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  • 1.
    Aittoniemi, J
    et al.
    Klin mikro Tampere, Finland.
    Turpeinen, H
    Virologen Turku, Finland.
    Tiitanen, M
    National Public Health Institute Helsinki, Finland.
    Knip, M
    Hospital for Children and Adolescents Helsinki, Finland.
    Simell, O
    Paediatrics Turku, Finland.
    Ilonen, J
    Virologen Turku, Finland.
    Vaarala, Outi
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics .
    Relation among mannose-binding lectin 2 genotype, β-cell autoantibodies, and risk for type 1 diabetes in Finnish children2008In: Human Immunology, ISSN 0198-8859, E-ISSN 1879-1166, Vol. 69, no 2, p. 108-111Article in journal (Refereed)
    Abstract [en]

    Mannose-binding lectin (MBL) is a key mediator of innate immunity, the insufficiency of which is caused by point mutations in the MBL2 gene. MBL insufficiency is associated with increased susceptibility to infections and certain autoimmune diseases, but its impact in the pathogenesis and risk of type 1 diabetes (T1D) is controversial. We investigated the significance of the MBL2 genotype on the risk of T1D in a Finnish study population comprising 470 diabetic children and 501 controls. Furthermore, the effect of MBL2 gene polymorphism on the emergence of β-cell autoantibodies in 289 unaffected children with human leukocyte antigen-conferred susceptibility to T1D was assessed. MBL genotype had no significant effect on the risk or onset age of T1D. However, children with the biallelic variant genotype reflecting total MBL deficiency tested positive more frequently for ≥3 autoantibodies compared with children with another genotype (odds ratio = 6.0, 95% confidence interval 1.3-28, p = 0.013). In conclusion, the MBL2 genotype did not affect susceptibility to T1D in children, and this finding does not support previous reports implicating a role of the MBL2 genotype as a factor predisposing to T1D. The association of the biallelic variant genotype with positivity for multiple autoantibodies suggests that intermolecular epitope spreading may be linked with impaired clearance of autoantigens as a result of MBL deficiency. © 2008 American Society for Histocompatibility and Immunogenetics.

  • 2.
    Akerblom, H.K.
    et al.
    Åkerblom, H.K., Biomedicum Helsinki Institute, B.P. 700, Haartmaninkatu 8, FIN-00029 HUS, Finland, Department of Pediatrics, University of Helsinki.
    Vaarala, Outi
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics.
    Hyoty, H.
    Hyöty, H., Department of Virology, University of Tampere, Finland.
    Ilonen, J.
    Institute of Microbiology and Pathology, University of Turku.
    Knip, M.
    Department of Pediatrics, University of Helsinki.
    Environmental factors in the etiology of type 1 diabetes2002In: American Journal of Medical Genetics, ISSN 0148-7299, E-ISSN 1096-8628, Vol. 115, no 1, p. 18-29Article, review/survey (Refereed)
    Abstract [en]

    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. © 2002 Wiley-Liss, Inc.

  • 3. Blomqvist, M
    et al.
    Juhela, S
    Erkkila, S
    Korhonen, S
    Simell, T
    Kupila, A
    Vaarala, Outi
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Barn.
    Simell, O
    Knip, M
    Ilonen, J
    Rotavirus infections and development of diabetes-associated autoantibodies during the first 2 years of life.2002In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 128, p. 511-515Article in journal (Refereed)
  • 4.
    Davydova, B.
    et al.
    Enterovirus Laboratory, Natl. Public Health Institute (KTL), Mannerheimintie 166, FIN-00300 Helsinki, Finland.
    Harkonen, T.
    Härkönen, T., Enterovirus Laboratory, Natl. Public Health Institute (KTL), Mannerheimintie 166, FIN-00300 Helsinki, Finland.
    Kaialainen, S.
    Enterovirus Laboratory, Natl. Public Health Institute (KTL), Mannerheimintie 166, FIN-00300 Helsinki, Finland.
    Hovi, T.
    Enterovirus Laboratory, Natl. Public Health Institute (KTL), Mannerheimintie 166, FIN-00300 Helsinki, Finland.
    Vaarala, Outi
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics .
    Roivainen, M.
    Enterovirus Laboratory, Natl. Public Health Institute (KTL), Mannerheimintie 166, FIN-00300 Helsinki, Finland.
    Coxsackievirus immunization delays onset of diabetes in non-obese diabetic mice2003In: Journal of Medical Virology, ISSN 0146-6615, E-ISSN 1096-9071, Vol. 69, no 4, p. 510-520Article in journal (Refereed)
    Abstract [en]

    Enteroviruses may be involved in the pathogenesis of Type 1 diabetes through different mechanisms including triggering of autoimmunity. The effect of immunization with coxsackievirus B4-E2 on diabetes incidence was studied in the non-obese diabetic mice, an animal model for human autoimmune insulin-dependent diabetes mellitus. The immunization delayed the onset of diabetes in the mice, and the effect was mediated at least partially by virus immunization-activated splenocytes as demonstrated by adoptive transfer experiments. Immunization resulted in a strong humoral immune response against the immunizing virus, formalin-inactivated coxsackievirus B4-E2. Cell-mediated immune responseto virus antigen was characterised by interferon gamma and interleukin 10 secretion. The immunization also resulted in increased antibody levels against several beta-cell autoantigens. By using epitope mapping we were able to show that in addition to reactivity with the known epitopes of viral proteins and tyrosine phosphatase A-2 or heat shock protein 60, responses to some other regions of autoantigens were enhanced. In preproinsulin, the response was restricted against an antigenic region earlier identified as DR4-dependent epitope. This reactivity can not be explained by homologous amino acid sequences and it is possible that enterovirus immunization might change the autoantigen specific TH1/TH2 balance in non-obese diabetic mice. In conclusion, our results suggest that coxsackievirus immunization increased humoral immune response to beta cell autoantigens and this was associated with a less destructive pathology for spontaneous diabetes in non-obese diabetic mice. © 2003 Wiley-Liss, Inc.

  • 5.
    Fagerås Böttcher, Malin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Hmani-Aifa, Mounira
    Linköping University, Department of Biomedicine and Surgery. Linköping University, Faculty of Health Sciences.
    Lindström Lundberg, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Jenmalm, Maria Christina
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Mai, Xiao-Mei
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Nilsson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Aniansson Zdolsek, Helena
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Björkstén, Bengt
    Centre for Allergy Research and Institute of Environmental Medicine, Karolinska Institute, Stockholm;.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Vaarala, Outi
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    A TLR4 polymorphism is associated with asthma and reduced lipopolysaccharide-induced interleukin-12(p70) responses in Swedish children2004In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 114, no 3, p. 561-567Article in journal (Refereed)
    Abstract [en]

    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-γ 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.

  • 6.
    Freese, Riita
    et al.
    Dept of Applied Chemistry and Microbiology Helsingfors Universitet, Finland.
    Vaarala, Outi
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Turpeinen, Anu
    Dept of Applied Chemistry and Microbiology Helsingfors Universitet, Finland.
    Mutanen, Marja
    Deptof Applied Chemistry and Microbiology Helsingfors Universitet, Finland.
    No difference in platelet activation or inflammation markers after diets rich or poor in vegetables, berries and apple in healthy subjects.2004In: European Journal of Nutrition, ISSN 1436-6207, E-ISSN 1436-6215, Vol. 43, p. 175-182Article in journal (Refereed)
  • 7.
    Gullstrand, Camilla
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Wahlberg Topp, Jeanette
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology and Gastroenterology UHL.
    Ilonen, Jorma
    Dept of Microbiology Kuopio, Finland.
    Vaarala, Outi
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Ludvigsson, Johnny
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Progression to type 1 diabetes and autoantibody positivity in relation to HLA-risk genotypes in children participating in the ABIS study2008In: Pediatric Diabetes, ISSN 1399-543X, E-ISSN 1399-5448, Vol. 9, no 3 PART 1, p. 182-190Article in journal (Refereed)
    Abstract [en]

    Background: Autoantibodies against beta-cell antigens together with human leukocyte antigen (HLA)-risk genotypes are used as predictive markers for type 1 diabetes (T1D). In this study, we have investigated the role of HLA-risk and -protective genotypes for development of beta-cell autoantibodies and progression to T1D in healthy children. Methods: T1D-related HLA genotypes and autoantibodies against glutamic acid decarboxylase [glutamic acid decarboxylase antibodies (GADA)] and islet antigen-2 (IA-2A) were studied at 1, 2.5 and 5 yr of age in unselected healthy children and children with T1D participating in the All Babies In Southeast Sweden (ABIS) study. Results: GADA or IA-2A positivity at 5 yr of age was associated with DR4-DQ8 haplotype and DR3-DQ2/DR4-DQ8 genotype. By the age of 6-7 yr, we identified 32 children with T1D among the 17 055 participants in the ABIS study. Eight of 2329 (0.3%) non-diabetic children had permanent autoantibodies, and 143 of 2329 (6%) children had transient autoantibodies. HLA-risk genotypes associated with T1D, whereas protective genotypes were seldom found in children with T1D. Children with permanent autoantibodies had more often risk-associated DR4-DQ8 haplotype than autoantibody-negative children. No associations with HLA-risk or -protective genotypes were found for transient autoantibodies. Conclusions: The strong relation between HLA-risk alleles and T1D once again confirmed that HLA-risk genotypes play an important role for development of T1D. However, HLA genotypes seem not to explain induction of autoantibodies, especially transient autoantibodies, in the general population, emphasizing the role of environmental factors in the initiation of autoimmunity. It seems that HLA-risk genotypes are responsible for maturation of the permanent autoantibody response. © 2008 The Authors Journal compilation © 2008 Blackwell Munksgaard.

