonians, Finns reported more infections during the first and second years of life. During the follow-up, Finnish children had 10 infections while Estonians only had 8 (p < 0.001). Finns also used more antibiotics and antipyretic-analgesics in each year during the follow-up. Russian Karelians reported the lowest frequency of infections and the most infrequent use of antibiotics and antipyretic-analgesics in the first two years of life.

Conclusion: Infections and the use of antibiotics and antipyretic-analgesics in early childhood were most frequent in Finland, where socio-economic conditions are the most developed and microbial encounters are sparse. This may reflect on the hygiene hypothesis, a less effective immune system that allows normally harmless microbes to attack and cause clinical infections.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/apa.14874DOI Listing
November 2019

Early-life exposure to common virus infections did not differ between coeliac disease patients and controls.

Acta Paediatr 2019 09 11;108(9):1709-1716. Epub 2019 Apr 11.

Department of Immunology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.

Aim: Our aim was to compare the presence of various common viruses (rhinovirus, enterovirus, adenovirus, Epstein-Barr virus, cytomegalovirus, norovirus, parechovirus) in stool and nasal swab samples as well as virus-specific antibodies in serum samples between children who developed coeliac disease and controls.

Methods: A case-control study was established based on the DIABIMMUNE Study cohorts. During the study, eight Estonian children and 21 Finnish children aged 1.5 years to five years developed coeliac disease and each was matched with a disease-free control. Nasal swabs and stool samples were taken at the age of three to six months and the serum samples at the time of diagnosis.

Results: Rhinovirus ribonucleic acid was detected in the nasal swabs from five coeliac disease children, but none of the control children (p = 0.05). There were no statistically significant differences in the level of viral antibodies between cases and controls. Enterovirus immunoglobulin G class antibodies were found more frequently in the Estonian than in the Finnish children (63% versus 23%, p = 0.02).

Conclusion: This study did not find any marked overall differences in laboratory-confirmed common viral infections between the children who developed coeliac disease and the controls. However, rhinovirus infections were detected slightly more often in those patients who developed coeliac disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/apa.14791DOI Listing
September 2019

Rhinoviruses in infancy and risk of immunoglobulin E sensitization.

J Med Virol 2019 08 25;91(8):1470-1478. Epub 2019 Mar 25.

Department of Virology, Faculty of Medical Sciences and Biotechnology, Tampere University, Tampere, Finland.

Previous data about the role of viruses in the development of allergic immunoglobulin E (IgE) sensitization are contradictory. The aim of this study was to determine the possible associations between exposure to different viruses (rhinovirus, enterovirus, norovirus, and parechovirus) during the first year of life and IgE sensitization. Viruses were analyzed from stool samples collected monthly from infants participating in a prospective birth cohort study. From that study, 244 IgE sensitized case children and 244 nonsensitized control children were identified based on their allergen-specific IgE antibody levels at the age of 6, 18, and 36 months. Stool samples (n = 4576) from the case and control children were screened for the presence of rhinovirus, enterovirus, norovirus, and parechovirus RNA by reverse transcription quantitative polymerase chain reaction. The study showed that rhinovirus was the most prevalent virus detected, present in 921 (20%) samples. None of the viruses were associated with IgE sensitization in the full cohort but after stratifying by sex, the number of rhinovirus positive samples was inversely associated with IgE sensitization in boys (odds ratio [OR]: 0.81; 95% confidence interval [CI]: 0.69-0.94; P = 0.006). There was also a temporal relation between rhinoviruses and IgE sensitization, as rhinovirus exposure during the first 6 months of life was associated with a reduced risk of subsequent IgE sensitization in boys (OR: 0.76; 95% CI: 0.6-0.94; P = 0.016). In conclusion, early exposure to rhinoviruses was inversely associated with IgE sensitization but this protective association was restricted to boys.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jmv.25455DOI Listing
August 2019

Development of atopic sensitization in Finnish and Estonian children: A latent class analysis in a multicenter cohort.

J Allergy Clin Immunol 2019 05 23;143(5):1904-1913.e9. Epub 2019 Jan 23.

Dr. von Hauner Children's Hospital, LMU Munich, Munich, Germany; German Center for Lung Research (DZL). Electronic address:

Background: The prevalence of atopy is associated with a Western lifestyle, as shown by studies comparing neighboring regions with different socioeconomic backgrounds. Atopy might reflect various conditions differing in their susceptibility to environmental factors.

