Publications by authors named "Janne K Nieminen"

13 Publications

  • Page 1 of 1

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

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

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

Early childhood infections have been implicated in the development of immune-mediated diseases, such as allergies, asthma, and type 1 diabetes. We set out to investigate the immunomodulatory effects of early viral infections experienced before the age of one year on the peripheral regulatory T cell population (Treg) and circulating cytokines in a birth-cohort study of Estonian and Finnish infants. We show here a temporal association of virus infection with the expression of FOXP3 in regulatory T cells. Infants with rhinovirus infection during the preceding 30 days had a higher FOXP3 expression in Treg cells and decreased levels of several cytokines related to Th1 and Th2 responses in comparison to the children without infections. In contrast, FOXP3 expression was significantly decreased in highly activated (CD4+CD127-/loCD25+FOXP3high) regulatory T cells (TregFOXP3high) in the infants who had enterovirus infection during the preceding 30 or 60 days. After enterovirus infections, the cytokine profile showed an upregulation of Th1- and Th17-related cytokines and a decreased activation of CCL22, which is a chemokine derived from dendritic cells and associated with Th2 deviation. Our results reveal that immunoregulatory mechanisms are up-regulated after rhinovirus infections, while enterovirus infections are associated with activation of proinflammatory pathways and decreased immune regulation.
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http://dx.doi.org/10.3389/fimmu.2020.567046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905218PMC
February 2021

Identification of two highly antigenic epitope markers predicting multiple sclerosis in optic neuritis patients.

EBioMedicine 2021 Feb 23;64:103211. Epub 2021 Jan 23.

Protobios Llc, Mäealuse 4, Tallinn 12618, Estonia; Department of Chemistry and Biotechnology, Tallinn University of Technology, Akadeemia tee 15, Tallinn 12618, Estonia. Electronic address:

Background: Optic neuritis (ON) can occur as an isolated episode or will develop to multiple sclerosis (MS) a chronic autoimmune disease. What predicts ON progression to MS remains poorly understood.

Methods: We characterised the antibody epitope repertoire in three independent clinical cohorts (discovery (n = 62), validation (n = 20) and external cohort (n = 421)) using mimotope variation analysis (MVA), a next generation phage display technology to identify epitopes that associate with prognosis of ON.

Findings: We observed distinct epitope profiles for ON, MS and the controls, whereas epitope repertoires of sera and CSF were highly similar. Two unique and highly immunogenic epitopes A and B were detected in subjects with ON progressing to MS. These epitopes A and B were strongly associated with herpesviral antigens (VCA p18 of  Epstein-Barr virus (EBV); gB of Cytomegalovirus (CMV)). ROC addressed 75% of MS subjects with ON onset correctly (at 75% sensitivity and 74.22% specificity) based on the two-epitope biomarker analysis.

Interpretation: This is the first report on epitope diagnostics for MS employing the unbiased strategy of MVA for identification of novel immunological features of disease.

Funding: The Estonian Ministry of Education, The Estonian Research Council (PRG573, PRG805 and PSG691), H2020-MSCA-RISE-2016 (SZTEST), H2020-NMBP-2017 (PANBIORA), Helsinki University Hospital, Mary and Georg C. Ehrnrooth, Finnish Eye, Sigrid Jusélius and Magnus Ehrnrooth Foundations.
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http://dx.doi.org/10.1016/j.ebiom.2021.103211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841498PMC
February 2021

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

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

Clinicum, University of Helsinki, Helsinki, Finland.