  • 8. Halminen, M
    et al.
    Juhela, S
    Vaarala, Outi
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Barn.
    Simell, O
    Induction of interferon-gamma and IL-4 production by mitogen and specific antigens in peripheral blood lymphocytes of Type 1 diabetes patients.2001In: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 34Article in journal (Refereed)
  • 9. Harkonen, T
    et al.
    Paananen, A
    Lankinen, H
    Hovi, T
    Vaarala, Outi
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics .
    Roivainen, M
    Enterovirus infection may induce humoral immune response reacting with islet cell autoantigens in humans2003In: Journal of Medical Virology, ISSN 0146-6615, E-ISSN 1096-9071, Vol. 69, no 3, p. 426-440Article in journal (Refereed)
    Abstract [en]

    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.

  • 10.
    Holmberg, Hanna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Vaarala, Outi
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Fälth-Magnusson, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Induction of diabetes-related autoantibodies below cutoff for "positivity" in young nondiabetic children2003In: Annals of the New York Academy of Sciences, ISSN 0077-8923, Vol. 1005, p. 269-274Article in journal (Refereed)
    Abstract [en]

    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 GAD65 (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 β cell autoantigens early in life. Our results suggest that the mechanisms of β cell tolerance to GAD and IA-2 differ in healthy children.

  • 11.
    Holmberg, Hanna
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics .
    Vaarala, Outi
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics .
    Fälth-Magnusson, Karin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Ludvigsson, Johnny
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Induction of diabetes-related autoantibodies below cut-off for positivity in young non-diabetic children.2003In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 46, p. 317-Conference paper (Other academic)
  • 12.
    Holmberg, Hanna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Vaarala, Outi
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Sadauskaite-Kuehne, Vaiva
    Laboratory of Paediatric Endocrinology, Institute of Endocrinology, Kaunas University of Medicine, Kaunas, Lithuania.
    Ilonen, Jorma
    Department of Virology, University of Turku, Turku, Finland.
    Padaiga, Žilvinas
    Department of Public Health, Kaunas University of Medicine, Kaunas, Lithuania.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Higher prevalence of autoantibodies to insulin and GAD65 in Swedish compared to Lithuanian children with type 1 diabetes2006In: Diabetes Research & Clinical Practice, ISSN 0168-8227, Vol. 72, no 3, p. 308-314Article in journal (Refereed)
    Abstract [en]

    We compared the prevalence of beta-cell autoantibodies and genetic risk factors in Sweden and Lithuania. Ninety-six patients from Sweden and 96 from Lithuania matched for age and gender (1–15 years old, median age 9.0 years) were included. We analyzed autoantibodies to insulin (IAA), glutamic acid decarboxylase (GADA) and the protein tyrosine phosphatase like IA-2 (IA-2A) as well as risk-associated polymorphisms of HLA, insulin and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) genes.

    The frequency of patients positive for IAA and GADA was higher in Sweden than in Lithuania (p=0.043 and 0.032). The differences remained even when the patients were matched for HLA, insulin and CTLA-4 risk genotypes. Patients with low levels of IAA had higher levels of HbA1c and ketones at diagnosis. The frequency of the risk haplotype DR4-DQ8 was higher in Swedish than in Lithuanian patients (p=0.004), as well as the high-risk combination of DR4-DQ8 and DR3-DQ2 haplotypes (p=0.009).

    Our results suggest that autoimmune process against insulin and GAD65 is more common at diagnosis in children in areas with high incidence of type 1 diabetes (T1D), independent of genetic risk markers. Furthermore, the disease in patients with insulin autoantibodies seems to be clinically milder.

  • 13.
    Holmberg, Hanna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Wahlberg (Topp), Jeanette
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Vaarala, Outi
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Short duration of breast-feeding as a risk-factor for β-cell autoantibodies in 5-year-old children from the general population2007In: British Journal of Nutrition, ISSN 0007-1145, Vol. 97, no 1, p. 111-116Article in journal (Refereed)
    Abstract [en]

    Breast-feeding has been suggested to have a protective effect against the development of type 1 diabetes. In the present study, we investigated the relation between duration of breast-feeding and β-cell autoantibodies in 5-year-old non-diabetic children who participated in a prospective population-based follow-up study (the All Babies in Southeast Sweden study). Autoantibodies to insulin (IAA), glutamic acid decarboxylase (GADA) and the protein tyrosine phosphatase-like IA-2 (IA-2A) were measured by radiobinding assays. A short duration of total breast-feeding was associated with an increased risk of GADA and/or IAA above the ninety-fifth percentile at 5 years of age (OR 2-09, 95% CI 1-45, 3-02; P<0-000) as well as with an increased risk of IAA above the ninety-fifth percentile at this age (OR 2-89, 95% CI 1-81, 4-62; P<0-000). A short duration of exclusive breast-feeding was associated with an increased risk of GADA, IAA and/or IA-2A above the ninety-ninth percentile (OR 2-01, 95% CI 1-08, 3-73; P = 0-028) as well as with an increased risk of IA-2A above the ninety-ninth percentile (OR 3-50, 95% CI 1-38, 8-92; P = 0-009) at 5 years of age. An early introduction of formula was associated with an increased risk of GADA, IAA and/or IA-2A above the ninety-ninth percentile (OR 1-84, 95% CI 1-01, 3-37; P = 0-047) at 5 years of age. The positive association between a short duration of both total and exclusive breast-feeding, as well as an early introduction of formula, and positivity for β-cell autoantibodies in children from the general population suggests that breast-feeding modifies the risk of β-cell autoimmunity, even years after finishing breast-feeding.

  • 14.
    Honkanen, Jarno
    et al.
    Department of Viral Diseases and Immunology, National Public Health Institute, Helsinki, Finland.
    Skarsvik, Susanne
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Knip, Mikael
    Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland and Department of Paediatrics, Tampere University Hospital, Tampere, Finland.
    Vaarala, Outi
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Poor in vitro induction of FOXP3 and ICOS in type 1 cytokine environment activated T-cells from children with type 1 diabetes2008In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 24, no 8, p. 635-641Article in journal (Refereed)
    Abstract [en]

    Background

    Type 1 diabetes (T1D) is characterised by loss of tolerance to beta-cell antigens, and the insulin-producing beta-cells in the pancreatic islets are destroyed by the host's own immune system. Immunological risk factors associated with T1D are related to the defects in the polarization of T-cells and in the function of regulatory T (Treg)-cells. We set out to study whether an impaired induction of regulatory mechanisms during the generation of T-cell responses upon stimulation is associated with T1D.

    Methods

    Naive T-cells were isolated from 18 children with recent T1D (0–14days from diagnosis; mean age 9.3 years), 11 children who had had T1D for at least 1 year (mean age 10.6) and 14 non-diabetic children (mean age 8.1). CD45RA+ T-cells were stimulated with PHA for 72 h in type 1 cytokine [interleukin (IL)-12 and anti-IL-4] or type 2 cytokine (IL-4 and anti-IL-12) environment. T-cell polarization and regulation related markers were analysed by quantitative reverse transcription polymerase chain reaction (QRT-PCR) (Th1 promoting T-bet, Th2 promoting GATA-3 and regulation related FOXP3, ICOS and NFATc2).

    Results

    Children with recently diagnosed T1D showed decreased induction of FOXP3, ICOS and NFATc2 in T-cells activated in type 1 cytokine milieu (p = 0.007, p = 0.001, and p = 0.02), whereas no differences between the diabetic and healthy children were seen in the up-regulation of activation markers, T-bet and GATA-3.

    Conclusions

    The poor induction of factors that mediate down-modulation of T-cell responses upon stimulation in type 1 cytokine environment may contribute to the development of autoreactive type 1 responses in T1D.