Objective: We sought to define phenotypes of atopic sensitization in early childhood and examine their association with allergic diseases and hereditary background in Finland and Estonia.

Methods: The analysis included 1603 Finnish and 1657 Estonian children from the DIABIMMUNE multicenter young children cohort. Specific IgE levels were measured at age 3, 4, and 5 years, respectively, and categorized into 3 CAP classes. Latent class analysis was performed with the statistical software package poLCA in R software.

Results: Both populations differed in terms of socioeconomic status and environmental determinants, such as pet ownership, farm-related exposure, time spent playing outdoors, and prevalence of allergic diseases (all P < .001). Nevertheless, we found similar latent classes in both populations: an unsensitized class, a food class, 2 inhalant classes differentiating between seasonal and perennial aeroallergens, and a severe atopy class. The latter was characterized by high total and specific IgE levels and strongly associated with wheeze (odds ratio [OR], 5.64 [95% CI, 3.07-10.52] and 4.56 [95% CI, 2.35-8.52]), allergic rhinitis (OR, 22.4 [95% CI, 11.67-44.54] and 13.97 [95% CI, 7.33-26.4]), and atopic eczema (OR, 9.39 [95% CI, 4.9-19.3] and 9.5 [95% CI, 5.2-17.5] for Finland and Estonia, respectively). Environmental differences were reflected in the larger seasonal inhalant atopy class in Finland, although composition of classes was comparable between countries.

Conclusion: Despite profound differences in environmental exposures, there might exist genuine patterns of atopic sensitization. The distribution of these patterns might determine the contribution of atopic sensitization to disease onset.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaci.2018.12.1014DOI Listing
May 2019

Characterization and non-parametric modeling of the developing serum proteome during infancy and early childhood.

Sci Rep 2018 04 12;8(1):5883. Epub 2018 Apr 12.

Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, FI-20520, Finland.

Children develop rapidly during the first years of life, and understanding the sources and associated levels of variation in the serum proteome is important when using serum proteins as markers for childhood diseases. The aim of this study was to establish a reference model for the evolution of a healthy serum proteome during early childhood. Label-free quantitative proteomics analyses were performed for 103 longitudinal serum samples collected from 15 children at birth and between the ages of 3-36 months. A flexible Gaussian process-based probabilistic modelling framework was developed to evaluate the effects of different variables, including age, living environment and individual variation, on the longitudinal expression profiles of 266 reliably identified and quantified serum proteins. Age was the most dominant factor influencing approximately half of the studied proteins, and the most prominent age-associated changes were observed already during the first year of life. High inter-individual variability was also observed for multiple proteins. These data provide important details on the maturing serum proteome during early life, and evaluate how patterns detected in cord blood are conserved in the first years of life. Additionally, our novel modelling approach provides a statistical framework to detect associations between covariates and non-linear time series data.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-018-24019-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5897447PMC
April 2018

Autoantibody Repertoire in APECED Patients Targets Two Distinct Subgroups of Proteins.

Front Immunol 2017 16;8:976. Epub 2017 Aug 16.

Institute of Biomedical and Translational Medicine, University of Tartu, Tartu, Estonia.

High titer autoantibodies produced by B lymphocytes are clinically important features of many common autoimmune diseases. APECED patients with deficient autoimmune regulator (AIRE) gene collectively display a broad repertoire of high titer autoantibodies, including some which are pathognomonic for major autoimmune diseases. AIRE deficiency severely reduces thymic expression of gene-products ordinarily restricted to discrete peripheral tissues, and developing T cells reactive to those gene-products are not inactivated during their development. However, the extent of the autoantibody repertoire in APECED and its relation to thymic expression of self-antigens are unclear. We here undertook a broad protein array approach to assess autoantibody repertoire in APECED patients. Our results show that in addition to shared autoantigen reactivities, APECED patients display high inter-individual variation in their autoantigen profiles, which collectively are enriched in evolutionarily conserved, cytosolic and nuclear phosphoproteins. The APECED autoantigens have two major origins; proteins expressed in thymic medullary epithelial cells and proteins expressed in lymphoid cells. These findings support the hypothesis that specific protein properties strongly contribute to the etiology of B cell autoimmunity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2017.00976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5561390PMC
August 2017

Intestinal virome changes precede autoimmunity in type I diabetes-susceptible children.

