9 research outputs found

    Immunological mechanisms in the pathogenesis of type 1 diabetes

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    Type 1 diabetes is a chronic autoimmune disease, in which insulin secreting beta cells in the pancreas are destroyed. The disease pathogenesis can be divided into an asymptomatic preclinical phase and symptomatic disease. The preclinical phase is characterised by the appearance of autoantibodies targeting pancreatic islet antigens and clinical onset of disease happens after the amount of functional beta cells becomes too low to sustain glucose homeostasis. While several genetic and environmental type 1 diabetes risk factors have been identified, the exact mechanism of the autoimmune process leading to the disease remains unknown. Additionally, strong heterogeneity in the disease pathogenesis has been observed and different possible pathways, or endotypes, to type 1 diabetes are suspected. The focus of this thesis was to investigate factors leading to heterogeneity in type 1 diabetes pathogenesis. Several type 1 diabetes predisposing genetic polymorphisms, including the loci NRP1, INS, UBASH3A and STAT4, were found to associate with specific phases of disease pathogenesis. Moreover, other disease risk polymorphisms, like PTPN22 and INS, associated significantly with suspected type 1 diabetes endotypes defined through the first appearing islet autoantibody. The autoimmune risk variant of PTPN22 was also associated with elevated total and na√Įve regulatory T cell frequencies. No gene expression differences could be detected in individual genes between children positive for multiple type 1 diabetes associated autoantibodies and their healthy controls in monocytes and monocyte-depleted peripheral blood mononuclear cells. However, gene sets relating to viral responses and a type I interferon response were upregulated in monocytes of multiple autoantibody positive children, compared to healthy controls. These data lend support to heterogeneity of type 1 diabetes with multiple possible pathways to disease onset.Immunologiset mekanismit tyypin 1 diabeteksen patogeneesissa Tyypin 1 diabetes on krooninen autoimmuunisairaus, jossa insuliinia tuottavat haiman betasolut tuhoutuvat. Taudinkulku voidaan jakaa oireettomaan prekliiniseen vaiheeseen ja oireiseen sairauteen. Prekliinisess√§ vaiheessa ilmaantuu autovasta-aineta haiman saarekesoluja vastaan ja sairauden kliininen puhkeaminen tapahtuu toiminnallisten betasolujen m√§√§r√§n laskiessa liian pieneksi sokeritasapainon yll√§pit√§miseen. Vaikka useita tyypin 1 diabetekselle altistavia perim√§- ja ymp√§rist√∂tekij√∂it√§ tunnetaan, tautiin johtavan autoimmuniiprosessin tarkkaa mekanismia ei tunneta. Taudinkulussa on lis√§ksi havaittu suurta vaihtelevuutta ja useiden rinnakkaisten tyypin 1 diabetekseen johtavien tautimekanisminen tai taudin endotyyppien arvellaan olevan mahdollisia. T√§ss√§ v√§it√∂skirjassa keskityttiin tyypin 1 diabeteksen patogeneesin heterogeniaan johtavien tekij√∂iden tutkimiseen. Useiden tyypin 1 diabetekselle altistavien geneettisten polymorfismien, kuten NRP1, INS, UBASH3A ja STAT4, havaittiin assosioituvan tiettyihin taudin patogeneesin vaiheisiin. Lis√§ksi toiset taudin riskipolymorfismit, kuten PTPN22 ja INS, assosioituivat merkitt√§v√§sti ensimm√§isen ilmestyneen autovasta-aineen mukaan m√§√§ritettyihin, oletettuihin taudin endotyyppeihin. PTPN22-geenin autoimmuunitaudeille altistava riskivariantti assosioitui my√∂s kohonneisiin regulatoristen T-solujen m√§√§riin kokonaispopulaatiossa ja naiiveissa soluissa. Useita tyypin 1 diabetekseen liitettyj√§ autovasta-aineita kehitt√§neiden lasten monosyyteiss√§ ja monosyytitt√∂miss√§ muissa perifeerisen veren mononukleaarisissa soluissa ei havaittu yksitt√§isten geenien v√§lisi√§ ekspressioeroja terveisiin kontrollilapsiin verrattuna. Virusvasteisiin ja tyypin I interferonivasteeseen liittyv√§t geeniryhmien ekspressiotasot olivat kuitenkin voimistuneet useita autovasta-aineita kehitt√§neiden lasten monosyyteiss√§ terveisiin kontrolleihin verrattuna. N√§m√§ tulokset tukevat n√§kemyst√§ tyypin 1 diabeteksen heterogeniasta ja useista mahdollisista poluista taudin puhkeamiseen

    Non-HLA Gene Polymorphisms in the Pathogenesis of Type 1 Diabetes : Phase and Endotype Specific Effects

