Immunoregulatory differences between adult onset type 1 diabetes and latent autoimmune diabetes in adults (LADA)

Magnus Hillman

Immunoregulatory differences between adult onset type 1 diabetes and latent autoimmune diabetes in adults (LADA)

Magnus Hillman

Medicin/akutsjukvård, Lund

Forskningsoutput: Avhandling › Doktorsavhandling (sammanläggning)

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Sammanfattning

Popular Abstract in Swedish
Autoimmun diabetes karakteriseras av cell medierad autoimmunitet mot insulinproducerande beta celler i Langerhanska öar. Typ 1 diabetes är den största typen av diabetes i barn och ungdomar och antas vara orsakad av Th1-cell drivet angrepp av beta celler. Den betydligt vanligare typ 2 diabetes antas inte vara en autoimmun sjukdom men diabetes specifika autoantikroppar (ICA eller GADA) hittas i 5-15% av fallen. Dessa patienter brukar benämnas latent autoimmun diabetes hos vuxna eller LADA. Det har aldrig varit helt klart om LADA är en helt egen sjukdom eller om den borde räknas till typ1 diabetes. Individer med LADA har bättre bevarad insulin sekretion och långsammare beta-cell död vid klinisk diagnos jämfört med typ 1 diabetes. Dessutom finns det vuxna patienter med typ 1 diabetes som delar det snabba sjukdomsförloppet som normalt ses vid typ 1 diabetes hos barn. Hypotesen var därför att den autoimmuna aktiviteten skiljer sig mellan typ 1 diabetes och LADA. Syftet var att identifiera några av de immunoregulatoriska egenskaper som kan förklara skillnaden i sjukdomsförlopp mellan dessa två grupper.

Heterozygoti för de diabetes associerade hög risk haplotyperna HLA DR3/DQ2-DR4/DQ8 ansågs vara en riskfaktor för både typ 1 diabetes hos vuxna och LADA. Dessutom visade homozygoti för mikrosatellitmarkören TNFa2 en ökad risk för både typ 1 diabetes och LADA, troligen beroende på kopplingsojämvikten mellan HLA haplotyperna. Närvaro av antingen HLA DR3/DQ2 eller DR4/DQ8 medförde också en signifikant ökad risk för typ 1 diabetes men inte för LADA.

Autoantikroppar riktade mot glutaminsyradekarboxylas 65 (GADA) var framförallt av IgG1 subklass vid både typ 1 diabetes och LADA. Däremot var IgG4 subklassen den näst vanligaste subklassen vid LADA men kunde inte detekteras hos patienter med typ 1 diabetes vid klinisk diagnos. Detta talar för ett större engagemang av Th2 celler i LADA jämför med typ 1 diabetes. Nivåerna av alla GADA IgG-subklasser minskade i typ 1 diabetes under tre år efter diagnos medan de förblev oförändrade i LADA. Detta indikerar på en kvarhållande skillnad i autoimmun respons mot beta cell antigenet GAD65 mellan grupperna. Den långsammare beta cell destruktionen i LADA kan bero på ett mer balanserat T-cell svar vilket reducerar den cytotoxiska Th1 cellmedierade responsen. Typ 1 diabetes och LADA kan därför anses vara olika varianter av beta cell autoimmunitet.

Originalspråk	engelska
Kvalifikation	Doktor
Tilldelande institution	Medicin/akutsjukvård, Lund
Handledare	Landin-Olsson, Mona, handledare
Tilldelningsdatum	2007 maj 16
Förlag	Department of Clinical Sciences, Lund University
ISBN (tryckt)	978-91-85559-61-9
Status	Published - 2007

Bibliografisk information

Defence details

Date: 2007-05-16
Time: 13:15
Place: BMC Segerfalk lecture hall

External reviewer(s)

Name: Nerup, Jörn
Title: Professor
Affiliation: Steno Diabetes Centra, Gentofte, Denmark