Proc Natl Acad Sci U S A 2017 07 10;114(30):E6166-E6175. Epub 2017 Jul 10.

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110;

Viruses have long been considered potential triggers of autoimmune diseases. Here we defined the intestinal virome from birth to the development of autoimmunity in children at risk for type 1 diabetes (T1D). A total of 220 virus-enriched preparations from serially collected fecal samples from 11 children (cases) who developed serum autoantibodies associated with T1D (of whom five developed clinical T1D) were compared with samples from controls. Intestinal viromes of case subjects were less diverse than those of controls. Among eukaryotic viruses, we identified significant enrichment of -related sequences in samples from controls in comparison with cases. Enterovirus, kobuvirus, parechovirus, parvovirus, and rotavirus sequences were frequently detected but were not associated with autoimmunity. For bacteriophages, we found higher Shannon diversity and richness in controls compared with cases and observed that changes in the intestinal virome over time differed between cases and controls. Using Random Forests analysis, we identified disease-associated viral bacteriophage contigs after subtraction of age-associated contigs. These disease-associated contigs were statistically linked to specific components of the bacterial microbiome. Thus, changes in the intestinal virome preceded autoimmunity in this cohort. Specific components of the virome were both directly and inversely associated with the development of human autoimmune disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1706359114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5544325PMC
July 2017

Exploring the risk factors for differences in the cumulative incidence of coeliac disease in two neighboring countries: the prospective DIABIMMUNE study.

Dig Liver Dis 2016 Nov 6;48(11):1296-1301. Epub 2016 Jul 6.

Department of Immunology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia. Electronic address:

Background: During the last several decades the prevalence of coeliac disease (CD) has increased worldwide.

Aim: To compare the cumulative incidence of CD between Estonian and Finnish children and to identify the risk factors.

Materials And Methods: Children were recruited as part of the DIABIMMUNE Study. In the birth cohort (BC) 258 children from Estonia and 305 from Finland, and in the young children's cohort (YCC) 1363 and 1384 children were followed up, respectively. The diagnosis of CD was made in accordance with the ESPGHAN guidelines-the presence of IgA-tTG antibodies and small bowel villous atrophy.

Results: During the study period 29 children developed CD. The cumulative incidence of CD was significantly higher in Finland (0.77% vs 0.27%; P=0.01). No difference was seen between the children with CD and the controls in the duration of breastfeeding or the age at cereal introduction. The BC children with CD had had significantly more episodes of infections with fever by the age of 12 months compared to the controls (3.4 vs 1.4; P=0.04).

Conclusion: The 5-year cumulative incidence of childhood CD is significantly higher in Finland than in Estonia. Sequential infections early in life may increase the risk for developing CD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.dld.2016.06.029DOI Listing
November 2016

Variation in Microbiome LPS Immunogenicity Contributes to Autoimmunity in Humans.

Cell 2016 May 28;165(4):842-53. Epub 2016 Apr 28.

Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address:

According to the hygiene hypothesis, the increasing incidence of autoimmune diseases in western countries may be explained by changes in early microbial exposure, leading to altered immune maturation. We followed gut microbiome development from birth until age three in 222 infants in Northern Europe, where early-onset autoimmune diseases are common in Finland and Estonia but are less prevalent in Russia. We found that Bacteroides species are lowly abundant in Russians but dominate in Finnish and Estonian infants. Therefore, their lipopolysaccharide (LPS) exposures arose primarily from Bacteroides rather than from Escherichia coli, which is a potent innate immune activator. We show that Bacteroides LPS is structurally distinct from E. coli LPS and inhibits innate immune signaling and endotoxin tolerance; furthermore, unlike LPS from E. coli, B. dorei LPS does not decrease incidence of autoimmune diabetes in non-obese diabetic mice. Early colonization by immunologically silencing microbiota may thus preclude aspects of immune education.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2016.04.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4950857PMC
May 2016

Increased Blood Levels of Growth Factors, Proinflammatory Cytokines, and Th17 Cytokines in Patients with Newly Diagnosed Type 1 Diabetes.

PLoS One 2015 4;10(12):e0142976. Epub 2015 Dec 4.

Department of Immunology, Institute of Bio- and Translational Medicine, University of Tartu, Estonia.