  • 15.
    Jonson, Carl-Oscar
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Hedman, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Faresjö, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Casas, Rosaura
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Ilonen, Jorma
    JDRF Center for Prevention of Type 1 Diabetes in Finland and Department of Virology, University of Turku, Turku, Finland .
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Vaarala, Outi
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    CTLA-4 Polymorfism, Type 1 Diabetes-risk Human Leukocyte Antigen-genotypes, insulin gene polymorphism and Regulatory T-cell Marker Expression in 5-year-old children2006In: Clinical & Experimental Immunology, ISSN 0009-9104, Vol. 145, no 1, p. 48-55Article in journal (Refereed)
    Abstract [en]

    Regulatory T cells (Treg) are involved in the maintenance of peripheral tolerance by suppression of autoreactive lymphocytes that have avoided thymic depletion. The defective function of Treg cells has recently attracted attention in autoimmune diseases such as type 1 diabetes (T1D), rheumatoid arthritis and multiple sclerosis. Susceptibility to these diseases is associated with specific human leucocyte antigen (HLA) class II and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) gene polymorphisms. This study aimed to investigate the relationship between HLA class II and CTLA +49 A/G polymorphisms associated with susceptibility to T1D and the number and characteristics of Treg cells in children. Samples from 47 5-year-old children who participated in the All Babies in South-east Sweden (ABIS) follow-up study were grouped according to the presence of the T1D risk-associated HLA genotype (DQA1*0501–DQB1*0201, DQA1*0301–DQB1*0302) or neutral HLA genotypes. Lower percentages of CD4+ T cells (= 0·03) and CD4+ CD25high cells (= 0·06) expressing intracellular CTLA-4 were detected in samples from children with CTLA-4 +49GG compared to children with the +49AA genotype. Similarly, lower percentages of CD4+ (= 0·002) and CD4+ CD25high (= 0·002) cells expressing CTLA-4 were observed in children positive for HLA DQA1*0501–DQB1*0201 and DQA1*0301–DQB1*0302 (= 0·04 for CD4+ and P = 0·02 for CD4+ CD25high) risk haplotypes when compared to children without these alleles. The percentage of CD25high cells among CD4+ cells was correlated inversely with CTLA-4 mRNA expression in PBMC (r = –0·56, P = 0·03). Decreased levels of CTLA-4 in CD4+ and CD4+ CD25high cells in individuals with CTLA-4 and HLA class II alleles associated with T1D may contribute to the initiation and/or progression of autoimmune response.

  • 16.
    Karlsson Faresjö, Maria
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Vaarala, Outi
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Thuswaldner, Sophie
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Ilonen, Jorma
    JDRF Center for Prevention of Type 1 Diabetes in Finland and the Department of Virology, University of Turku, Turku, Finland.
    Hinkkanen, Ari
    Åbo Akademi, Turku University, Turku, Finland.
    Ludvigsson, Johnny
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Diminished IFN-γ response to diabetes-associated autoantigens in children at diagnosis and during follow up of type 1 diabetes2006In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 22, no 6, p. 462-470Article in journal (Refereed)
    Abstract [en]

    Background

    Imbalance of T-helper (Th)1- and Th2-like cytokines has been associated with type 1 diabetes. We therefore studied the immune deviation in antigen-specific T cells from diagnosis onwards in type 1 diabetic children.

    Methods

    Peripheral blood mononuclear cells (PBMC) were collected from 15 children after 4 days, 3 months and 18 months of being diagnosed with type 1 diabetes, from 15 healthy children matched by age and gender to the type 1 diabetic children and from 14 children with and 35 children without HLA-risk genes. Secretion of interferon-γ (IFN-γ) and interleukin-4 (IL-4) was detected by ELISPOT after stimulation with glutamic acid decarboxylase (GAD65, protein and aa 247–279), recombinant tyrosinphosphatase (IA-2), insulin, ovalbumin and phytohaemagglutinin (PHA).

    Results

    Secretion of IFN-γ in PBMC stimulated with GAD65 (p < 0.05), the GAD65-peptide (p < 0.01), IA-2 (p < 0.01), and insulin (p < 0.01) was lower in diabetic children at diagnosis than in healthy children. Stimulation of PBMC with GAD65 and IA-2 decreased the secretion of IFN-γ in children with HLA-risk genotype. Spontaneous and antigen-induced IFN-γ secretion increased significantly after diagnosis of the disease, but did not exceed the levels observed in healthy children. Fasting C-peptide levels at diagnosis correlated with insulin-induced IFN-γ (R = 0.52; p = 0.05) and negatively with spontaneous IL-4 secretion (R = −0.62; p < 0.05).

    Conclusion

    A diminished IFN-γ secretion and the association of fasting C-peptide levels with cytokine response in children with type 1 diabetes suggest that factors related to β-cell function in type 1 diabetes may modify T-cell function. Thus, the T-cell responses detected at or after diagnosis may not reflect the pathogenic process leading to type 1 diabetes.

  • 17. Karttunen, A
    et al.
    Pöyry, T
    Vaarala, Outi
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Barn.
    Ilonen, J
    Hovi, T
    Roivainen, M
    Hyypiä, T
    Variation in enterovirus receptor genes.2003In: Journal of Medical Virology, ISSN 0146-6615, E-ISSN 1096-9071, Vol. 70, p. 99-108Article in journal (Refereed)
  • 18. Kervinen, H
    et al.
    Huittinen, T
    Vaarala, Outi
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Barn.
    Leinonen, M
    Saikku, P
    Manninen, V
    Mänttäri, M
    Antibodies to human heat shock protein 60, hypertension and dyslipidemia. A study of joint effects on coronary risk.2003In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 169, p. 339-344Article in journal (Refereed)
  • 19. Kervinen, H
    et al.
    Palosuo, T
    Manninen, V
    Tenkanen, L
    Vaarala, Outi
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Barn.
    Manttari, M
    Joint effects of C-reactive protein and other risk factors on acute coronary events.2001In: American Heart Journal, ISSN 0002-8703, E-ISSN 1097-6744, Vol. 25, p. 131-141Article in journal (Refereed)
  • 20.
    Knip, Mikael
    et al.
    Finland .
    Veijola, Riitta
    Finland .
    Virtanen, Suvi
    Finland .
    Hyöty, Heikki
    Finland .
    Vaarala, Outi
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Åkerblom, Hans
    Finland .
    Environmental triggers and determinants of type 1 diabetes2005In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 54, no SUPPL. 2Article in journal (Refereed)
    Abstract [en]

    Type 1 diabetes is perceived as a chronic immune-mediated disease with a subclinical prodromal period characterized by selective loss of insulin-producing β-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. © 2005 by the American Diabetes Association.

  • 21. Korpinen, E
    et al.
    Groop, PH
    Fagerudd, JA
    Teppo, AM
    Akerblom, H
    Vaarala, Outi
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Barn.
    Increased secretion of TGF-beta1 by peripheral blood mononuclear cells from patients with Type 1 diabetes mellitus with diabetic nephropathy.2001In: Diabetic Medicine, ISSN 0742-3071, E-ISSN 1464-5491, Vol. 18, p. 121-125Article in journal (Refereed)
  • 22.
    Lahdenperä, Anne
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Fälth-Magnusson, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Högberg, Lotta
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Norrköping.
    Vaarala, Outi
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    The effect of gluten-free diet on Th1--Th2--Th3-associated intestinal immune responses in celiac disease2011In: SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY, ISSN 0036-5521, Vol. 46, no 5, p. 538-549Article in journal (Refereed)
    Abstract [en]

    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.

  • 23.
    Laine, Antti-Pekka
    et al.
    Immunogenetics Laboratory, University of Turku, Finland.
    Holmberg, Hanna
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Nilsson, Anita
    Department of Endocrinology and Paediatrics, University Hospital Malmö, University of Lund, Sweden.
    Örtqvist, Eva
    Astrid Lindgren’s Children Hospital, Karolinska Hospital, Stockholm, Sweden.
    Kiviniemi, Minna
    Immunogenetics Laboratory, University of Turku, Finland.
    Vaarala, Outi
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Department of Viral Diseases and Immunology, National Public Health Institute, Helsinki, Finland.
    Åkerblom, Hans K
    Hospital for Children and Adolescents, University of Helsinki, Finland.
    Simell, Olli
    Department of Paediatrics, University of Turku, Turku, Finland.
    Knip, Mikael
    Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland / Department of Pediatrics, Tampere University Hospital, Tampere, Finland.
    Ludvigsson, Johnny
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Ivarsson, Sten-A
    Department of Endocrinology and Paediatrics, University Hospital Malmö, University of Lund, Sweden.
    Larsson, Karin
    Department of Endocrinology and Paediatrics, University Hospital Malmö, University of Lund, Sweden.
    Lernmark, Åke
    Department of Endocrinology and Paediatrics, University Hospital Malmö, University of Lund, Sweden.
    Ilonen, Jorma
    Immunogenetics Laboratory, University of Turku, Finland / Department of Clinical Microbiology, University of Kuopio, Finland.
    Two insulin gene single nucleotide polymorphisms associated with type 1 diabetes risk in the Finnish and Swedish populations2007In: Disease Markers, ISSN 0278-0240, E-ISSN 1875-8630, Vol. 23, no 3, p. 139-45Article in journal (Refereed)
    Abstract [en]

    We have developed high-throughput tests for the detection of the insulin gene region SNPs -23HphI and -2221MspI. The potential of these markers to enhance the efficiency of type 1 diabetes risk screening was then evaluated by analyzing them in Finnish and Swedish populations. Blood spots on filter paper were analyzed using PCR followed by sequence-specific hybridization and time-resolved fluorometry reading. Distribution of the genotypes at both positions differed significantly among the affected children compared to the controls. The risk genotypes (CC, AA) were significantly more common in Finland than in Sweden, both among patients and controls. The VNTR genotype homozygous for the protective class III alleles showed a significantly stronger protective effect than the heterozygote (p=0.02). Analyzing both SNPs enabled the detection of VNTR class III subclasses IIIA and IIIB. The observed significance between effects of the protective genotypes was due to the strong protective effect of the IIIA/IIIA genotype. IIIA/IIIA was the only genotype with significant discrepancy between protective effects compared to the other class III genotypes. These observations suggest that heterogeneity between the protective IDDM2 lineages could exist, and analyzing both -23HphI and -2221MspI would thus potentially enhance the sensitivity and specificity of type 1 diabetes risk estimation.