---

<div class="article_info">C Törn, M Hillman, C.B Sanjeevi and M Landin-Olsson. <span class="article_issue_date">2006</span>. <span class="article_title">Polymorphisms of TNF microsatellite marker a and HLA-DR-DQ in diabetes mellitus-a study in 609 Swedish subjects.</span> <span class="journal_series_title">Hum Immunol</span>, <span class="journal_volume">vol 67</span> <span class="journal_pages">pp 527-534</span>.</div>
<div class="article_info">M Hillman, C Törn, H Thorgeirsson and M Landin-Olsson. <span class="article_issue_date">2004</span>. <span class="article_title">IgG(4)-subclass of glutamic acid decarboxylase antibody is more frequent in latent autoimmune diabetes in adults than in type 1 diabetes.</span> <span class="journal_series_title">Diabetologia</span>, <span class="journal_volume">vol 47</span> <span class="journal_pages">pp 1984-1989</span>.</div>
<div class="article_info">M Hillman, C Törn and M Landin-Olsson. <span class="article_issue_date"></span>. <span class="article_title">Determination of GADA IgG subclasses – A comparison of three immunoprecipitation assays (IPAs).</span> (submitted)</div>
<div class="article_info">M Hillman, C Törn and M Landin-Olsson. <span class="article_issue_date"></span>. <span class="article_title">The GAD65Ab IgG subclass profile differs between T1DM and LADA up to three years after clinical onset.</span> (manuscript)</div>

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title = "Immunoregulatory differences between adult onset type 1 diabetes and latent autoimmune diabetes in adults (LADA)",

abstract = "Autoimmune diabetes is characterized by cell mediated autoimmunity against insulin producing beta cells in pancreatic islets. Type 1 diabetes is the major cause of diabetes in children and adolescents and is believed to be mediated by a Thl driven destruction of beta cells. The much more prevalent type 2 diabetes is not considered as an autoimmune disease but diabetes specific autoantibodies (ICA or GADA) are found in 5-15% of the cases. These subjects are referred to as latent autoimmune diabetes in adults (LADA). It has been questioned if LADA is a unique entity or should be considered as type 1 diabetes. Subjects with LADA have a better preserved insulin secretion and a slower progression to beta cell failure at clinical onset compared to subjects with type 1 diabetes. Furthermore, there are adult onset type 1 diabetic patients that share the rapid progression to beta cell failure with juvenile onset diabetes. The hypothesis was therefore that type 1 diabetes and LADA have different autoimmune activity. The aim was to identify some of the immunoregulatory events that could explain differences in disease progression between the groups. Heterozygosity of the diabetes associated high risk HLA haplotypes DR3/DQ2-DR4/DQ8 was considered as a risk factor for both adult onset type 1 diabetes and LADA. Also homozygosity for the microsatellite marker TNFa2 conferred an increased risk for both type 1 diabetes and LADA even though this was probably due to linkage disequilibrium with the HLA haplotypes. However, presence of either one of HLA DR3/DQ2 or DR4/DQ8 conferred an increased risk of type 1 diabetes but not LADA. Autoantibodies directed against glutamic acid decarboxylase 65 (GADA) were predominantly of the IgGl subclass in both adult onset type 1 diabetes and LADA. Moreover, the IgG4 subclass was the second most common subclass in LADA but below detection limit in type 1 diabetes at clinical onset. This suggests a larger involvement of Th2 cells in LADA compared to in type 1 diabetes. The levels of all the GADA IgG subclasses decreased in type 1 diabetes three years after clinical onset while LADA remained their subclass profiles indicating a sustained difference in autoimmune response against the beta cell antigen GAD65 between the groups. The slower progression of beta cell failure in LADA might be due to a more balanced T cell response that reduces the cytotoxic Thl cell mediated response. Type 1 diabetes and LADA could thus be considered as different variations of autoimmunity.",

keywords = "Endokrinologi, sekretion, diabetologi, diabetology, secreting systems, Isotype class switch, Endocrinology, LADA, Autoantibodies, Autoimmunity, Type 1 diabetes",

