Immunoendocrinology: Scientific and Clinical Aspects (eBook)

Immunoendocrinology:Scientific and Clinical Aspects 3
Dedication 5
Preface 7
Contents 9
Contributors 11
Part I:Immunoendocrinology: Scientific and Clinical Aspects 15
Chapter 1: Primer on Immunoendocrinology 16
INTRODUCTION 16
HUMAN AND MURINE MHC GENES 18
TCR GENE REARRANGEMENT 20
CENTRAL AND PERIPHERAL TOLERANCE 22
CONCLUSIONS 23
REFERENCES 25
Chapter 2: Discovering Novel Antigens 28
INTRODUCTION 28
Islet Cell Autoantibody 31
B CELL AUTOANTIGEN DISCOVERY 33
Screening l gt-11 Expression Libraries 33
Screening Fusion-Peptide Libraries 35
Western Blotting of Human Islet Extracts with T1D Sera 35
Immunoprecipitation of Islet Antigens with T1D Patient Sera 35
Glycolipid Preabsorption of the ICA Reaction 35
Screening Ganglioside ELISAs with T1D Sera 36
Generation of Hybridomas of Islet Infiltrating B Lymphocytes and Identification of Their Cognate Antigen 36
Screening Nucleic Acid Programmable Protein Arrays 36
Candidate B Cell Gene Approach 37
Displaced Binding of mAbs by T1D Sera 39
Proteomics 40
T CELL AUTOANTIGEN DISCOVERY 40
T Cell Responses to Epitope Libraries 41
IGRP 41
Dystrophia Myotonica Kinase 42
ZnT8 AS A TARGET OF T1D AUTOIMMUNITY 42
ZnT8 Autoantibody Detection 43
Immunodominant Epitopes 44
CONCLUSIONS 46
REFERENCES 47
Chapter 3: Developing and Validating High Sensitivity/Specificity Autoantibody Assays 53
AUTOANTIBODIES AS HETERO GENEOUS ANALYTES 54
CONSIDERATIONS ON THE TARGET OR COGNATE AUTOANTIGEN 55
CHARACTERISTICS OF THE AUTOANTIBODY DETECTION ASSAY 56
ASSAY SPECIFICITY AND DISEASE RELEVANCE 57
HIGH QUALITY STANDARDISED ASSAYS 58
THRESHOLDS FOR POSITIVITY 59
FUTURE PERSPECTIVES 61
REFERENCES 62
Chapter 4: Characterizing T-Cell Autoimmunity 65
MAINTENANCE OF TOLERANCE TO SELF-ANTIGENS 65
PERIPHERAL AUTOREACTIVITY IN T1D 70
THERAPEUTIC TARGETING OF ANTIGEN-SPECIFIC AUTOREACTIVE T CELLS 73
REFERENCES 75
Chapter 5: Metabolic Syndrome and Inflammation 81
INTRODUCTION 81
Definition and Diagnostic Criteria of the Metabolic Syndrome 83
Interactions Between Metabolic Syndrome, Oxidative Stress, and Inflammation 84
ROLE OF INFLAMMATION IN METABOLIC SYNDROME AND TYPE 2 DIABETES 87
C-Reactive Protein 88
PROINFLAMMATORY CYTOKINES 90
TNFa and IL-1b 90
IL-6 92
MCP-1 92
Resistin 93
Plasminogen-Activator Inhibitor 1 93
INNATE IMMUNITY IN DIABETES AND OBESITY-RELATED INFLAMMATION 93
IS THE INFLAMMASOME INVOLVED IN TYPE 2 DIABETES AND METABOLIC SYNDROME? 94
EFFECTS ON INFLAMMATION BY MOST WIDELY USED DRUGS FOR INSULIN RESISTANCE AND METABOLIC SYNDROME 96
CONCLUDING REMARKS 97
REFERENCES 97
Part II:Syndromes 105
Chapter 6: The Mouse Model of Autoimmune Polyglandular Syndrome Type 1 106
THE Aire-KNOCKOUT MOUSE AS A MODEL OF HUMAN APS-1 106
APS-1 in Humans: A Monogenic Autoimmune Disease Resulting from Mutations in the AIRE Gene 106