  • 24.
    Ljungberg, Martin
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Korpela, Riita
    Valio Ltd, Helsinki, Finland.
    Ilonen, Jorma
    Department of Clinical Microbiology, University of Kuopio, Kuopio, Finland and Immunogenetics Laboratory, University of Turku, Turku, Finland.
    Ludvigsson, Johnny
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Vaarala, Outi
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Department of Viral Diseases and Immunology, National Public Health Institute, Helsinki, Finland.
    Probiotics for the Prevention of Beta Cell Autoimmunity in Children at Genetic Risk of Type 1 Diabetes—the PRODIA Study2006In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1079, p. 360-364Article in journal (Refereed)
    Abstract [en]

    The final aim of the PRODIA study is to determine whether the use of probiotics during the first 6 months of life decreases the appearance of type 1 diabetes mellitus (T1DM)-associated autoantibodies in children with genetic risk for T1DM. A pilot study including 200 subjects was planned to show whether the use of probiotics during the first 6 months of life is safe and feasible. The prevalence of autoantibodies among the study subjects at 6, 12, and 24 months of age was at levels close to the expected and the clinical follow-up did not either indicate problems in the feasibility of the study.

  • 25.
    Ljungberg, Martin
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Lindström, Anna
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Ilonen, Jorma
    Department of Clinical Microbiology, University ofKuopio, Kuopio and Immunogenetics Laboratory, University ofTurku, Turku, Finland.
    Korpela, Riitta
    Valio Ltd, Helsinki, Finland.
    Ludvigsson, Johnny
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Vaarala, Outi
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Department of Viral Diseases and Immunology, Laboratory for Immunobiology, National Public Health Institute, Helsinki, Finland.
    Probiotics modulate monocytes in infants at genetic risk of type 1 diabetesManuscript (preprint) (Other academic)
    Abstract [en]

    n/a

  • 26.
    Ludvigsson, Johnny
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Faresjö, Maria
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics .
    Hjorth, Maria
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics .
    Axelsson, Stina
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics .
    Chéramy, Mikael
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics .
    Pihl, Mikael
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics .
    Vaarala, Outi
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics .
    Forsander, Gun
    Ivarsson, Sten
    Johansson, Calle
    Lindh, Agne
    Nilsson, NO
    Åman, Jan
    Örtqvist, Eva
    Zerhouni, Peter
    Casas, Rosaura
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics .
    GAD treatment and insulin secretion in recent-onset type 1 diabetes2008In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 359, no 18, p. 1909-1920Article in journal (Refereed)
    Abstract [en]

    Background: The 65-kD isoform of glutamic acid decarboxylase (GAD) is a major autoantigen in patients with type 1 diabetes mellitus. This trial assessed the ability of alum-formulated GAD (GAD-alum) to reverse recent-onset type 1 diabetes in patients 10 to 18 years of age. Methods: We randomly assigned 70 patients with type 1 diabetes who had fasting C-peptide levels above 0.1 nmol per liter (0.3 ng per milliliter) and GAD autoantibodies, recruited within 18 months after receiving the diagnosis of diabetes, to receive subcutaneous injections of 20 μg of GAD-alum (35 patients) or placebo (alum alone, 35 patients) on study days 1 and 30. At day 1 and months 3, 9, 15, 21, and 30, patients underwent a mixed-meal tolerance test to stimulate residual insulin secretion (measured as the C-peptide level). The effect of GAD-alum on the immune system was also studied. Results: Insulin secretion gradually decreased in both study groups. The study treatment had no significant effect on change in fasting C-peptide level after 15 months (the primary end point). Fasting C-peptide levels declined from baseline levels significantly less over 30 months in the GAD-alum group than in the placebo group (-0.21 vs. -0.27 nmol per liter [-0.62 vs. -0.81 ng per milliliter], P = 0.045), as did stimulated secretion measured as the area under the curve (-0.72 vs. -1.02 nmol per liter per 2 hours [-2.20 vs. -3.08 ng per milliliter per 2 hours], P = 0.04). No protective effect was seen in patients treated 6 months or more after receiving the diagnosis. Adverse events appeared to be mild and similar in frequency between the two groups. The GAD-alum treatment induced a GAD-specific immune response. Conclusions: GAD-alum may contribute to the preservation of residual insulin secretion in patients with recent-onset type 1 diabetes, although it did not change the insulin requirement. (ClinicalTrials.gov number, NCT00435981.) Copyright © 2008 Massachusetts Medical Society. All rights reserved.

  • 27.
    Ludvigsson, Jonas
    et al.
    Dept of Pediatrics, Örebro hospital.
    Eylert, Maike
    Clinical Epidemiology Unit, Dept of Medicine, KS, Stockholm.
    Ilonen, Jorma
    Dept of Virology, Turku, Finland.
    Ludvigsson, Johnny
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Vaarala, Outi
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Effect of HLA DQ2, dietary exposure and coeliac disease on the development of antibody response to gliadin in children2006In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 41, no 8, p. 919-928Article in journal (Refereed)
    Abstract [en]

    Objective. To study the effect of HLA DQ2, dietary history and development of coeliac disease (CD) on the induction of antibody response to wheat gliadin and cow's milk, beta-lactoglobulin between 1 and 2.5 years of age in children who developed CD and in healthy children. Material and methods. Infants participating in a birth cohort study (the ABIS study) in Sweden were studied. Thirty-nine children developed CD (=cases), confirmed through biopsy, during follow-up until 2.5-5 years of age. A total of 181 healthy control children were matched for duration of exclusive breast-feeding, birth-weight, gender, maternal smoking and season of birth. IgG and IgA antigliadin and anti-beta-lactoglobulin antibodies were measured using enzyme immunoassay (EIA). The effects of HLA-risk genotypes, DQ2 and DQ8, on CD were also considered. Results. Children who developed CD had higher IgG and IgA antigliadin and anti-beta-lactoglobulin antibody levels at 1 year of age than controls (all comparisons: p <0.001). Similar differences were seen between cases with as yet undiagnosed CD by 1 year of age and controls, and also when cases were compared with HLA-matched controls. Higher levels of IgG and IgA antibodies to beta-lactoglobulin (p = 0.003, p = 0.001), but not to gliadin, were found in treated cases versus controls at 2.5 years of age. HLA-DQ2-positive healthy children had lower levels of IgG and IgA antigliadin antibodies than HLA-DQ2 negative controls at 1 year of age (p = 0.004, p = 0.012). Conclusions. Enhanced humoral response emerging not only to gliadin, but also to other food antigens seems to be primarily associated with CD. Poor induction of antibody response to wheat gliadin in healthy children with the HLA-DQ2 risk molecule could at least partly explain the genetic predisposition to gluten intolerance and CD. © 2006 Taylor & Francis.

  • 28.
    Lundberg, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Andersson Wikberg, Lars
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Ilonen, Jorma
    Immunogenetics Laboratory, University of Turku, Turku, Finland.
    Vaarala, Outi
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Böttcher (Fagerås), Malin
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Lipopolysaccharide-Induced Immune Responses in Relation to the TLR4(Asp299Gly) Gene Polymorphism2008In: Clinical and Vaccine Immunology, ISSN 1556-6811, E-ISSN 1556-679X, Vol. 15, no 12, p. 1878-1883Article in journal (Refereed)
    Abstract [en]

    Altered microbial exposure is a possible explanation for the increase of allergies in the Western world. However, genetic factors influence microbially induced immune responses. We have investigated the TLR4(Asp299Gly) gene polymorphism and its possible association with receptor expression of circulating peripheral blood monocytes and the in vitro cytokine responses and phosphorylation of intracellular signaling proteins in peripheral blood mononuclear cells (PBMC) stimulated with lipopolysaccharide (LPS) from Escherichia coli and Salmonella enterica serotype Typhimurium. We studied 34 of the predominant haplotype TLR4 Asp299 (AA) and 8 heterozygote Asp299Gly (AG) individuals. TLR4 expression levels were similar in the two genotype groups. Serovar Typhimurium LPS induced interleukin-12p70 from PBMC, and the degree of phosphorylation of the intracellular signaling protein I kappa B alpha in PBMC was lower in the AG than the AA group (P = 0.03 and P = 0.04, respectively). These results were not seen, however, when PMBC were stimulated with E. coli-derived LPS. Based on these results, we propose that TLR4(Asp299Gly) gene polymorphism and the bacterial origin of LPS should be considered when environmental LPS exposure is evaluated in disease risk or protection.