Recent studies suggest that the cross-talk between the gut microbiota and human immune system during the first year of life is an important regulator of the later development of atopic diseases. We explored the changes in the gut microbiota, blood regulatory T cells, and atopic sensitization in a birth-cohort of Estonian and Finnish children followed from 3 to 36 months of age. We describe here an infant Treg phenotype characterized by high Treg frequency, the maturation of Treg population characterized by a decrease in their frequency accompanied with an increase in the highly activated Treg cells. These changes in Treg population associated first with the relative abundance of Bifidobacterium longum followed by increasing colonization with butyrate producing bacteria. High bifidobacterial abundance in the neonatal microbiota appeared to be protective, while colonization with and was associated with later risk of allergy. Estonian children with lower risk of IgE mediated allergic diseases than Finnish children showed an earlier maturation of the gut microbiota, detected as earlier switch to an increasing abundance of butyrate-producing bacteria, combined with an earlier maturation of Treg cell phenotype and total IgE production. The children with established allergic diseases by age 3 showed a decreased abundance of butyrate producing . These results suggest that as well as the maintenance of a bifidobacterial dominated gut microbiota is important during the first weeks of life, the overtake by butyrate producing bacteria seems to be a beneficial shift, which should not be postponed.
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http://dx.doi.org/10.3389/fimmu.2019.02494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842923PMC
October 2020

Predisposition to Childhood Otitis Media and Genetic Polymorphisms within the Toll-Like Receptor 4 (TLR4) Locus.

PLoS One 2015 15;10(7):e0132551. Epub 2015 Jul 15.

Department of Otorhinolaryngology, Helsinki University Central Hospital, Helsinki, Finland.

Background: Predisposition to childhood otitis media (OM) has a strong genetic component, with polymorphisms in innate immunity genes suspected to contribute to risk. Studies on several genes have been conducted, but most associations have failed to replicate in independent cohorts.

Methods: We investigated 53 gene polymorphisms in a Finnish cohort of 624 cases and 778 controls. A positive association signal was followed up in a tagging approach and tested in an independent Finnish cohort of 205 cases, in a British cohort of 1269 trios, as well as in two cohorts from the United States (US); one with 403 families and the other with 100 cases and 104 controls.

Results: In the initial Finnish cohort, the SNP rs5030717 in the TLR4 gene region showed significant association (OR 1.33, P = .003) to OM. Tagging SNP analysis of the gene found rs1329060 (OR 1.33, P = .002) and rs1329057 (OR 1.29, P = .003) also to be associated. In the more severe phenotype the association was stronger. This finding was supported by an independent Finnish case cohort, but the associations failed to replicate in the British and US cohorts. In studies on TLR4 signaling in 20 study subjects, the three-marker risk haplotype correlated with a decreased TNFα secretion in myeloid dendritic cells.

Conclusions: The TLR4 gene locus, regulating the innate immune response, influences the genetic predisposition to childhood OM in a subpopulation of patients. Environmental factors likely modulate the genetic components contributing to the risk of OM.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0132551PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4503307PMC
May 2016

Whole-Genome Sequencing Identifies STAT4 as a Putative Susceptibility Gene in Classic Kaposi Sarcoma.

J Infect Dis 2015 Jun 9;211(11):1842-51. Epub 2014 Dec 9.

Department of Medical Genetics Genome-Scale Biology Research Programs Unit.

Background: Classic Kaposi sarcoma (cKS) is an inflammatory tumor caused by human herpesvirus 8 (HHV-8) commonly observed in elderly men of Mediterranean origin. We studied a Finnish family of 5 affected individuals in 2 generations. Except for atypical mycobacterial infection of the index case, the affected individuals did not have notable histories of infection.

Methods: We performed genome and exome sequencing and mapped shared chromosomal regions to identify genetic predisposition in the family.

Results: We identified 12 protein-coding candidate variants that segregated in the 3 affected cousins from whom we had samples. The affected mother of the index case was an obligatory carrier. Among the 12 candidates was a rare heterozygous substitution rs141331848 (c.1337C>T, p.Thr446Ile) in the DNA-binding domain of STAT4. The variant was not present in 242 Finnish control genomes or 180 additional regional controls. Activated T-helper cells from the HHV-8-negative variant carriers showed reduced interferon γ production, compared with age and sex matched wild-type individuals. We screened STAT4 in additional 18 familial KS cases and the variant site from 56 sporadic KS cases but detected no pathogenic mutations.

