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Identification, Characterization and Application of Autoantigens in Type 1 Diabetes Mellitus

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Identification, Characterization and Application of Autoantigens in Type 1 Diabetes Mellitus IDENTIFICATION, CHARACTERIZATION AND APPLICATION OF AUTOANTIGENS IN TYPE 1 DIABETES MELLITUS Henk-Jan Aanstoot IDENTIFICATION, CHARACTERIZATION AND APPLICATION OF AUTOANTIGENS IN TYPE 1 DIABETES MELLITUS IDENTIFICATIE, KARAKTERISERING EN TOEPASSINGEN VAN AUTOANTIGENEN BIJ TYPE 1 DIABETES MELLITUS PROEFSCHRIFT TER VERKRIJGING VAN DE GRAAD VAN DOCTOR AAN DE ERASMUS UNIVERSITEIT ROTTERDAM OP GEZAG VAN DE RECTOR MAGNIFICUS Prof. Dr. P.WC. AKKERMANS M.Lit EN VOLGENS BESLUIT VAN HET COLLEGE VAN DEKANEN. DE OPENBARE VERDEDIGING ZAL PLAATSVINDEN OP VRIJDAG 5 NOVEMBER 1993 OM 16.00 UUR DOOR HENDRIK-JAN AANSTOOT GEBOREN TE DEVENTER OFFSETDRUKKEA!J HAVEKA BV, ALBL.ASSERDAM PROMOTIECOMMISSIE PROMOTORES: Prof. Dr. H.K.A. Visser Prof. Dr. H. Galjaard CO-PROMOTOR: Dr. G.J. Bruining OVERIGE LEDEN: Prof. Dr. S.W.J. Lamberts Prof Dr. R. Benner The work presented in this thesis was generously supported by grants from the "Ter Meulen Fonds" (Koninklijke Nederlandse Academie van Wetenschappen), the "Albert Renold Fellowship" of the European Association for the Study of Diabetes (EASD), the Sophia Foundation for Medical Research (SSWO), the Child Health and Wellbeing Fund, Rotterdam and Novo-Nordisk A/S, Denmark. Additional generous support was given by the Rotterdam Council of Clinical Genetics (Stichting Klinische Genetica Rotterdam). Printing of this thesis was possible with generous support form Novo-Nordisk, Nederland B. V. 'Door de vreugde van de ontdekking verblind, zullen wij niet uit het oog verliezen, dat het insuline nog s/echts een eerste schrede is op den weg eener oorzakelijke behandeling der suikerziekte' A.A. Hijmans van den Berg, 1925, Utrecht , Voordrachten over suikerziekte, 278. opgedragen aan de grate mensen van morgen 7 CONTENTS OUTLINE AND AIMS OF THIS THESIS 11 Chapter 1 GENERAL INTRODUCTION 13 1 .1 Diabetes Mellitus. 1. 1. 1 The Diabelic Syndrome 15 1.1.2 Classification of Diabetes Mellitus. 15 1 . 2 Type 1 Diabetes Mellitus 1.2.1 Epidemiological Characteristics 18 1.2.2 Impact on l-lealth Care. 20 1.2.3 Natural Course and Complications. 21 1 . 3 The Islets of Langerhans. 1.3.1 Anatomy of the Islets. 23 1.3.2 The Micro Society in the Islets of langerhans 24 1.3.3 Islet Development and the Relations Between Neurons 26 and 13-cells. 1.4 The Pathology of the Pancreas in Type 1 Diabetes Mellitus. 1.4.1 Studies in Post-mortem Pancreas Tissues of Diabetic Patients 31 1.4.2 The Concept of Autoimmunity in Type 1 Diabetes Mellitus. 32 1.5 Studies on Etiology and Pathogenesis in Type 1 Diabetes Mellitus. 1.5.1 Animal Models of Type 1 Dabetes Mellitus. 34 1.5.2 Genetic factors in Type 1 Diabetes Mellitus. 35 1.5.2.1 The Major Histocompatibility Complex (MHC). 35 i .5.2.2 Genetics of Type 1 Diabetes Mellitus. 37 1.5.3 Environmental Factors in Type 1 Diabetes Mellitus. 41 1.5.3.1 Viral Infections and Type 1 Diabetes Mellitus. 42 1.5.3.2 Chemicals, Food Components and Type 1 Diabetes Mellitus 43 1.5.4 The Immune System: Components and Mechanisms of Tolerance. 45 1.5.5 Tolerance and Autoimmunity. 49 1.5.6 Cellular Autoimmunity in Type 1 Diabetes Mellitus: T-lymphocytes. 