The Mouse Model of APS-1 Broadly Recapitulates the Autoimmunity Observed in Human APS-1 108
THE MECHANISM OF Aire-DEFICIENCY UNRAVELED IN MICE 111
Aire’s Expression in the Thymus Provides Clues to Its Function 111
Thymic Epithelial Cells Are Unique Sources of TSA Expression 112
Aire Regulates Expression of TSAs in mTECs 112
The Molecular Mechanism of AIRE Function 114
Cellular Mechanisms of Disease in Aire-Deficient Mice 117
Defining the Antigen-Specific Response in Aire-Knockout Mice: Identification of Disease-Relevant Autoantigens 118
Unique Autosomal Dominant AIRE Allele Modeled in Mouse 119
Extrathymic Aire Expression and Peripheral Self-Tolerance 120
CONCLUSIONS 121
References 121
Chapter 7: Autoimmune Polyendocrine Syndrome Type I: Man 125
INTRODUCTION 125
ENDOCRINE MANIFESTATIONS 127
Hypoparathyroidism 127
Adrenal Insufficiency 128
Gonadal Insufficiency 129
Type 1 Diabetes 129
Thyroid Disease 129
MUCOCUTANEOUS CANDIDIASIS 129
Chronic Mucocutaneous Candidiasis 129
GASTRO-INTESTINAL MANIFESTATIONS 130
ECTODERMAL MANIFESTATIONS 131
Eye Manifestations 131
Skin Manifestations 131
Enamel Dysplasia 131
Other and Rare Manifestations 132
Diagnosis 132
Natural Course and Follow-Up 132
Future Prospects 133
REFERENCES 136
Chapter 8: IPEX Syndrome: Clinical Profile, Biological Features, and Current Treatment 139
INTRODUCTION 139
CLINICAL MANIFESTATIONS AND LABORATORY FINDINGS 140
FOXP3 STRUCTURE AND FUNCTION 144
REGULATORY T CELLS IN IPEX 145
THERAPIES FOR IPEX: CURRENT LIMITATIONS AND FUTURE PERSPECTIVES 147
CONCLUSIONS 149
REFERENCES 149
Chapter 9: Autoimmune Polyendocrine Syndrome Type 2: Pathophysiology, Natural History, and Clinical Manifestations 153
PATHO-PHYSIOLOGY 155
Overlapping Genetic Risk (Table 9.2) 155
Environmental Factors 158
Markers of the Autoimmune Process (Table 9.2) 158
Markers of Gland Failure 159
Clinical Disease (Table 9.2) 160
DIAGNOSIS AND TREATMENT 161
CONCLUSION 162
REFERENCES 162
Chapter 10: Drug-Induced Endocrine Autoimmunity 166
INTERFERON ALPHA 167
The interferons are a group of proteins that are characterized by antiviral activity, growth regulatory properties, and a wide 167
THYROID DYSFUNCTION 168
AUTOIMMUNE IFNa-INDUCED THYROIDITIS 168
AUTOIMMUNE HYPOTHYROIDISM 168
GRAVES’ DISEASE 169
Predisposition 170
GENETIC FACTORS 170
NONGENETIC FACTORS 171
Pathogenesis 172
Direct Effects of IFNa 172
NONAUTO-IMMUNE INTERFERON-INDUCED THYROIDITIS 173
Diabetes Mellitus 174
EPIDEMIOLOGY 174
PATHOGENESIS 175
THE NATURAL HISTORY OF T1D DURING IFNa TREATMENT 176
Adrenal Dysfunction 178
Pituitary Dysfunction 178
INTERLEUKIN 2 178
IPILIMUMAB (ANTI-CTLA4 ANTIBODY) 179
GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR 179
CAMPATH-1H (ALEMTUZUMAB) 180
AMIODARONE 180
ANTIRETROVIRAL THERAPY 181
SULFHYDRYL COMPOUNDS AND INSULIN AUTOIMMUNE SYNDROME 181