Conclusions: Our data suggest that STAT4 is a potential cKS-predisposition gene, but further functional and genetic validation is needed.
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http://dx.doi.org/10.1093/infdis/jiu667DOI Listing
June 2015

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

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

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

Upregulation of IL-17 immunity and detrimental effects of IL-17 on human islets have been implicated in human type 1 diabetes. In animal models, the plasticity of Th1/Th17 cells contributes to the development of autoimmune diabetes. In this study, we demonstrate that the upregulation of the IL-17 pathway and Th1/Th17 plasticity in peripheral blood are markers of advanced β cell autoimmunity and impaired β cell function in human type 1 diabetes. Activated Th17 immunity was observed in the late stage of preclinical diabetes in children with β cell autoimmunity and impaired glucose tolerance, but not in children with early β cell autoimmunity. We found an increased ratio of IFN-γ/IL-17 expression in Th17 cells in children with advanced β cell autoimmunity, which correlated with HbA1c and plasma glucose concentrations in an oral glucose tolerance test, and thus impaired β cell function. Low expression of Helios was seen in Th17 cells, suggesting that Th1/Th17 cells are not converted thymus-derived regulatory T cells. Our results suggest that the development of Th1/Th17 plasticity may serve as a biomarker of disease progression from β cell autoantibody positivity to type 1 diabetes. These data in human type 1 diabetes emphasize the role of Th1/Th17 plasticity as a potential contributor to tissue destruction in autoimmune conditions.
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http://dx.doi.org/10.4049/jimmunol.1401653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4273995PMC
January 2015

High-fat meals induce systemic cytokine release without evidence of endotoxemia-mediated cytokine production from circulating monocytes or myeloid dendritic cells.

Acta Diabetol 2015 Apr 3;52(2):315-22. Epub 2014 Sep 3.

Folkhälsan Research Center, Biomedicum Helsinki (Room C317b), Haartmaninkatu 8, 00290, Helsinki, Finland.

Aims: Dietary fats have been shown to promote the translocation of bacterial endotoxins from the gut into circulation, which may induce systemic inflammation and modulate the inflammatory response of circulating immune cells. The aim of this study was to determine the effect of the postprandial milieu on inflammation and the inflammatory response of antigen presenting cells in the context of type 1 diabetes (T1D).

Materials And Methods: Eleven patients with T1D and eleven nondiabetic controls were recruited as part of the FinnDiane study and given two fatty meals during 1 day. Cytokine responses in monocytes and myeloid dendritic cells (mDCs) as well as serum lipopolysaccharide activity levels, triglyceride concentrations and cytokine concentrations were measured from fasting and postprandial blood samples.

Results: Postprandially, patients with T1D and controls showed significant increases in eight inflammatory cytokines (IL-6, TNF-α, IL-1β, IFN-α, IL-10, IFN-γ, IL-12 and MIP-1β) without concomitant increase in serum LPS activity. Serum cytokine production was similar in both groups. No postprandial change was seen in the IL-6, TNF-α or IL-1β production of mDCs or monocytes. At fasting, diabetic mDCs exhibited higher LPS-induced IL-6 and IL-1β production than controls.

Conclusions: Acute high-fat meals increase circulating cytokines but have no effect on serum lipopolysaccharide activity levels or cytokine production in circulating mDCs or monocytes. Our results suggest that postprandial increase in serum cytokine levels is neither mediated by circulating endotoxins nor the activation of circulating innate cells. The production of high-fat meal-induced inflammatory markers is most likely regulated at the tissue level.
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http://dx.doi.org/10.1007/s00592-014-0641-8DOI Listing
April 2015

Patients with type 1 diabetes show signs of vascular dysfunction in response to multiple high-fat meals.

Nutr Metab (Lond) 2014 13;11:28. Epub 2014 Jun 13.

Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum, Helsinki, Finland ; Department of Medicine, Division of Nephrology, Helsinki University Central Hospital, Helsinki, Finland ; Diabetes & Obesity Research Program, Research Program's Unit, University of Helsinki, Helsinki, Finland.