author = "Magnus Hillman",

note = "Defence details Date: 2007-05-16 Time: 13:15 Place: BMC Segerfalk lecture hall External reviewer(s) Name: Nerup, J{\"o}rn Title: Professor Affiliation: Steno Diabetes Centra, Gentofte, Denmark --- <div class={"}article_info{"}>C T{\"o}rn, M Hillman, C.B Sanjeevi and M Landin-Olsson. <span class={"}article_issue_date{"}>2006</span>. <span class={"}article_title{"}>Polymorphisms of TNF microsatellite marker a and HLA-DR-DQ in diabetes mellitus-a study in 609 Swedish subjects.</span> <span class={"}journal_series_title{"}>Hum Immunol</span>, <span class={"}journal_volume{"}>vol 67</span> <span class={"}journal_pages{"}>pp 527-534</span>.</div> <div class={"}article_info{"}>M Hillman, C T{\"o}rn, H Thorgeirsson and M Landin-Olsson. <span class={"}article_issue_date{"}>2004</span>. <span class={"}article_title{"}>IgG(4)-subclass of glutamic acid decarboxylase antibody is more frequent in latent autoimmune diabetes in adults than in type 1 diabetes.</span> <span class={"}journal_series_title{"}>Diabetologia</span>, <span class={"}journal_volume{"}>vol 47</span> <span class={"}journal_pages{"}>pp 1984-1989</span>.</div> <div class={"}article_info{"}>M Hillman, C T{\"o}rn and M Landin-Olsson. <span class={"}article_issue_date{"}></span>. <span class={"}article_title{"}>Determination of GADA IgG subclasses – A comparison of three immunoprecipitation assays (IPAs).</span> (submitted)</div> <div class={"}article_info{"}>M Hillman, C T{\"o}rn and M Landin-Olsson. <span class={"}article_issue_date{"}></span>. <span class={"}article_title{"}>The GAD65Ab IgG subclass profile differs between T1DM and LADA up to three years after clinical onset.</span> (manuscript)</div>",

year = "2007",

language = "English",

isbn = "978-91-85559-61-9",

publisher = "Department of Clinical Sciences, Lund University",

type = "Doctoral Thesis (compilation)",

school = "Medicine/Emergency Medicine, Lund",

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T1 - Immunoregulatory differences between adult onset type 1 diabetes and latent autoimmune diabetes in adults (LADA)

AU - Hillman, Magnus

N1 - Defence details Date: 2007-05-16 Time: 13:15 Place: BMC Segerfalk lecture hall External reviewer(s) Name: Nerup, Jörn Title: Professor Affiliation: Steno Diabetes Centra, Gentofte, Denmark --- <div class="article_info">C Törn, M Hillman, C.B Sanjeevi and M Landin-Olsson. <span class="article_issue_date">2006</span>. <span class="article_title">Polymorphisms of TNF microsatellite marker a and HLA-DR-DQ in diabetes mellitus-a study in 609 Swedish subjects.</span> <span class="journal_series_title">Hum Immunol</span>, <span class="journal_volume">vol 67</span> <span class="journal_pages">pp 527-534</span>.</div> <div class="article_info">M Hillman, C Törn, H Thorgeirsson and M Landin-Olsson. <span class="article_issue_date">2004</span>. <span class="article_title">IgG(4)-subclass of glutamic acid decarboxylase antibody is more frequent in latent autoimmune diabetes in adults than in type 1 diabetes.</span> <span class="journal_series_title">Diabetologia</span>, <span class="journal_volume">vol 47</span> <span class="journal_pages">pp 1984-1989</span>.</div> <div class="article_info">M Hillman, C Törn and M Landin-Olsson. <span class="article_issue_date"></span>. <span class="article_title">Determination of GADA IgG subclasses – A comparison of three immunoprecipitation assays (IPAs).</span> (submitted)</div> <div class="article_info">M Hillman, C Törn and M Landin-Olsson. <span class="article_issue_date"></span>. <span class="article_title">The GAD65Ab IgG subclass profile differs between T1DM and LADA up to three years after clinical onset.</span> (manuscript)</div>