  • 29.
    Luopajärvi, Kristiina
    et al.
    Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland.
    Skarsvik, Susanne
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Ilonen, Jorma
    Turku Immunology Centre and Department of Virology, University of Turku, Turku, Finland.
    Åkerblom, Hans K.
    Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland.
    Vaarala, Outi
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Reduced expression of CCR4 on cord blood T lymphocytes in neonates at genetic risk of type 1 diabetesManuscript (preprint) (Other academic)
    Abstract [en]

    In type 1 diabetes the T cell polarization and expression of chemokine receptors have been reported to be aberrant. We asked whether these aberrancies are present already at birth in neonates carrying HLA risk haplotypes for type 1 diabetes.

    Cord blood (CB) samples were obtained from neonates taking part in the Trial to Reduce IDDM in Genetically at Risk (TRIGR) and the Finnish Dietary Intervention Trial for Prevention of Type 1 Diabetes (FINDIA) studies and were screened for type 1 diabetes-associated HLA risk genotypes (HLA DR3-DQ2 and/or DR4-DQ8 without protective alleles). CB lymphocytes were stimulated with phytohemagglutinin (PHA) in type 1 (IL-12, anti-IL4) or type 2 (IL-4, anti-IL12) cytokine environment for 6 days. The expression of chemokine- and cytokine receptors on T cells was determined by flow cytometry, cytokines were analyzed with ELISA, and transcription factors were analyzed using real-time RT-PCR.

    When compared to the control group, neonates carrying alleles DQ2/DQ8 or DQ8 showed reduced percentage of CD4 T cells expressing CCR4 and lower levels of CCR4 mRNA after culture of CB lymphocytes in type 2 cytokine environment. In addition, these neonates had significantly lower secretion of iL-13 and expression of GATA-3 after culture of CB lymphocytes in type 2 cytok:ine environment in comparison to neonates with no increased genetic risk of type 1 diabetes.

    These results suggest aberrancies in the in vitro regulation of type 2 immune responses in children with increased genetic risk of type 1 diabetes when compared to neonates without HLA risk haplotypes suggesting that the HLA genotype may affect the T cell polarization already at birth. Aberrant induction ofT cell polarization may contribute to development of autoimmunity later in life.

  • 30.
    Luopajärvi, Kristiina
    et al.
    Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland.
    Skarsvik, Susanne
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Ilonen, Jorma
    Department of Clinical Microbiology, University of Kuopio, Kuopio and Immunogenetics Laboratory, University of Turku, Turku, Finland.
    Åkerblom, Hans
    Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland.
    Vaarala, Outi
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Reduced CCR4, interleukin-13 and GATA-3 up-regulation in response to type 2 cytokines of cord blood T lymphocytes in infants at genetic risk of type 1 diabetes2007In: Immunology, ISSN 0019-2805, E-ISSN 1365-2567, Vol. 121, no 2, p. 189-196Article in journal (Refereed)
    Abstract [en]

    Aberrancies in T-cell polarization including expression of chemokine receptors have been reported in human leucocyte antigen (HLA) class II associated autoimmune diseases, such as type 1 diabetes (T1D) and rheumatoid arthritis. We asked whether these aberrancies are present at birth in newborn infants carrying the HLA risk haplotypes for T1D. Sixty-seven cord blood (CB) samples from infants were screened for T1D-associated HLA risk genotypes (HLA-DR4-DQ8 and/or DR3-DQ2 without protective alleles). CB lymphocytes were stimulated with phytohaemagglutinin in type 1 (interleukin (IL)-12, anti-IL4) or type 2 (IL-4, anti-IL12) cytokine environment for 6 days. The expression of chemokine and cytokine receptors on T cells was determined by flow cytometry, secretion of cytokines was analysed with enzyme-linked immunosorbent assay, and transcription factors were analysed using real-time reverse transcriptase–polymerase chain reaction. After culture of CB lymphocytes in type 2 cytokine environment newborn infants carrying DR4-DQ8 haplotype (n = 18) showed reduced percentage of CD4 T cells expressing CCR4 (P = 0·009) and the level of CCR4 mRNA was decreased (P = 0·008). In addition, lower secretion of IL-13 and expression of GATA-3 in CB lymphocytes cultured in type 2 cytokine environment were found in the infants with DR4-DQ8 haplotype (P = 0·020 and P = 0·004, respectively) in comparison to newborn infants without DR4-DQ8 and DR3-DQ2 haplotypes (n = 37). Poor in vitro induction of type 2 immune responses in newborn infants with DR4-DQ8 haplotype suggests that the HLA genotype associated with risk of autoimmunity may affect the T cell polarization already at birth, which in turn may contribute to the risk for autoimmunity later in life.

  • 31.
    Marschan, E
    et al.
    University of Helsinki .
    Honkanen, J
    University of Helsinki .
    Kukkonen, K
    University of Helsinki .
    Kuitunen, M
    University of Helsinki .
    Savilahti, E
    University of Helsinki .
    Vaarala, Outi
    University of Helsinki .
    Increased activation of GATA-3, IL-2 and IL-5 of cord blood mononuclear cells in infants with igE sensitization2008In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 19, no 2, p. 132-139Article in journal (Refereed)
    Abstract [en]

    Risk of allergic diseases has been linked to abnormal patterns of fetal immune development, suggesting that priming of the immune system may occur in utero. The aim of the study was to investigate whether the pattern of immune response in cord blood mononuclear cells (CBMC) shows association with allergic diseases and IgE sensitization at 2 yr of age, and to study the effect of maternal probiotic supplementation on CBMC immune responses. CBMC were isolated from 98 neonates in a randomized double-blinded intervention study. CBMC were stimulated with beta-lactoglobulin, and phytohemaglutinin (PHA). Secretion of interferon-gamma (IFN-γ), interleukin-5 (IL-5), and IL-13 was measured by an ELISA; IL-2, IL-4, and IL-10 by a cytokine bead assay. T-cell polarization-associated IL-4 receptor and IL-12R expressions, and the respective transcription factors GATA-3 and T-bet were analyzed with RT-PCR. The above responses were compared with the development of allergic diseases and IgE sensitization at 2 yr of age, and with the maternal probiotic or placebo supplementation. PHA-stimulated GATA-3 expression and IL-2 secretion in CBMC were higher in IgE-sensitized children at an age of 2 yr than in the non-sensitized, non-allergic children (p = 0.03 and 0.026). PHA-induced expression of GATA-3 correlated with IL-5 (p = 0.003, r = 0.300) and IL-13 (p = 0.007, r = 0.278) secretion of CBMC, and IL-5 secretion of β-lactoglobulin-stimulated CBMC was higher in IgE-sensitized children at 2 yr of age than in the non-sensitized, non-allergic children (p = 0.013). Probiotic bacteria had no effect on CBMC immune responses. In CBMC-enhanced induction of GATA-3, which activates several Th2 cytokines genes, was a risk factor for IgE sensitization. The immune deviation towards Th2-type immunity developed already in utero and seemed to modulate the pattern of immune response favoring an IgE response to environmental antigens.