Background: A high-fat diet promotes postprandial systemic inflammation and metabolic endotoxemia. We investigated the effects of three consecutive high-fat meals on endotoxemia, inflammation, vascular function, and postprandial lipid metabolism in patients with type 1 diabetes.

Methods: Non-diabetic controls (n = 34) and patients with type 1 diabetes (n = 37) were given three high-caloric, fat-containing meals during one day. Blood samples were drawn at fasting (8:00) and every two hours thereafter until 18:00. Applanation tonometry was used to assess changes in the augmentation index during the investigation day.

Results: Three consecutive high-fat meals had only a modest effect on serum LPS-activity levels and inflammatory markers throughout the day in both groups. Of note, patients with type 1 diabetes were unable to decrease the augmentation index in response to the high-fat meals. The most profound effects of the consecutive fat loads were seen in chylomicron and HDL-metabolism. The triglyceride-rich lipoprotein remnant marker, apoB-48, was elevated in patients compared to controls both at fasting (p = 0.014) and postprandially (p = 0.035). The activities of the HDL-associated enzymes PLTP (p < 0.001), and CETP (p = 0.007) were higher and paraoxonase (PON-1) activity, an anti-oxidative enzyme bound to HDL, decreased in patients with type 1 diabetes (p = 0.027).

Conclusions: In response to high-fat meals, early signs of vascular dysfunction alongside accumulation of chylomicron remnants, higher augmentation index, and decreased PON-1 activity were observed in patients with type 1 diabetes. The high-fat meals had no significant impact on postprandial LPS-activity in non-diabetic subjects or patients with type 1 diabetes suggesting that metabolic endotoxemia may be more central in patients with chronic metabolic disturbances such as obesity, type 2 diabetes, or diabetic kidney disease.
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http://dx.doi.org/10.1186/1743-7075-11-28DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4067102PMC
June 2014

Dendritic cells from Crohn's disease patients show aberrant STAT1 and STAT3 signaling.

PLoS One 2013 7;8(8):e70738. Epub 2013 Aug 7.

Immune Response Unit, Department of Vaccination and Immune Protection, National Institute for Health and Welfare, Helsinki, Finland.

Abnormalities of dendritic cells (DCs) and STAT proteins have been reported in Crohn's disease (CD). Studies on JAK/STAT signaling in DCs are, however, lacking in CD. We applied a flowcytometric single-cell-based phosphoepitope assay to evaluate STAT1 and STAT3 pathways in DC subsets from CD patients. In addition, circulating DC counts were determined, together with the activation-related immunophenotype. We found that IL-6- and IFN-α-induced STAT3 phosphorylation and IFN-α-induced STAT1 phosphorylation were impaired in plasmacytoid DCs (pDCs) from CD patients (P = 0.005, P = 0.013, and P = 0.006, respectively). In myeloid DCs (mDCs), IFN-α-induced STAT1 and STAT3 phosphorylation were attenuated (P<0.001 and P = 0.048, respectively), but IL-10-induced STAT3 phosphorylation was enhanced (P = 0.026). IFN-γ-induced STAT1 signaling was intact in both DC subtypes. Elevated plasma IL-6 levels were detected in CD (P = 0.004), which strongly correlated with disease activity (ρ = 0.690, P<0.001) but not with IL-6-induced STAT3 phosphorylation. The numbers of pDCs and BDCA3+ mDCs were decreased, and CD40 expression on CD1c+ mDCs was increased in CD. When elucidating the effect of IL-6 signaling on pDC function, we observed that IL-6 treatment of healthy donor pDCs affected the maturation of and modified the T-cell priming by pDCs, favoring Th2 over Th1 type of response and the expression of IL-10 in T cells. Our results implicate DC signaling in human CD. Reduced IL-6 responsiveness in pDCs, together with the attenuated IFN-α-induced signaling in both DC subtypes, may contribute to the immunological dysregulation in CD patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0070738PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3737363PMC
August 2014

Altered phenotype of peripheral blood dendritic cells in pediatric type 1 diabetes.