PY - 2007

Y1 - 2007

N2 - Autoimmune diabetes is characterized by cell mediated autoimmunity against insulin producing beta cells in pancreatic islets. Type 1 diabetes is the major cause of diabetes in children and adolescents and is believed to be mediated by a Thl driven destruction of beta cells. The much more prevalent type 2 diabetes is not considered as an autoimmune disease but diabetes specific autoantibodies (ICA or GADA) are found in 5-15% of the cases. These subjects are referred to as latent autoimmune diabetes in adults (LADA). It has been questioned if LADA is a unique entity or should be considered as type 1 diabetes. Subjects with LADA have a better preserved insulin secretion and a slower progression to beta cell failure at clinical onset compared to subjects with type 1 diabetes. Furthermore, there are adult onset type 1 diabetic patients that share the rapid progression to beta cell failure with juvenile onset diabetes. The hypothesis was therefore that type 1 diabetes and LADA have different autoimmune activity. The aim was to identify some of the immunoregulatory events that could explain differences in disease progression between the groups. Heterozygosity of the diabetes associated high risk HLA haplotypes DR3/DQ2-DR4/DQ8 was considered as a risk factor for both adult onset type 1 diabetes and LADA. Also homozygosity for the microsatellite marker TNFa2 conferred an increased risk for both type 1 diabetes and LADA even though this was probably due to linkage disequilibrium with the HLA haplotypes. However, presence of either one of HLA DR3/DQ2 or DR4/DQ8 conferred an increased risk of type 1 diabetes but not LADA. Autoantibodies directed against glutamic acid decarboxylase 65 (GADA) were predominantly of the IgGl subclass in both adult onset type 1 diabetes and LADA. Moreover, the IgG4 subclass was the second most common subclass in LADA but below detection limit in type 1 diabetes at clinical onset. This suggests a larger involvement of Th2 cells in LADA compared to in type 1 diabetes. The levels of all the GADA IgG subclasses decreased in type 1 diabetes three years after clinical onset while LADA remained their subclass profiles indicating a sustained difference in autoimmune response against the beta cell antigen GAD65 between the groups. The slower progression of beta cell failure in LADA might be due to a more balanced T cell response that reduces the cytotoxic Thl cell mediated response. Type 1 diabetes and LADA could thus be considered as different variations of autoimmunity.

AB - Autoimmune diabetes is characterized by cell mediated autoimmunity against insulin producing beta cells in pancreatic islets. Type 1 diabetes is the major cause of diabetes in children and adolescents and is believed to be mediated by a Thl driven destruction of beta cells. The much more prevalent type 2 diabetes is not considered as an autoimmune disease but diabetes specific autoantibodies (ICA or GADA) are found in 5-15% of the cases. These subjects are referred to as latent autoimmune diabetes in adults (LADA). It has been questioned if LADA is a unique entity or should be considered as type 1 diabetes. Subjects with LADA have a better preserved insulin secretion and a slower progression to beta cell failure at clinical onset compared to subjects with type 1 diabetes. Furthermore, there are adult onset type 1 diabetic patients that share the rapid progression to beta cell failure with juvenile onset diabetes. The hypothesis was therefore that type 1 diabetes and LADA have different autoimmune activity. The aim was to identify some of the immunoregulatory events that could explain differences in disease progression between the groups. Heterozygosity of the diabetes associated high risk HLA haplotypes DR3/DQ2-DR4/DQ8 was considered as a risk factor for both adult onset type 1 diabetes and LADA. Also homozygosity for the microsatellite marker TNFa2 conferred an increased risk for both type 1 diabetes and LADA even though this was probably due to linkage disequilibrium with the HLA haplotypes. However, presence of either one of HLA DR3/DQ2 or DR4/DQ8 conferred an increased risk of type 1 diabetes but not LADA. Autoantibodies directed against glutamic acid decarboxylase 65 (GADA) were predominantly of the IgGl subclass in both adult onset type 1 diabetes and LADA. Moreover, the IgG4 subclass was the second most common subclass in LADA but below detection limit in type 1 diabetes at clinical onset. This suggests a larger involvement of Th2 cells in LADA compared to in type 1 diabetes. The levels of all the GADA IgG subclasses decreased in type 1 diabetes three years after clinical onset while LADA remained their subclass profiles indicating a sustained difference in autoimmune response against the beta cell antigen GAD65 between the groups. The slower progression of beta cell failure in LADA might be due to a more balanced T cell response that reduces the cytotoxic Thl cell mediated response. Type 1 diabetes and LADA could thus be considered as different variations of autoimmunity.

KW - Endokrinologi

KW - sekretion

KW - diabetologi

KW - diabetology

KW - secreting systems

KW - Isotype class switch

KW - Endocrinology

KW - LADA

KW - Autoantibodies

KW - Autoimmunity

KW - Type 1 diabetes

M3 - Doctoral Thesis (compilation)

SN - 978-91-85559-61-9

PB - Department of Clinical Sciences, Lund University

ER -

Immunoregulatory differences between adult onset type 1 diabetes and latent autoimmune diabetes in adults (LADA)

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