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    The non-HLA loci conferring susceptibility to type 1 diabetes determine approximately half of the genetic disease risk, and several of them have been shown to affect immune-cell or pancreatic beta-cell functions. A number of these loci have shown associations with the appearance of autoantibodies or with progression from seroconversion to clinical type 1 diabetes. In the current study, we have re-analyzed 21 of our loci with prior association evidence using an expanded DIPP follow-up cohort of 976 autoantibody positive cases and 1,910 matched controls. Survival analysis using Cox regression was applied for time periods from birth to seroconversion and from seroconversion to type 1 diabetes. The appearance of autoantibodies was also analyzed in endotypes, which are defined by the first appearing autoantibody, either IAA or GADA. Analyzing the time period from birth to seroconversion, we were able to replicate our previous association findings at PTPN22, INS, and NRP1. Novel findings included associations with ERBB3, UBASH3A, PTPN2, and FUT2. In the time period from seroconversion to clinical type 1 diabetes, prior associations with PTPN2, CD226, and PTPN22 were replicated, and a novel association with STAT4 was observed. Analyzing the appearance of autoantibodies in endotypes, the PTPN22 association was specific for IAA-first. In the progression phase, STAT4 was specific for IAA-first and ERBB3 to GADA-first. In conclusion, our results further the knowledge of the function of non-HLA risk polymorphisms in detailing endotype specificity and timing of disease development.Peer reviewe

    Non-HLA Gene Polymorphisms in the Pathogenesis of Type 1 Diabetes: Phase and Endotype Specific Effects

    Get PDF
    The non-HLA loci conferring susceptibility to type 1 diabetes determine approximately half of the genetic disease risk, and several of them have been shown to affect immune-cell or pancreatic beta-cell functions. A number of these loci have shown associations with the appearance of autoantibodies or with progression from seroconversion to clinical type 1 diabetes. In the current study, we have re-analyzed 21 of our loci with prior association evidence using an expanded DIPP follow-up cohort of 976 autoantibody positive cases and 1,910 matched controls. Survival analysis using Cox regression was applied for time periods from birth to seroconversion and from seroconversion to type 1 diabetes. The appearance of autoantibodies was also analyzed in endotypes, which are defined by the first appearing autoantibody, either IAA or GADA. Analyzing the time period from birth to seroconversion, we were able to replicate our previous association findings at PTPN22, INS, and NRP1. Novel findings included associations with ERBB3, UBASH3A, PTPN2, and FUT2. In the time period from seroconversion to clinical type 1 diabetes, prior associations with PTPN2, CD226, and PTPN22 were replicated, and a novel association with STAT4 was observed. Analyzing the appearance of autoantibodies in endotypes, the PTPN22 association was specific for IAA-first. In the progression phase, STAT4 was specific for IAA-first and ERBB3 to GADA-first. In conclusion, our results further the knowledge of the function of non-HLA risk polymorphisms in detailing endotype specificity and timing of disease development

    Viral infection-related gene upregulation in monocytes in children with signs of beta-cell autoimmunity

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    Objective: The pathogenesis of type 1 diabetes (T1D) is associated with genetic predisposition and immunological changes during presymptomatic disease. Differences in immune cell subset numbers and phenotypes between T1D patients and healthy controls have been described; however, the role and function of these changes in the pathogenesis is still unclear. Here we aimed to analyze the transcriptomic landscapes of peripheral blood mononuclear cells (PBMCs) during presymptomatic disease. Methods: Transcriptomic differences in PBMCs were compared between cases positive for islet autoantibodies and autoantibody negative controls (9 case-control pairs) and further in monocytes and lymphocytes separately in autoantibody positive subjects and control subjects (25 case-control pairs). Results: No significant differential expression was found in either data set. However, when gene set enrichment analysis was performed, the gene sets "defence response to virus" (FDR Conclusion: Gene set enrichment analysis of children with T1D-associated autoimmunity revealed changes in pathways relevant for virus infection in PBMCs, particularly in monocytes. Virus infections have been repeatedly implicated in the pathogenesis of T1D. These results support the viral hypothesis by suggesting altered immune activation of viral immune pathways in monocytes during diabetes.Peer reviewe

    Viral infection-related gene upregulation in monocytes in children with signs of ő≤-cell autoimmunity