Diabetes Care 2012 Nov 11;35(11):2303-10. Epub 2012 Jul 11.

Immune Response Unit, Department of Vaccination and Immune Protection, National Institute for Health and Welfare, Helsinki, Finland.

Objective: Dendritic cells (DCs) are largely responsible for the activation and fine-tuning of T-cell responses. Altered numbers of blood DCs have been reported in type 1 diabetes (T1D). We aimed at characterizing the less well-known phenotypic properties of DCs in T1D.

Research Design And Methods: In a case-control setting, samples from a total of 90 children were studied by flow cytometry or by quantitative real-time PCR (qPCR).

Results: We found decreased numbers of myeloid DCs (mDCs) (8.97 vs. 13.4 cells/μL, P = 0.009, n = 31) and plasmacytoid DCs (pDCs) (9.47 vs. 14.6 cells/μL, P = 0.018, n = 30) in recent-onset T1D. Using a panel of antibodies against functionally important DC markers, we detected a decreased expression of CC chemokine receptor 2 (CCR2) on mDCs (percentage above negative control, P = 0.002, n = 29) and pDCs (median intensity, P = 0.003, n = 30) from T1D patients. In an independent series of children, the reduced expression of CCR2 was confirmed by qPCR in isolated mDCs (P = 0.043, n = 20). Serum concentrations of CCR2 ligands monocyte chemotactic protein-1 and -3 did not differ between the groups. A trend for an enhanced responsiveness of the nuclear factor-κB pathway (P = 0.063, n = 39) was seen in mDCs from children with β-cell autoantibodies, which is possibly related to the reduced CCR2 expression, since CCR2 on mDCs was downregulated by nuclear factor-κB-activating agents.

Conclusions: Given the role of CCR2 in DC chemotaxis and in DC-elicited Th1 differentiation, our results may indicate a functionally important DC abnormality in T1D affecting the initiation and quality of immune responses.
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http://dx.doi.org/10.2337/dc11-2460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3476907PMC
November 2012

Expansion of CD4+CD25+FOXP3+ regulatory T cells in infants of mothers with type 1 diabetes.

Pediatr Diabetes 2012 Aug 15;13(5):400-7. Epub 2012 Feb 15.

Immune Response Unit, Department of Vaccination and Immune Protection, National Institute for Health and Welfare, Helsinki, Finland.

Background: Reduced risk for type 1 diabetes (T1D) has been reported in the offspring of mothers with T1D when compared with children of affected fathers.

Objective: To evaluate the hypothesis that exposure of the offspring to maternal insulin therapy induces regulatory mechanisms in utero, we compared the FOXP3 expressing regulatory T cells in cord blood (CB) of infants born to mothers with or without T1D.

Subjects And Methods: Cord blood mononuclear cells (CBMCs) from 20 infants with maternal T1D and from 20 infants with an unaffected mother were analyzed for the numbers of CD4+CD25+FOXP3+ cells ex vivo and after in vitro stimulation with human insulin by flow cytometry. The mRNA expression of FOXP3, NFATc2, STIM1, interleukin (IL)-10, and transforming growth factor (TGF)-β was measured by real-time reverse transcription polymerase chain reaction.

Results: The percentage of FOXP3+ cells in CD4+CD25(high) cells was higher in the CB of the infants with maternal T1D when compared with the infants of unaffected mothers (p = 0.023). After in vitro insulin stimulation an increase in the percentage of FOXP3+ cells in CD4+CD25(high) cells (p = 0.0002) as well as upregulation of FOXP3, NFATc2, STIM1, IL-10, and TGF-β transcripts in CBMCs (p < 0.013 for all; Wilcoxon test) was observed only in the offspring of mothers with T1D, in whom the disease-related PTPN22 allele was associated with reduced STIM1 and NFATc2 response in insulin-stimulated CBMCs (p = 0.007 and p = 0.014).