The production of several cytokines could be dysregulated in type 1 diabetes (T1D). In particular, the activation of T helper (Th) type 1 (Th1) cells has been proposed to underlie the autoimmune pathogenesis of the disease, although roles for inflammatory processes and the Th17 pathway have also been shown. Nevertheless, despite evidence for the role of cytokines before and at the onset of T1D, the corresponding findings are inconsistent across studies. Moreover, conflicting data exist regarding the blood cytokine levels in T1D patients. The current study was performed to investigate genetic and autoantibody markers in association with the peripheral blood cytokine profiles by xMap multiplex technology in newly diagnosed young T1D patients and age-matched healthy controls. The onset of young-age T1D was characterized by the upregulation of growth factors, including granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin (IL)-7, the proinflammatory cytokine IL-1β (but not IL-6 or tumor necrosis factor [TNF]-α), Th17 cytokines, and the regulatory cytokines IL-10 and IL-27. Ketoacidosis and autoantibodies (anti-IA-2 and -ZnT8), but not human leukocyte antigen (HLA) genotype, influenced the blood cytokine levels. These findings broaden the current understanding of the dysregulation of systemic levels of several key cytokines at the young-age onset of T1D and provide a further basis for the development of novel immunoregulatory treatments in this disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0142976PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4670260PMC
June 2016

Circulating IGF1 and IGFBP3 in relation to the development of β-cell autoimmunity in young children.

Eur J Endocrinol 2015 Aug 6;173(2):129-37. Epub 2015 May 6.

Department of PediatricsUniversity of Tartu, N. Lunini 6 51014 Tartu, EstoniaChildren's Clinic of Tartu University HospitalN. Lunini 6, Tartu, EstoniaChildren's Hospital and Jorvi HospitalUniversity of Helsinki and Helsinki University Central Hospital, Helsinki, FinlandImmunogenetics LaboratoryUniversity of Turku, Turku, FinlandDepartment of Clinical MicrobiologyUniversity of Eastern Finland, Kuopio, FinlandDiabetes and Obesity Research ProgramUniversity of Helsinki, Helsinki, FinlandFolkhälsan Research CenterHelsinki, Finland andDepartment of PediatricsTampere University Hospital, Tampere, Finland Department of PediatricsUniversity of Tartu, N. Lunini 6 51014 Tartu, EstoniaChildren's Clinic of Tartu University HospitalN. Lunini 6, Tartu, EstoniaChildren's Hospital and Jorvi HospitalUniversity of Helsinki and Helsinki University Central Hospital, Helsinki, FinlandImmunogenetics LaboratoryUniversity of Turku, Turku, FinlandDepartment of Clinical MicrobiologyUniversity of Eastern Finland, Kuopio, FinlandDiabetes and Obesity Research ProgramUniversity of Helsinki, Helsinki, FinlandFolkhälsan Research CenterHelsinki, Finland andDepartment of PediatricsTampere University Hospital, Tampere, Finland.

Objective: This study aimed at investigating the role of IGF1 and IGF binding protein 3 (IGFBP3) in the development of β-cell autoimmunity.

Methods: Five hundred and sixty-three subjects with HLA-conferred susceptibility to type 1 diabetes (T1D) were monitored for signs of seroconversion to positivity for insulin and/or GAD, IA2, and zinc transporter 8 autoantibodies by the age of 3 years. In 40 subjects who developed at least one autoantibody, IGF1 and IGFBP3 plasma concentrations were measured and compared with 80 control subjects who remained negative for autoantibodies, and were matched for age, sex, country of origin, and HLA genotype. The increments of IGF1, IGFBP3, and IGF1/IGFBP3 molar ratio before and after seroconverison were compared with corresponding time intervals in controls.

Results: The IGF1 concentrations at the age of 12 months and the IGF1/IGFBP3 ratio at the age of 24 months were lower in the autoantibody-positive children (P<0.05). The increase in circulating IGFBP3 was significantly higher in the autoantibody-positive children before seroconversion than in the corresponding time intervals in controls (0.43 mg/l; 95% CI 0.29-0.56 vs 0.22 mg/l; 95% CI 0.10-0.34 mg/l; P<0.01). Children carrying the high-risk HLA genotype had lower plasma IGF1 and IGFBP3 concentrations at the age of 24 months than those with low-risk genotypes (P<0.05 and < 0.01 respectively).