54 1.5.7 Other Cells of the Immune System. 57 1.5.8 Cytokines. 58 8 1.5.9 Humoral Autoimmunity and Type 1 Diabetes Mellitus. 59 1.5.9.1 Islet Cell Cytoplasmic Antibodies. 61 1.5.9.2 Insulin Autoantibodies. 63 1.5.9.3 Autoantibodies to the 64kD/GAD. 64 1.5.9.4 Autoantibodies to a 38kD Protein. 67 1.5.9.5 Other Autoantibodies in Type 1 Diabetes Mellitus. 67 Chapter 2 THE 64kD AUTOANTIGEN IN TYPE 1 DIABETES IS THE GABA 63 SYNTHESIZING ENZYME GLUTAMIC ACID DECARBOXYLASE (GAD): Identification, characterization and implications of GAD in type 1 diabetes mellitus and Stiff-man Syndrome. 2. 1 Identification of the 64K autoantigen in insulin dependent diabetes as the 85 GABA synthesizing enzyme glutamic acid decarboxylase. (Steinunn Baekkeskov, Henk-Jan Aanstoot, Stephan Christgau, Annette Reetz, Michele Solimena, Marilia Cascalho, Franco Folli, Hanne Richter­ Oiesen and Pietro De Camilli, Nature 1990;347:151~156.) 2.2 Stiff~man Syndrome and Insulin Dependent Diabetes Mellitus: Similarities and 93 Differences in Autoimmune Reactions. H. Aanstoot, A. Michaels, S. Christgau, Y. Shi, J. Kim and S. Baekkeskov. In: Motor Unit Hyperactivity States, R.B. Layzer et aJ (eds.), Raven Press, Ltd New York, 1993). 2.3. Studies on the characterization of GAD in B~cells and neurons. 111 2.3.1 Pancreatic B~cells Express Two Autoantigenic Forms of Glutamic Acid 113 Decarboxylase, a 65-kDa Hydrophilic Form and a 64kDa Amphiphilic Form Which Can Be Both Membrane-bound and Soluble. Stephan Christgau, Helen Schierbeck, Henk-Jan Aanstoot, Lissi Aagaard, Kathi Begley, Hans Kofod, Kim Hejnaes and Steinunn Baekkeskov, J. Bioi. Chern. 1991 ;266:21257-21264. 2.3.2 Membrane Anchoring of the Autoantigen GAD65 to Microvesicles in 123 Pancreatic B-cetls by Patmitoylation in the NH2-Terminal Domain. Stephan Christgau, Henk-Jan Aanstoot, Helen Schierbeck, Kathi Begley, Soren Tullin, Kim Hejnaes and Steinunn Baekkeskov. J. Cell Bioi. 1992;118:309-320. 9 Chapter 3 AUTOANTIBODIES TO GAD IN TYPE-1 DIABETES MELLITUS. 137 3.1 Autoantibodies to Glutamic Acid Decarboxylase (GAD) in Type~i Diabetes 139 Mellitus: Improved Analysis in Newly Diagnosed Patients Using Recombinant GAD65 and Comparison With Analysis of 64k/GAD Antibodies Using Rat Islets. Henk·Jan Aanstoot, John Kim, Marc Jaffe, Stephan Christgau, Yuguang Shi, Joan Qan, Jaques Molenaar, G.Jan Bruining and Steinunn Baekkeskov. Submitted for publication. 3.2 Value of Antibodies to GAD65 Combined with Islet Cell Cytoplasmic Antibodies 157 for Predicing Type-1 (Insulin Dependent) Diabetes Mellitus in a Childhood Population. Henk-Jan Aanstoot, Engilbert Sigurdsson, Yuguang Shi, Stephan Christgau, Joan Quan, Derek Grobbee, G.Jan Bruining, Jaques L Molenaar, Albert Hofman and Steinunn Baekkeskov. Submitted for publication. Chapter 4 THE 38kD AUTOANTIGEN IN TYPE 1 DIABETES MELLITUS. 177 4. 1 Identification and Characterization of a 38k0 Pancreatic B-cell Antigen Which Together With Glutamic Acid Decarboxylase Marks the Early Phases of Autoimmune Responses in Type 1 Diabetes. Henk~Jan Aanstoot, John Kim, Mikael Knip, Mark Atkinson, Peter Mose-Larsen, Stephan Fey, Qin Fu, Johnny Ludvigsson, Mona Landin, Jan Bruining, Noel Maclaren, Hans Akerblom and Steinunn Baekkeskov. Submitted for publication. Chapter 5 GENERAL DISCUSSION 199 5.1 The 64kD Antigen in GAD: Biochemical Function and Characteristics in brain 201 5.2 Tissue