Conclusions: We suggest that maternal insulin treatment induces expansion of regulatory T cells in the fetus, which might contribute to the lower risk of diabetes in children with maternal vs. paternal diabetes.
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http://dx.doi.org/10.1111/j.1399-5448.2012.00852.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4225542PMC
August 2012

Poor cytokine-induced phosphorylation in chronic myeloid leukemia patients at diagnosis is effectively reversed by tyrosine kinase inhibitor therapy.

Exp Hematol 2011 Jan 12;39(1):102-113.e1. Epub 2010 Oct 12.

Hematology Research Unit, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.

Objective: In chronic myeloid leukemia (CML), uncontrolled tyrosine kinase activity of the BCR-ABL1 oncoprotein results in aberrant signaling pathways and increased cell proliferation. Acquired immune tolerance to leukemic antigens further enables tumor cell expansion. Tyrosine kinase inhibitor (TKI) therapy interferes with the immunoregulatory system by targeting off-target kinases both in malignant and nonmalignant cells. The aim of this study was to analyze the immune cell function by phosphoprotein profiling in CML patients.

Materials And Methods: Blood samples from diagnostic phase and TKI-treated patients were analyzed by multicolor phosphoprotein flow cytometry enabling measurements at the single-cell level. Both unstimulated baseline activation status and cytokine-induced responses were evaluated.

Results: In diagnostic-phase and imatinib-treated patients, the baseline phosphoprotein activation status was similar to healthy controls. In dasatinib-treated patients, basal phosphoprotein levels were slightly decreased; in particular, the signal transduction and activator of transcription protein 3 pathway was affected in both myeloid and lymphoid cells. The activation responses to various cytokines, granulocyte-macrophage colony-stimulating factor in particular were significantly suppressed in untreated CML patients. During imatinib and dasatinib therapy, the aberrantly suppressed phosphorylation responses were normalized.

Conclusions: Cytokine responses are hampered in untreated CML patients, which may have an effect on various immunological processes in vivo. Interestingly, during TKI treatment, phosphorylation responses were normal, suggesting that TKI treatment does not alter the reactivity of healthy immune effector cells. However, dasatinib treatment was associated with diminished basal activation of the immunosuppressive signal transduction and activator of transcription protein 3 signaling pathway, which could have clinical significance in reversing the lymphocyte anergy against tumor cells.
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http://dx.doi.org/10.1016/j.exphem.2010.09.005DOI Listing
January 2011

IL-17 immunity in human type 1 diabetes.

J Immunol 2010 Aug 30;185(3):1959-67. Epub 2010 Jun 30.

Immune Response Unit, National Institute for Health and Welfare, Helsinki, Finland.

Th17 immunity has been shown to regulate autoimmune diabetes in mice. IL-17 neutralization prevented development of diabetes when given postinitiation of insulitis but not earlier, suggesting interference with the effector phase of the disease. Islet-cell Ag-specific Th17 cells converted into IFN-gamma-secreting Th1-like cells and caused diabetes in mice recipients. The role of IL-17 in human type 1 diabetes (T1D) is, however, not established. In this study, we show upregulation of Th17 immunity in peripheral blood T cells from children with T1D. This was characterized by increased IL-17 secretion and expression of IL-17, IL-22, and retinoic acid-related orphan receptor C isoform 2, but also FOXP3 transcripts upon T cell activation in vitro. Also, circulating memory CD4 cells from children with T1D showed the same pattern of IL-17, IL-22 and FOXP3 mRNA upregulation, indicating IL-17 pathway activation in vivo. IL-17-positive T cells appeared to be CD4(+) cells expressing TCR-alphabeta and CCR6, and a subpopulation showed coproduction of IFN-gamma. Given the Th17 immunity in T1D, we demonstrated that IL-17 had detrimental effects on human islet cells in vitro; it potentiated both inflammatory and proapoptotic responses. Our findings highlight the role of IL-17 immunity in the pathogenesis of human T1D and point to a potential therapeutic strategy.
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http://dx.doi.org/10.4049/jimmunol.1000788DOI Listing
August 2010