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    Objective: The pathogenesis of type 1 diabetes (T1D) is associated with genetic predisposition and immunological changes during presymptomatic disease. Differences in immune cell subset numbers and phenotypes between T1D patients and healthy controls have been described; however, the role and function of these changes in the pathogenesis is still unclear. Here we aimed to analyze the transcriptomic landscapes of peripheral blood mononuclear cells (PBMCs) during presymptomatic disease.Methods: Transcriptomic differences in PBMCs were compared between cases positive for islet autoantibodies and autoantibody negative controls (9 case-control pairs) and further in monocytes and lymphocytes separately in autoantibody positive subjects and control subjects (25 case-control pairs).Results: No significant differential expression was found in either data set. However, when gene set enrichment analysis was performed, the gene sets "defence response to virus" (FDR <0.001, ranking 2), "response to virus" (FDR <0.001, ranking 3) and "response to type I interferon" (FDR = 0.002, ranking 12) were enriched in the upregulated genes among PBMCs in cases. Upon further analysis, this was also seen in monocytes in cases (FDR = 0.01, ranking 2; FDR = 0.04, ranking 3 and FDR = 0.02, ranking 1, respectively) but not in lymphocytes.Conclusion: Gene set enrichment analysis of children with T1D-associated autoimmunity revealed changes in pathways relevant for virus infection in PBMCs, particularly in monocytes. Virus infections have been repeatedly implicated in the pathogenesis of T1D. These results support the viral hypothesis by suggesting altered immune activation of viral immune pathways in monocytes during diabetes

    Type 1 diabetes linked PTPN22 gene polymorphism is associated with the frequency of circulating regulatory T cells

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    Dysfunction of FOXP3‚Äźpositive regulatory T¬†cells (Tregs) likely plays a major role in the pathogenesis of multiple autoimmune diseases including type 1 diabetes (T1D). Whether genetic polymorphisms associated with the risk of autoimmune diseases affect Treg frequency or function is currently unclear. Here, we analysed the effect of T1D‚Äźassociated major HLA class II haplotypes and seven single nucleotide polymorphisms in six non‚ÄźHLA genes [INS¬†(rs689),¬†PTPN22¬†(rs2476601),¬†IL2RA¬†(rs12722495 and¬† rs2104286),¬†PTPN2¬†(rs45450798),¬†CTLA4¬†(rs3087243), and¬†ERBB3¬†(rs2292239)] on peripheral blood Treg frequencies. These were determined by flow cytometry in 65 subjects who had progressed to T1D, 86 islet autoantibody‚Äźpositive at‚Äźrisk subjects, and 215 islet autoantibody‚Äźnegative healthy controls. The¬†PTPN22¬†rs2476601 risk allele A was associated with an increase in total (p¬†= 6 √ó 10‚ąí6) and na√Įve (p¬†= 4 √ó 10‚ąí5) CD4+CD25+CD127lowFOXP3+ Treg frequencies. These findings were validated in a separate cohort comprising ten trios of healthy islet autoantibody‚Äźnegative children carrying each of the three¬†PTPN22¬†rs2476601 genotypes AA, AG, and GG (p¬†= 0.005 for total and¬†p¬†= 0.03 for na√Įve Tregs, respectively). In conclusion, our analysis implicates the autoimmune¬†PTPN22¬†rs2476601 risk allele A in controlling the frequency of Tregs in human peripheral blood.</p

    Varhaisen sytomegalovirusinfektion ja perimän vaikutus lymfosyyttialaluokkien kehittymiseen lapsilla

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    Valkosolujen alaluokkien määräsuhteiden kypsyminen vaihtelee yksilöiden välillä. Usein varhaislapsuudessa sairastetun sytomegalovirusinfektion (CMV) tiedetään vaikuttavan valkosolujen kehittymiseen. On viitteitä siitä, että CMV-infektio vaikuttaa tyypin 1 diabeteksen patogeneesiin. Diabeteksen riskiin vaikuttavat myös useat geenipolymorfismit ja useiden polymorfismien riskivaikutuksen ajatellaan välittyvän lymfosyyttien määrän ja toiminnan kautta. Riskipolymorfismien tarkat vaikutukset tunnetaan kuitenkin huonosti. Tutkimuksessa käytettiin prospektiiviseen DIPP-tutkimukseen (Diabetes Prediction and Prevention) osallistuvien lasten DNA- ja plasmanäytteitä. Varhaislapsuuden CMV-infektio todettiin entsyymi-immunologisella (EIA) IgG-vasta-ainemäärityksellä ja diabetekseen liitettyjen yhden nukleotidin polymorfismien genotyypit määritettiin kvantititatiivisella polymeraasiketjureaktiolla kuudesta geenistä: INS (rs689), PTPN22 (rs2476601), IL2RA (rs2104286), PTPN2 (rs45450798), ERBB3 (rs2292239) ja CTLA4 (rs3087243). Lasten lymfosyyttialaluokkien suhteelliset osuudet oli aiemmin analysoitu virtaussytometrian avulla ja heistä oli lisäksi määritetty diabetesalttiuteen assosioituvat HLA-DR/DQ-genotyypit. CMV-tartunta assosioitui regulatoristen T-muistisolujen osuuden alenemiseen. PTPN22-geenin tyypin 1 diabetekseen liittyvä polymorfismi assosioitui regulatoristen T-solujen ja erityisesti naiivien regulatoristen T-solujen lisääntyneeseen osuuteen. ERBB3-geenin diabetesriskipolymorfismi assosioitui korkeampaan tyypin 1 auttaja-T-solujen ja alentuneeseen tyypin 17 auttaja-T-solujen osuuteen. Tyypin 1 diabetekseen liittyvä kudosantigeenihaplotyyppi HLA-DR3-DQ2 assosioitui kohonneeseen naiivien B-solujen ja alentuneeseen IgG-vasta-ainetta tuottavien B-muistisolujen osuuteen. Tulokset varmistavat hypoteesin, että sekä varhainen CMV-infektio että tyypin 1 diabetekseen liitetyt riskipolymorfismit ja HLA-DR/DQ-genotyyppi vaikuttavat lymfosyyttialaluokkien kehittymiseen lapsuudessa. Löydösten merkitys tyypin 1 diabeteksen patogeneesissä vaatii lisäselvityksiä