  • 32. Marttila, J
    et al.
    Juhela, S
    Vaarala, Outi
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Barn.
    Hyöty, H
    Roivainen, M
    Hinkkanen, A
    Vilja, P
    Simell, O
    Ilonen, J
    Responses of coxsackievirus B4-specific T-cell lines to 2C protein- characterization of epitopes with special reference to the GAD65 homology region2001In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 284, p. 131-141Article in journal (Refereed)
  • 33.
    Mäkelä, Miia
    et al.
    Immunogenetics Lab, University of Turku, Finland.
    Vaarala, Outi
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Hermann, Robert
    Immunogenomics Lab, Cell Screen Applied Biomedi cal Res Center, Budapest. Hungary.
    Salminen, Kimmo
    Dept of Virology, Turku, Finland.
    Vahlberg, Tero
    Dept of Biostatistics University of Turku, Finland.
    Veijola, Riita
    Dept of Pediatrics, University of Oulu, Finland.
    Hyöty, Heikki
    Dept of Virology, University of Tampere, Finland.
    Knip, Mikael
    Hospital for Children and Adolescents, University of Helsinki, Finland.
    Simell, Olli
    Immunogenetics Lab, University of Turku, Finland.
    Ilonen, Jorma
    Dept of Clin Microbiology, University of Kuopio, Finland.
    Enteral virus infections in early childhood and an enhanced type 1 diabetes-associated antibody response to dietary insulin2006In: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 27, no 1, p. 54-61Article in journal (Refereed)
    Abstract [en]

    Enteral virus infections may trigger the development of β-cell-specific autoimmunity by interacting with the gut-associated lymphoid system. We analyzed the effect of three different virus infections on immunization to dietary insulin in children carrying increased genetic risk for type 1 diabetes. Forty-six of 238 children developed multiple diabetes-associated autoantibodies and 31 clinical diabetes (median follow-up time 75 months). Insulin-binding antibodies were measured with EIA method (median follow-up time 24 months). Antibodies to enteroviruses, rotavirus and adenovirus were measured with EIA in samples drawn at birth and the ages of 3 and 6 months. Nineteen enterovirus, 14 rotavirus and 8 adenovirus infections were diagnosed. At the ages of 6, 12, and 18 months, the concentrations of insulin-binding antibodies were higher in children with postnatal entero-, rota- and/or adenovirus infections than in children without these infections. Children who subsequently developed ICA or IA-2 antibodies or clinical type 1 diabetes had higher concentrations of insulin-binding antibodies than children who remained autoantibody negative. Our data suggest that enteral virus infections can enhance immune response to insulin, induced primarily by bovine insulin in cow's milk. An enhanced antibody response to dietary insulin preceded the development of β-cell specific autoimmunity and type 1 diabetes. © 2006 Elsevier Ltd. All rights reserved.

  • 34.
    Niers, L.E.M.
    et al.
    Center for Pediatric Allergology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Lundlaan 6, 3508 AB Utrecht, Netherlands.
    Rijkers, G.T.
    Center for Pediatric Allergology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Lundlaan 6, 3508 AB Utrecht, Netherlands.
    Timmerman, H.M.
    Center for Pediatric Allergology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Lundlaan 6, 3508 AB Utrecht, Netherlands.
    Knol, E.F.
    Center for Pediatric Allergology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Lundlaan 6, 3508 AB Utrecht, Netherlands.
    Hoekstra, M.O.
    Center for Pediatric Allergology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Lundlaan 6, 3508 AB Utrecht, Netherlands.
    Pohjavuori, E.
    Hosp. for Children and Adolescents, University of Helsinki, Haartmaninkatu 8, FIN-00029, Helsinki, Finland.
    Viljanen, M.
    Skin and Allergy Hospital, Helsinki, Finland.
    Korpela, R.
    Inst. of Biomedicine, Pharmacology, University of Helsinki, Helsinki, Finland, Valio Research and Development, Helsinki, Finland.
    Kuitunen, M.
    Skin and Allergy Hospital, Helsinki, Finland.
    Tiittanen, M.
    Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland.
    Vaarala, Outi
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics .
    Savilahti, E.
    Hosp. for Children and Adolescents, University of Helsinki, Haartmaninkatu 8, FIN-00029, Helsinki, Finland.
    Probiotics for cow's milk allergy: Classification after intervention2005Other (Other academic)
    Abstract [en]

    [No abstract available]

  • 35.
    Nissinen, R
    et al.
    Dept of Molecular Medicine Helsinki, Finland.
    Leirisalo-Repo, M
    Dept of Medicine Helsinki, Finland.
    Halme, L
    Dept of Surgery Helsinki, Finland.
    Färkkilä, M
    Dept of Medicine Helsinki, Finland.
    Vaarala, Outi
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Immune activation in the small intestine in patients with rheumatoid arthritis2004In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 63, no 10, p. 1327-1330Article in journal (Refereed)
    Abstract [en]

    Objectives: To determine whether inflammation in the gut associated immune system is activated in rheumatoid arthritis (RA). The expression of chemokine receptor- (CCR4, CCR5) and cytokine- (interleukin (IL)2, IL10, interferon γ (IFNγ), tumour necrosis factor α (TNFα), and transforming growth factor β (TGFβ)) specific mRNA in intestinal biopsy samples from patients with RA was examined. Methods: Duodenal biopsy samples from 13 patients with RA and 15 control subjects were studied. The mRNA expression of CCR4, CCR5, IL2, IL10, IFNγ, TNFα, and TGFβ in intestinal biopsy samples was demonstrated by real time quantitative reverse transcriptase-polymerase chain reaction. Results: The mRNA expression of CCR4, CCR5, and IL10 in intestinal biopsy samples was increased in patients with RA in comparison with control subjects (p = 0.001, p = 0.046, p = 0.019). No difference in the expression levels of IL2, IFNγ, TNFα, or TGFβ was seen between patients with RA and controls. Conclusions: The increased intestinal mRNA expression of IL10, CCR5, and CCR4 suggests that gut associated immune cells are activated in patients with RA.

  • 36.
    Nissinen, R
    et al.
    Dept of Mol Med National Publ Health, Helsingfors, Finland.
    Leirisalo-Repo, M
    Dept of Medicine, Div of Rheumatol Central Hospital, Helsingfors, Finland.
    Peltomaa, R
    Dept of MEdicine, Div of Rheumatol Central Hospital, Helsingfors, Finland.
    Palosuo, T
    Dept of Health and Functional Capacity National Public Health Inst, Helsingfors, Finland.
    Vaarala, Outi
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Cytokine and chemokine receptor profile of peripheral blood mononuclear cells during treatment with infliximab in patients with active rheumatoid arthritis2004In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 63, no 6, p. 681-687Article in journal (Refereed)
    Abstract [en]

    Objectives: To analyse immunological changes during treatment with a monoclonal anti-tumour necrosis factor α (TNFα) antibody, infliximab, in patients with rheumatoid arthritis (RA). Methods: 25 patients with RA and 5 patients with other arthritides were studied during the first 6 weeks of treatment with infliximab. At the start of treatment and after 2 and 6 weeks, spontaneous expression of CCR3 and CCR5 on peripheral blood T cells and monocytes was studied by flow cytometry. The secretion and mRNA expression of interferon γ (IFNγ), interleukin (IL)4, IL5, and TNFα from phytohaemagglutinin (PHA) stimulated peripheral blood mononuclear cells was measured with an ELISA and RT-PCR. Plasma levels of C reactive protein, serum amyloid protein A, rheumatoid factor, and antibodies to filaggrin and citrullinated cyclic peptide were measured with an ELISA. Results: The number of CD4 T cells and CD14 monocytes expressing CCR3 (p = 0.013, p = 0.009, respectively) and CD8 T cells expressing CCR5 (p = 0.040) as well as PHA stimulated secretion of IL4 and IFNγ (p<0.05) increased during treatment in patients with RA. 15 (60%) patients with RA achieved clinical response (at least ACR20) during the first 2 weeks. The number of T cells expressing CCR3 and CCR5 was higher before treatment in non-responders than in responders (p<0.05). The number of T cells increased in responders. Conclusion: Increase in secretion of Th1 and Th2 cytokines together with induced expression of chemokine receptors on T cells and monocytes suggest restoration of peripheral cell mediated immunity and blockade of the accumulation of inflammatory cells in joints as response to treatment.

  • 37. Nissinen, R
    et al.
    Leirisalo-Repo, M
    Tiittanen, M
    Julkunen, H
    Hirvonen, H
    Palosuo, T
    Vaarala, Outi
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Barn.
    CCR3, CCR5, IL-4 and IFN-gamma expression on synovial and peripheral T-cells and monocytes in patients with rheumatoid arthritis.2003In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 30, p. 1928-1934Article in journal (Refereed)
  • 38. Paajanen, L
    et al.
    Kokkonen, J
    Karttunen, TJ
    Tuure, T
    Korpela, R
    Vaarala, Outi
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Intestinal cytokine mRNA expression in delayed-type cow's milk allergy2006In: Journal of Pediatric Gastroenterology and Nutrition - JPGN, ISSN 0277-2116, E-ISSN 1536-4801, Vol. 43, no 4, p. 470-476Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: The aim of the study was to investigate the characteristics of intestinal immune activation (ie, a chemokine receptor and cytokine expression profile) in delayed-type cow's milk allergy (CMA) appearing in the form of gastrointestinal symptoms. PATIENTS AND METHODS: In all biopsy samples taken from the duodenum and/or the terminal ileum, 30 were studied for the expression of interferon-gamma, transforming growth factor-beta, chemokine receptor (CCR)-4, CCR-5, IL-2, IL-6, IL-10, IL-12p35, IL-12p40 and IL-18 specific mRNA by real-time quantitative reverse transcriptase-polymerase chain reaction in 26 children ages 3 to 15 years: 10 with untreated delayed-type CMA, 6 with celiac disease (CD) and 10 controls. RESULTS: The children with delayed-type CMA showed lower IL-2 and IL-18 mRNA expression in the duodenum (both P = 0.055) and higher CCR-4 and IL-6 mRNA expression in the terminal ileum (P = 0.055, P = 0.016) compared with the controls. The children with CD exhibited slightly higher expression of interferon-gamma and CCR-4 mRNA (P = 0.054, P = 0.053) and lower expression of IL-18 mRNA (P = 0.004) in the duodenal samples compared with the controls. The mRNA expression levels of regulatory cytokines, transforming growth factor-beta and IL-10 remained similar in all 3 groups. CONCLUSIONS: The children with delayed-type gastrointestinal CMA showed a unique pattern of local intestinal hypersensitivity with Th2 response-related characteristics, a profile differing clearly from the children with CD. © 2006 Lippincott Williams & Wilkins, Inc.