Conclusions: Circulating IGF1 and IGFBP3 appear to have a role in early development of β-cell autoimmunity. The decreased IGF1 concentrations in children with the high-risk HLA genotype may contribute to the reduced growth previously described in such children.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/EJE-14-1078DOI Listing
August 2015

The dynamics of the human infant gut microbiome in development and in progression toward type 1 diabetes.

Cell Host Microbe 2015 Feb 5;17(2):260-73. Epub 2015 Feb 5.

Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address:

Colonization of the fetal and infant gut microbiome results in dynamic changes in diversity, which can impact disease susceptibility. To examine the relationship between human gut microbiome dynamics throughout infancy and type 1 diabetes (T1D), we examined a cohort of 33 infants genetically predisposed to T1D. Modeling trajectories of microbial abundances through infancy revealed a subset of microbial relationships shared across most subjects. Although strain composition of a given species was highly variable between individuals, it was stable within individuals throughout infancy. Metabolic composition and metabolic pathway abundance remained constant across time. A marked drop in alpha-diversity was observed in T1D progressors in the time window between seroconversion and T1D diagnosis, accompanied by spikes in inflammation-favoring organisms, gene functions, and serum and stool metabolites. This work identifies trends in the development of the human infant gut microbiome along with specific alterations that precede T1D onset and distinguish T1D progressors from nonprogressors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.chom.2015.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4689191PMC
February 2015

Low serum free thyroxine level in a girl with McCune-Albright syndrome.

BMJ Case Rep 2015 Jan 5;2015. Epub 2015 Jan 5.

Department of Pediatrics, University of Tartu, Tartu, Estonia Department of General Paediatrics, Children's Clinic of Tartu University Hospital, Tartu, Estonia.

A 17-year-old girl with McCune-Albright syndrome (MAS) was suspected of having central hypothyroidism based on an inappropriately normal thyroid-stimulating hormone (TSH) and low free thyroxine (fT4). She was clinically euthyroid and her pituitary appeared normal on MRI. Treatment of hypothyroidism with levothyroxine resulted in suppression of TSH with a low fT4 and high free triiodothyronine (fT3) concentration and hence iatrogenic hyperthyroidism was diagnosed. After discontinuation of levothyroxine, the TSH and fT3 normalised while fT4 remained low. Increased conversion of thyroxine (T4) to triiodothyronine (T3) can be part of MAS. Therefore, fT3 and fT4 should both be measured when evaluating thyroid function in patients with MAS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bcr-2014-206497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4289761PMC
January 2015

Th1/Th17 plasticity is a marker of advanced β cell autoimmunity and impaired glucose tolerance in humans.

J Immunol 2015 Jan 5;194(1):68-75. Epub 2014 Dec 5.

Children's Hospital, University of Helsinki and Helsinki University Central Hospital, 00281 Helsinki, Finland; Respiratory, Inflammatory and Autoimmune Diseases, Innovative Medicine, AstraZeneca, 43183 Mölndal, Sweden

Upregulation of IL-17 immunity and detrimental effects of IL-17 on human islets have been implicated in human type 1 diabetes. In animal models, the plasticity of Th1/Th17 cells contributes to the development of autoimmune diabetes. In this study, we demonstrate that the upregulation of the IL-17 pathway and Th1/Th17 plasticity in peripheral blood are markers of advanced β cell autoimmunity and impaired β cell function in human type 1 diabetes. Activated Th17 immunity was observed in the late stage of preclinical diabetes in children with β cell autoimmunity and impaired glucose tolerance, but not in children with early β cell autoimmunity. We found an increased ratio of IFN-γ/IL-17 expression in Th17 cells in children with advanced β cell autoimmunity, which correlated with HbA1c and plasma glucose concentrations in an oral glucose tolerance test, and thus impaired β cell function. Low expression of Helios was seen in Th17 cells, suggesting that Th1/Th17 cells are not converted thymus-derived regulatory T cells. Our results suggest that the development of Th1/Th17 plasticity may serve as a biomarker of disease progression from β cell autoantibody positivity to type 1 diabetes. These data in human type 1 diabetes emphasize the role of Th1/Th17 plasticity as a potential contributor to tissue destruction in autoimmune conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4049/jimmunol.1401653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4273995PMC
January 2015

The ease of falsifying blood glucose measurements.

Diabetes Res Clin Pract 2014 Jun 19;104(3):e57. Epub 2014 Mar 19.