Distribution and GABA-ergic System in the Pancreas 205 5.3 Type 1 Diabetes Mellitus: An Immunological Disturbance 208 5.4 GAD and the 38kD Molecule in Future Type 1 Diabetes Research 212 5.5 Prediction and Prevention of Type 1 Diabetes Mellitus 217 Chapter S LIST OF ABBREVIATIONS 237 SUMMARY I SAMENVATTING 239 DANKWOORD 247 CURRICULUM VITAE 249 10 Outline 11 Outline ol !his thesis Type 1 diabetes mellitus or insulin dependent diabetes mellitus is a disease characterized by the selective destruction of insulin producing B-cells in the islets of Langerhans. The exact cause of this destruction is unknown, but is mediated by cells of the immune system. The immune system has a remarkable ability to rec­ ognize self from non-self, thereby providing a constant surveillance-mechanism that protects us for foreign invaders. This mechanism has failed in type 1 diabetes and attacks and destroys B-cells. The autoimmune basis of type 1 diabetes is de­ scribed in chapter 1. The central problem in autoimmunity is why and how the im­ mune system sometimes fails to distinguish between self and non-self. Re-instruct­ ing the immune system or blocking faulty immune reactions could result in primary­ or secondary prevention of type 1 Diabetes Mellitus. This requires however, the molecular dissection of the process, including the identification of B-cell proteins involved in the autoimmune reactions. This thesis aims to contribute to this by the identification and characterization of two humoral autoantigens in type 1 Diabetes Mellitus, a 64kD and a 38kD protein. These aims are specified as follows: 1. Identification of the 64kD autoantigen in type 1 Diabetes Mellitus. 2. Biochemical and Cell biological characterization of the 64kD protein. 3. Identification of the 38kD autoantigen in type 1 Diabetes Mellitus. 4. Biochemical and Cell biological characterization of the 38kD protein. 5. Analysis of the frequencies of autoantibodies to the 64kD and the 38kD auto­ antigen at clinical diagnosis and in the prediabetic period. 6. Assessment of the predictive value of these autoantibodies, in particular in relation to other markers of autoimmune B-cell destruction. In chapter 2 experimental work is presented that identified the 64kD auto­ antigen as the neurotransmitter y-amino butyric acid (GABA) synthesizing enzyme Glutamic Acid Decarboxylase (GAD). This identification was the result of the com­ bination of clinical and laboratory data. The 64kD/GAD autoantigen was found to be a target for humoral autoimmunity in both type 1 Diabetes Mellitus and in the neurological disease Stiff-man syndrome. Differences between the two diseases in antigenicity towards GAD were found. From biochemical and cell biological studies presented in chapter 2 it was concluded that the 2 forms of GAD, found in pancreatic islets of Langerhans were identical to the 2 forms found in brain. One form of GAD has a molecular weight of 67kD and is usually referred to as GADs?. This molecule is water soluble. The second form of GAD was originally described as the 64kD autoantigen. The calculated molecular weight is 65kD and hence this Outline 12 molecule is now referred to as GAD65· GAD65 can be soluble and membrane bound. We found that membrane binding of GAD65 is a two-step process. The second step involves palmitoylation of the protein.
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