  • 39. Paajanen, L
    et al.
    Tuure, T
    Vaarala, Outi
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics .
    Korpela, R
    Homogenization of milk has no effect on milk-specific antibodies in healthy adults2005In: Milchwissenschaft, ISSN 0026-3788, Vol. 60, no 3, p. 239-241Article in journal (Refereed)
    Abstract [en]

    It has been claimed that some consumers tolerate unhomogenized cow's milk better than homogenized cow's milk. The aim of this study was to compare the effect of homogenized and unhomogenized milk on the production of specific antibodies against cow's milk proteins (casein, beta-lactoglobulin) and bovine insulin. Thirty-six milk-tolerant volunteers were challenged with homogenized and unhomogenized cow's milk for 28 days in a randomized, open, cross-over study (>400 ml of milk daily). From serum samples taken at baseline and at the end of both milk challenges IgG and IgA were measured by ELISA against casein, beta-lactoglobulin and bovine insulin, and IgE against casein. The antibody production of the subjects remained constant for over 2 months, with no differences between the challenges with homogenized and unhomogenized milk. Inter-individual variation was greater than the intra-individual variation or the variation between the milk challenges. The order of the milk challenges did not affect the results. In conclusion, there seems to be no difference in the immunological responses to homogenized and unhomogenized milk in healthy adults with a good tolerance of milk.

  • 40.
    Paajanen, Laura
    et al.
    Foundation for Nutrition Research, Finland .
    Vaarala, Outi
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Karttunen, Riitta
    Dept of Pediatrics and Medical Microbiology, Oulu Finland .
    Tuure, Tuula
    Valio Ltd, Finland.
    Korpela, Riitta
    Valio Ltd, Finland .
    Kokkonen, Jorma
    Dept of Pediatrics and Medical Microbiology, Oulu, Finland .
    Increased IFN-γ secretion from duodenal biopsy samples in delayed-type cow's milk allergy2005In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 16, no 5, p. 439-444Article in journal (Refereed)
    Abstract [en]

    A delayed and local gastrointestinal hypersensitivity to cow's milk (CM) protein is difficult to diagnose and there are limited data on this disorder. The aim of this study was to investigate local intestinal cytokine secretion in the upper small intestine in children with delayed-type cow's milk allergy (CMA). Duodenal biopsy samples from 31 children with delayed CMA, 14 with celiac disease (CD), and 14 healthy controls were studied for the spontaneous release of IFN-γ, TNF-α, IL-2, IL-4, IL-5, and IL-10, measured by cytometric bead array, and of TGF-β and IL-6 measured by ELISA. The children with delayed CMA secreted more IFN-γ than the controls (p = 0.006) and the children with CD (p = 0.006). The children with CD secreted more IL-6 compared to the controls (p = 0.008) and the children with delayed CMA (p = 0.002). The children with delayed CMA who had continuously been exposed to CM secreted less TGF-β than the children with delayed CMA who avoided CM (p = 0.050), and showed a tendency towards lower secretion compared to the controls (p = 0.078). Secretions of TNF-α, IL-2, IL-4, IL-5, and IL-10 were low in general, however, the children with delayed CMA who did not avoid CM secreted more IL-4 and IL-10 than the controls (p = 0.016, 0.059). In conclusion, the children with delayed CMA showed up-regulation of IFN-γ. Interestingly, TGF-β secretion was up-regulated in those children with delayed CMA who avoided CM suggesting recovery of regulation mechanisms. © 2005 Blackwell Munksgaard.

  • 41.
    Paananen, A
    et al.
    Finland.
    Savolainen-Kopra, C
    Finland.
    Kaijalainen, S
    Finland.
    Vaarala, Outi
    National Public Health Institute, Helsinki.
    Hovi, T
    Finland.
    Roivainen, M
    Finland.
    Genetic and phenotypic diversity of echovirus 30 strains and pathogenesis of type 1 diabetes2007In: Journal of Medical Virology, ISSN 0146-6615, E-ISSN 1096-9071, Vol. 79, no 7, p. 945-955Article in journal (Refereed)
    Abstract [en]

      Several enterovirus serotypes should be considered as potentially diabetogenic. The capacity of an enterovirus to kill or impair the functions of human -cells can vary among the strains within a given serotype as shown previously for echovirus 9 and 30 (E-30). The evolution of E-30 has also shown patterns correlating with the global increase of type 1 diabetes incidence. In the present study, antigenic properties of a set of E-30 isolates were investigated and the results correlated with the previously documented -cell destructive phenotype of the strains, or to genetic clustering of the strains. No simple correlation between the three properties was observed. A full-length infectious clone was constructed and sequenced from one of the isolates found to be most destructive to -cells (E-30/14916net87). Phylogenetic analyses demonstrated that this strain was closely related to the E-30 prototype strain at the capsid coding region while outside the capsid region prototype strains of several other human enterovirus B serotypes clustered more closely. This suggests that the relatively greater pathogenicity of the strain might be based on properties of the genome outside of the structural protein coding region. Neutralizing antibody assays on sera from 100 type 1 diabetic patients and 100 controls using three different E-30 strains did not reveal differences between the groups. This finding does not support a previous proposition of aberrant antibody responses to E-30 in diabetic patients. It is concluded that identification of the genetic counterparts of pathogenicity of E-30 strains requires further studies.

  • 42.
    Pajanen, Laura
    et al.
    Finland .
    Korpela, Riita
    Finland .
    Tuuren, Tuulua
    Finland .
    Honkanen, Jarno
    Finland .
    Järvelä, Irma
    Finland .
    Ilonen, Jorma
    Finland .
    Knip, Mikael
    Finland .
    Vaarala, Outi
    Finland .
    Kokkonen, Jorma
    Finland .
    Cow milk is not responsible for most gastrointestinal immune-like syndromes - evidence from a population-based study.2005In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 82, no 6, p. 1327-1335Article in journal (Refereed)
    Abstract [en]

    Background: Gastrointestinal hypersensitivity to cow milk (CM) may be more common among school-aged children and young adults than previously thought.

    Objective: The objective was to study various gastrointestinal complaints and the immunologic mechanisms associated with food-related, especially CM-related, gastrointestinal disorders in young adults.

    Design: Of 827 subjects aged 16–21 y who completed a questionnaire on food-related gastrointestinal symptoms, 49 symptomatic subjects agreed to a clinical examination, including an interview, blood tests, a lactose-maldigestion test, a blinded CM challenge and, in severely symptomatic subjects (n = 12), an endoscopic examination. Twenty-nine subjects served as controls.

    Results: Approximately 10% of the subjects reported having major gastrointestinal symptoms, mainly food-related (n = 70 of 86), during the preceding year. Specific organic disease was found in 2 symptomatic subjects: 1 case of celiac disease and 1 of colitis. The result of the lactose-maldigestion test was positive in 16 of the remaining 47 symptomatic subjects, but only 4 carried the C/C-13910 genotype for adult-type hypolactasia. The symptomatic subjects had restricted their consumption of certain foods, particularly CM. However, in a blinded challenge, CM-induced symptoms were rare. The symptomatic subjects had higher plasma soluble intercellular adhesion molecule 1 (P = 0.007) and lower granzyme A (P = 0.001) concentrations than did the control subjects. Duodenal biopsy samples tended to have higher intraepithelial CD3+ cell counts (P = 0.065) and a higher expression of transforming growth factor ß (P = 0.073) and interleukin 12p35 messenger RNA (P = 0.075) than did the control subjects.

    Conclusions: In an unselected cohort of young adults, 8% reported food-related gastrointestinal symptoms. The finding of immunologic activity implied the existence of a food-related gastrointestinal syndrome but not one induced by CM.