Department of Pediatrics, University of Tartu, Estonia; Department of General Paediatrics, Children's Clinic of Tartu University Hospital, Tartu, Estonia.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.diabres.2014.03.006DOI Listing
June 2014

Coffin-Siris Syndrome with obesity, macrocephaly, hepatomegaly and hyperinsulinism caused by a mutation in the ARID1B gene.

Eur J Hum Genet 2014 Nov 26;22(11):1327-9. Epub 2014 Feb 26.

1] Department of Paediatrics, University of Tartu, Tartu, Estonia [2] United Laboratories, Department of Genetics, Tartu University Hospital, Tartu, Estonia.

Coffin-Siris Syndrome (CSS, MIM 135900) is a rare genetic disorder, and mutations in ARID1B were recently shown to cause CSS. In this study, we report a novel ARID1B mutation identified by whole-exome sequencing in a patient with clinical features of CSS. We identified a novel heterozygous frameshift mutation c.1584delG in exon 2 of ARID1B (NM_020732.3) predicting a premature stop codon p.(Leu528Phefs*65). Sanger sequencing confirmed the c.1584delG mutation as a de novo in the proband and that it was not present either in her parents, half-sister or half-brother. Clinically, the patient presented with extreme obesity, macrocephaly, hepatomegaly, hyperinsulinism and polycystic ovarian syndrome (PCOS), which have previously not been described in CSS patients. We suggest that obesity, macrocephaly, hepatomegaly and/or PCOS may be added to the list of clinical features of ARID1B mutations, but further clinical reports are required to make a definite conclusion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ejhg.2014.25DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4200437PMC
November 2014

Expression of B7 and CD28 family genes in newly diagnosed type 1 diabetes.

Hum Immunol 2013 Oct 31;74(10):1251-7. Epub 2013 Jul 31.

Department of Immunology, Institute of Biomedicine, University of Tartu, Ravila 19, Tartu 50411, Estonia; Centre for Translational Medicine, University of Tartu, Ravila 19, Tartu 50411, Estonia.

Type-1 diabetes (T1D) is caused by T-cell mediated autoimmune reaction directed against the insulin-secreting beta cells. We hypothesized that in addition to antigen/MHC recognition the co-stimulatory B7 and CD28 pathway is also strongly affected in T1D. CD80, CD86, CD28, CTLA4, ICOS and CD25 mRNA expression was characterized in 49 newly diagnosed young T1D patients (mean age 11 ± 5 years, 25 male/24 women) and 31 controls (mean age 14 ± 7 years, 14 male/17 women). In addition, polymorphisms in CTLA4 (rs231806, rs231775, rs3087243) were genotyped and soluble CTLA4 plasma levels measured by ELISA. T1D patients presented with higher peripheral blood expression levels of CD80 (Mann-Whitney U-test, p=0.0001) and lower ICOS levels compared to healthy controls (Glm adjusted for age, p=0.0004). CD80 expression in T1D patients correlated with expression of two CTLA4 splice variants (Spearman's rank correlation, rho=0.56, p=0.0002 for sCTLA4; rho=0.61, p<0.0001 for flCTLA4). In controls, CD80 expression correlated with CD25 expression (Spearman's rank correlation, rho=0.57, p=0.002). A strong correlation was observed between sCTLA4 and flCTLA4 (Spearman's rank correlation, rho=0.94, p<0.0001). We also found a tendency that the CTLA4 +49A/G polymorphism influenced sCTLA4 mRNA expression in T1D individuals and was lowest in individuals with the GG genotype (Mann-Whitney U-test, p=0.039). However, we could not identify associations between gene expression and plasma levels of sCTLA4. To summarize, we expect that newly diagnosed T1D among children and adolescents is associated with activation of CD80 and CTLA4 in peripheral blood. Additional studies will be needed to elucidate the role of CD80/CTLA4 signaling in T1D.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.humimm.2013.07.007DOI Listing
October 2013

MODY2 caused by a novel mutation of GCK gene.

J Pediatr Endocrinol Metab 2012 ;25(7-8):801-3

Faculty of Medicine, University of Tartu, Tartu, Estonia.