    Type 1 diabetes linked PTPN22 gene polymorphism is associated with the frequency of circulating regulatory T cells

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    Abstract Dysfunction of FOXP3‚Äźpositive regulatory T cells (Tregs) likely plays a major role in the pathogenesis of multiple autoimmune diseases including type 1 diabetes (T1D). Whether genetic polymorphisms associated with the risk of autoimmune diseases affect Treg frequency or function is currently unclear. Here, we analysed the effect of T1D‚Äźassociated major HLA class II haplotypes and seven single nucleotide polymorphisms in six non‚ÄźHLA genes [INS (rs689), PTPN22 (rs2476601), IL2RA (rs12722495 and rs2104286), PTPN2 (rs45450798), CTLA4 (rs3087243), and ERBB3 (rs2292239)] on peripheral blood Treg frequencies. These were determined by flow cytometry in 65 subjects who had progressed to T1D, 86 islet autoantibody‚Äźpositive at‚Äźrisk subjects, and 215 islet autoantibody‚Äźnegative healthy controls. The PTPN22 rs2476601 risk allele A was associated with an increase in total (p = 6 √ó 10‚ĀĽ‚Ā∂) and na√Įve (p = 4 √ó 10‚ĀĽ‚ĀĶ) CD4+CD25+CD127lowFOXP3+ Treg frequencies. These findings were validated in a separate cohort comprising ten trios of healthy islet autoantibody‚Äźnegative children carrying each of the three PTPN22 rs2476601 genotypes AA, AG, and GG (p = 0.005 for total and p = 0.03 for na√Įve Tregs, respectively). In conclusion, our analysis implicates the autoimmune PTPN22 rs2476601 risk allele A in controlling the frequency of Tregs in human peripheral blood

    Viral infection-related gene upregulation in monocytes in children with signs of ő≤-cell autoimmunity

    No full text
    Abstract Objective: The pathogenesis of type 1 diabetes (T1D) is associated with genetic predisposition and immunological changes during presymptomatic disease. Differencesin immune cell subset numbers and phenotypes between T1D patients and healthy controls have been described; however, the role and function of these changes in the pathogenesis is still unclear. Here we aimed to analyze the transcriptomic landscapes of peripheral blood mononuclear cells (PBMCs) during presymptomatic disease. Methods: Transcriptomic differences in PBMCs were compared between cases positive for islet autoantibodies and autoantibody negative controls (9 case‚Äďcontrol pairs)and further in monocytes and lymphocytes separately in autoantibody positive subjects and control subjects (25 case‚Äďcontrol pairs). Results: No significant differential expression was found in either data set. However, when gene set enrichment analysis was performed, the gene sets ‚Äúdefence response to virus‚ÄĚ (FDR &lt;0.001, ranking 2), ‚Äúresponse to virus‚ÄĚ (FDR &lt;0.001, ranking 3) and ‚Äúresponse to type I interferon‚ÄĚ (FDR=0.002, ranking 12) were enriched in the upregulated genes among PBMCs in cases. Upon further analysis, this was also seen in monocytes in cases (FDR=0.01, ranking 2; FDR=0.04, ranking 3 and FDR=0.02, ranking 1, respectively) but not in lymphocytes. Conclusion: Gene set enrichment analysis of children with T1D-associated autoimmunity revealed changes in pathways relevant for virus infection in PBMCs, particularly in monocytes. Virus infections have been repeatedly implicated in the pathogenesis of T1D. These results support the viral hypothesis by suggesting altered immune activation of viral immune pathways in monocytes during diabetes
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