  • 43.
    Piirainen, Laura
    et al.
    National Public Health Inst Helsinki ,Finland.
    Haahtela, Saula
    Skin and allergy hospital Helsinki University, Finland.
    Helin, Timo
    Skin and allergy hospital Helsinki University, Finland.
    Korpela, Riita
    Valio Ltd Research Center Helsinki, Finland.
    Haahtela, Tari
    Skin and allergy hospital Helsinki, Finland.
    Vaarala, Outi
    National Public Health Institute, Laboratory for Immunobiology, Helsinki.
    Effect of Lactobacillus rhamnosus GG on rBet v1 and rMal d1 specific IgA in the saliva of patients with birch pollen allergy2008In: Annals of Allergy, Asthma & Immunology, ISSN 1081-1206, E-ISSN 1534-4436, Vol. 100, no 4, p. 338-342Article in journal (Refereed)
    Abstract [en]

    Background: Lactobacillus rhamnosus GG (LGG) has demonstrated promising results in the treatment and prevention of atopic eczema.

     

     

    Objective: To study the effects of LGG on the oral immune response in adolescents and adults with birch pollen allergy combined with oral allergy syndrome.

     

     

    Methods: Patients received either LGG (n = 19) or a placebo (n = 19) for 5.5 months (from February 8 to August 6, 1999), starting 2.5 months before the birch pollen season. An oral apple challenge test was performed before, during, and after the pollen season. Saliva samples were collected before and after the challenges, and serum samples were collected before the challenges. Total IgA, IgG, and IgM and rBet v1 and rMal d1 specific IgA, IgG, IgG1, and IgG4 levels were measured from saliva with an enzyme-linked immunosorbent assay (ELISA). Serum rBet v1 specific IgE ELISA and birch radioallergosorbent testing were performed.

     

     

    Results: After 5.5 months, rBet v1 and rMal d1 specific IgA levels had increased from baseline in the LGG compared with the placebo group (Δ rBet v1 IgA, 0.319 vs −0.136 relative units; P = .02; Δ rMal d1 IgA, 0.097 vs −0.117, P = .02). rBet v1 specific IgE serum levels did not differ between the groups. In the LGG group, rBet v1 specific IgE levels correlated positively with stimulated total IgA (P = .04) and IgG (P = .003) in saliva. In the placebo group, rBet v1 specific IgE levels correlated negatively with stimulated rBet v1 and rMal d1 IgA levels (P = .009 for both) and IgG (P = .02 and P = .03, respectively).

     

     

    Conclusion: LGG showed immunostimulating effects on oral mucosa seen as increased allergen specific IgA levels in saliva.

  • 44.
    Pohjavuori, Emma
    et al.
    Hospital for Children and Adolescents Helsingfors, Finland.
    Viljanen, Mirva
    Skin and Allergy Hospital Helsingfors, Finland.
    Korpela, Riita
    Inst of Biomedicine, Pharmacology Helsingfors Universitet, Finland.
    Kuitunen, Mikael
    Skin and Allergy Hospital Helsingfors, Finland.
    Tiittanen, Minna
    Dept of Molecular Medicine Helsingfors, Finland.
    Vaarala, Outi
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Savilahti, Erkki
    Hospital for Children and Adolescents Helsingfors, Finland.
    Lactobacillus GG effect in increasing IFN-gamma production in infants with cow's milk allergy.2004In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 114, p. 131-136Article in journal (Refereed)
    Abstract [en]

    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 T(H)1 immunomodulatory signals. MIX, although containing LGG, appears to modulate the immune responses differently.

  • 45. Puurunen, M
    et al.
    Palosuo, T
    Lassila, R
    Anttila, M
    Vaarala, Outi
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Barn.
    Immunologic and hematologic properties of antiabodies to prothrombin and plasminogen in a mouse model.2001In: Lupus, ISSN 0961-2033, E-ISSN 1477-0962, Vol. 10, p. 108-115Article in journal (Refereed)
  • 46.
    Pöntynen, Nora
    et al.
    Dept of Molecular Medicine National Public Health Institute, Helsinki, Finland.
    Miettinen, Aaro
    Dept of Bacteriology and Immunology University of Helsinki, Finland.
    Petteri Arstila, T
    Dept of Bacteriology and Immunology, University of Helsinki, Finland.
    Kämple, O
    Dept of Medical Sciences University of Uppsala, Sweden.
    Alimohammadi, Mohammad
    Dept of Medical Sciences University of Uppsala, Sweden.
    Vaarala, Outi
    National Public Health Institute, Helsinki.
    Peltonen, Leena
    Dept of Molecular Medicine National Public Health Institute, Helsinki, Finland.
    Ulmanen, Ismo
    Dept of Molecular Medicine National Public Health Institute, Helsinki, Finland.
    Aire deficient mice do not develop the same profile of tissue-specific autoantibodies as APECED patients2006In: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 27, no 2, p. 96-104Article in journal (Refereed)
    Abstract [en]

    Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, or APS1), is a monogenic autoimmune disease caused by mutations in the autoimmune regulator (AIRE) gene. The three main components of APECED are chronic mucocuteaneous candidiasis, hypoparathyroidism and adrenocortical insufficiency. However, several additional endocrine or other autoimmune disease components, or ectodermal dystrophies form the individually variable clinical picture of APECED. An important feature of APECED is a spectrum of well-characterized circulating autoantibodies, reacting against tissue-specific autoantigens. Aire deficient mice develop some characteristics of APECED phenotype. In order to investigate whether the Aire deficient mice produce autoantibodies similar to human APECED, we studied the reactivity of Aire mouse sera against mouse homologues of 11 human APECED antigens. None of the APECED antigens indicated elevated reactivity in the Aire knock-out mouse sera, implying the absence of APECED associated autoantibodies in Aire deficient mice. These findings were supported by the failure of the autoantigens to activate mouse T-cells. Furthermore, Aire knock-out mice did not express increased levels of anti-nuclear antibodies compared to wt mice. This study indicates that spontaneous induction of tissue-specific autoantibodies similar to APECED does not occur in the rodent model suggesting differences in the immunopathogenic mechanisms between mice and men.

  • 47.
    Rydgren, T
    et al.
    Finland.
    Vaarala, Outi
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Sandler, S
    Finland.
    Simvastatin protects against multiple low-dose streptozotocin-induced type 1 diabetes in CD-1 mice and recurrence of disease in nonobese diabetic mice2007In: Journal of Pharmacology and Experimental Therapeutics, ISSN 0022-3565, E-ISSN 1521-0103, Vol. 323, no 1, p. 180-185Article in journal (Refereed)
    Abstract [en]

    Statins are drugs well known for their cholesterol-lowering properties. Lately, statins have been shown to possess anti-inflammatory properties that might be attributed to inhibition of leukocyte adhesion and migration to sites of inflammation. Therefore, we have explored the effects of administration of simvastatin (30 mg/kg body weight given i.p. once a day, from days 4-14) on the development of diabetes induced by multiple low-dose streptozotocin (MLDS) in CD-1 mice, a type 1 diabetes model. We found that treatment with simvastatin could delay and in certain mice fully protect against MLDS-induced diabetes. The protective effect could last up to 3 weeks after simvastatin treatment was ended. Morphological examinations of the pancreas suggest that simvastatin might reduce the islet inflammation. Based on experiments in vitro, using isolated pancreatic islets, we conclude that the protective effect of simvastatin is not mediated by a direct effect on streptozotocin action but rather the result of an immunomodulatory effect. This was reinforced by the finding that simvastatin treatment also prolonged islet function in the recurrence of disease model in diabetic nonobese diabetic mice. Copyright © 2007 by The American Society for Pharmacology and Experimental Therapeutics.

  • 48. Saijets, Salla
    et al.
    Ylipaasto, P
    Vaarala, Outi
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Barn.
    Hovi, Tapani
    Roivainen, Merja
    Enterovirus infection and activation of human umbilical vein endothelial cells2003In: Journal of Medical Virology, ISSN 0146-6615, E-ISSN 1096-9071, Vol. 70, no 3, p. 430-439Article in journal (Refereed)
    Abstract [en]

    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-1▀ 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.

  • 49.
    Savilahti, Erkki
    et al.
    Hospital for Children and Adolescents Helsinki, Finland.
    Siltanen, Mirjami
    Hospital for Children and Adolescents Helsinki, Finland.
    Kajosaari, Merja
    Hospital for Children and Adolescents Helsinki, Finland.
    Vaarala, Outi
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Saarinen, Kristiina
    Hospital for Children and Adolescents Helsinki, Finland.
    IgA antibodies, TGF-β1 and -β2, and Soluble CD14 in the colostrum and development of atopy by age 42005In: Pediatric Research, ISSN 0031-3998, E-ISSN 1530-0447, Vol. 58, no 6, p. 1300-1305Article in journal (Refereed)
    Abstract [en]

    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)-β 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-β1 and -β2. 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. Copyright © 2005 International Pediatric Research Foundation, Inc.

  • 50.
    Sepa, Anneli
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Wahlberg, Jeanette
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Vaarala, Outi
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Frodi, Ann
    Linköping University, Department of Behavioural Sciences and Learning, Psychology. Linköping University, Faculty of Arts and Sciences.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Psychological stress may induce diabetes-related autoimmunity in infancy2005In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 28, no 2, p. 290-295Article in journal (Refereed)
    Abstract [en]

    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.

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