Maturity-onset diabetes of the young type 2 (MODY2) is an autosomal dominant inherited disease caused by heterozygous inactivating mutations in the glucokinase (GCK) gene and is characterized by mild noninsulin-dependent fasting hyperglycemia. It is treated with diet only, and complications are extremely rare. We present a report of a family with MODY2 caused by a novel NM_000162.3:c.878T>C mutation in exon 8 of the GCK gene. Testing for MODY2 and reporting all novel mutations are important to avoid difficulties in the interpretation of genetic test results and to provide fast and definitive diagnosis for all patients with this disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1515/jpem-2012-0137DOI Listing
January 2013

Birth weight in newborn infants with different diabetes-associated HLA genotypes in three neighbouring countries: Finland, Estonia and Russian Karelia.

Diabetes Metab Res Rev 2012 Jul 10;28(5):455-61. Epub 2012 Apr 10.

Department of Pediatrics, University of Tartu, Tartu, Estonia.

Background: Human leukocyte antigen (HLA) genotypes associated with increased risk for type 1 diabetes mellitus (T1D) have been reported to be associated with increased birth weight. We set out to investigate the association between HLA haplotypes conferring risk for T1D and birth weight and search for possible differences in the strength of these associations among populations with contrasting incidence of T1D.

Methods: As a part of the EU-funded DIABIMMUNE study, genotyping for the HLA haplotypes associated with T1D was performed in 8369 newborn infants from Estonia, Finland and Russian Karelia. Infants born before 35 gestational weeks, from mothers with diabetes, and multiple pregnancies were excluded. Relative birth weight, expressed in standard deviation scores, was estimated for each gestational week, sex and country. The standard deviation scores were calculated internally using the actual population studied. According to their HLA haplotypes, participants were divided into risk groups, and the distribution of birth weight between quartiles was analysed.

Results: We did not find any direct association between various HLA risk-associated genotypes (HLA DR3-DQ2/DR4-DQ8, DR3-DQ2/X or DR4-DQ8/X) and birth weight. We observed a significant relationship between increased relative birth weight and the protective HLA-DR2-DQ6 and DR13-DQ6 haplotypes. This association was significant only when these haplotypes were found together with the DR4-DQ8 haplotype.

Conclusions: The previously reported association between HLA-risk haplotypes for T1D and an increased birth weight was not confirmed. This suggests that the mechanisms behind the association between high birth weight and risk for T1D may be not directly HLA related.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/dmrr.2303DOI Listing
July 2012

Vehicle-associated closed trauma-induced stroke in a 27-day-old girl.

Medicina (Kaunas) 2010 ;46(9):624-7

Department of Neurology and Neurorehabilitation, Children's Clinic, Tartu University Hospital, Tartu, Estonia.

Birth trauma, but not postnatal trauma, has been recognized as a cause of cerebral infarction in newborns. We report a case of cerebral infarction in a 27-day-old girl after a car accident. During the car accident, the child was properly restrained to the child's safety seat. The patient was admitted to the hospital for observation because of pronounced irritability. There were no focal neurological symptoms on admission. Twenty-eight hours after the accident, the child developed focal tonic-clonic seizures and mild right-sided hemiparesis. The seizures were successfully treated with phenobarbital at a dose of 30 mg per day. Computed tomography and magnetic resonance imagining performed on the second and third days after the accident, respectively, showed subdural hemorrhage in the occipital regions and cerebral ischemia in the left parieto-occipital region. Control imaging 10 days later showed signs of reperfusion. Persistent child irritability after head trauma is one of the indicating factors for performing an emergency computed tomography scan of the head.
View Article and Find Full Text PDF

Download full-text PDF

Source
June 2011

Three-year follow-up of a girl with chronic paroxysmal hemicrania.

Pediatr Neurol 2009 Jan;40(1):68-9

Children's Clinic, Tartu University Hospital, Tartu, Estonia.

This is a follow-up report of a girl, 5 years 4 months old, with classic symptoms of chronic paroxysmal hemicrania from the age of 2 years 3 months who had a complete response to indomethacin therapy. The patient suffered from frequent episodes of severe unilateral headaches for 1 year and 10 months before the diagnosis of chronic paroxysmal hemicrania was established. Indomethacin treatment lasted for 2 years and 6 months. During the first year of treatment, several doses of indomethacin were missed, which was followed by immediate return of hemicrania episodes and then quick resolution of symptoms after administration of indomethacin. After 2 years and 6 months of treatment, the parents missed the treatment for 1 week and the episodes did not recur. The treatment was discontinued. The patient was free from pain and off the medication 1 year later.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pediatrneurol.2008.10.002DOI Listing
January 2009