REFERENCES 183
Part III:Specific Diseases 189
Chapter 11: The BB Rat 190
INTRODUCTION 190
DESCRIPTION OF THE INSULITIS IN BBDP RATS 191
BETA CELLS IN THE DEVELOPMENT OF DIABETES IN THE BBDP RAT 191
ANTIGEN-PRESENTING CELLS IN THE DEVELOPMENT OF DIABETES IN THE BBDP RAT 192
T CELLS IN THE DEVELOPMENT OF DIABETES IN THE BBDP RAT 194
OTHER LEUKOCYTES IN THE DEVELOPMENT OF DIABETES IN THE BBDP RAT 198
CONCLUSION 198
REFERENCES 199
Chapter 12: Immunopathogenesis of the NOD Mouse 205
INTRODUCTION 205
GENETICS 206
INNATE IMMUNITY 208
ADAPTIVE IMMUNITY 208
B Lymphocytes 208
T Lymphocytes 209
REGULATORY T CELLS IN NOD MICE 210
HUMANIZED MICE 211
“IMMUNOLOGIC HOMUNCULUS” HYPOTHESIS 212
THE NOD AS A PRECLINICAL MODEL 213
CONCLUSIONS 214
ACKNOWLEDGMENT 214
REFERENCES 214
Chapter 13: Virus-Induced Type 1 Diabetes in the Rat 220
TYPE 1 DIABETES 220
THE BIOBREEDING AND LEW1.WR1 RAT MODELS OF DIABETES 221
KILHAM RAT PARVOVIRUS AND DIABETES INDUCTION 221
PARVOVIRUSES AND AUTOIMMUNITY IN HUMANS 224
HUMORAL AND CELLULAR IMMUNITY TO KRV IN THE BBDR RAT 224
KRV-INDUCED TREG DOWN-MODULATION 225
THE ROLE OF TLR PATHWAYS IN KRV-INDUCED DIABETES 225
KRV-INDUCED PROINFLAM-MATORY PATHWAYS IN THE BBDR RAT 227
GENES INVOLVED IN KRV-INDUCED T1D 229
SUMMARY 230
REFERENCES 231
Chapter 14: Autoimmune Pathology of Type 1 Diabetes 235
INTRODUCTION 235
THE CONUNDRUM OF EVALUATING HUMAN PANCREAS 236
WHAT IS “INSULITIS?” 238
THE PANCREAS BEFORE AND AFTER CLINICAL ONSET OF T1D 239
SIX KEY FEATURES OF b CELL-CONTAINING ISLETS IN HUMAN T1D AT CLINICAL PRESENTATION 241
Feature 1: Cells Composing the Insulitis Lesion 241
Feature 2: Fas Expression 243
Feature 3: b Cell Apoptosis 243
Feature 4: Aberrant b Cell Expression of Class II MHC 243
Feature 5: Hyperexpression of Class I MHC by Insulin-Containing Islets 246
Feature 6: b cell Expression of Interferon a 247
REGENERATION IN THE PANCREAS OF HUMAN T1D: FACT OR FICTION? 248
NON-AUTOIMMUNE FORMS OF T1D 249
T1D Secondary to a Clinical History of T2D 249
T1D Secondary to Persistent Hyperinsulinemic Hypoglycemia of Infancy (PHHI) 250
Monogenic Forms of T1D 250
CONCLUSIONS 251
REFERENCES 252
Chapter 15: Genetics of Type 1 Diabetes 254
INTRODUCTION 254
ANIMAL MODELS 256
TYPE 1A DIABETES OF MAN 257
Descriptive Genetics 257
The Major Histocompatibility Complex 258
Nonmajor Histocompatibility Complex Genes 261
The Insulin Gene (Chromosome 11p) 261
PTPN22 (Chromosome 1p13) 262
CTLA4 (Chromosome 2q31) 262
IL2RA (Il2 Receptor Alpha Chain-CD25-Chromosome 10p15-p14) 262
Additional Loci 262
Combinatorial Analysis 264
Gene/Environment 264
CONCLUSIONS 264
REFERENCES 265
Chapter 16: Epidemiology of Type 1 Diabetes 269
NATURAL HISTORY OF TYPE 1 DIABETES 270
PREVALENCE AND INCIDENCE 271
TYPE 1 DIABETES ETIOLOGY 273
Genetic Risk Factors for Type 1 Diabetes 273
Environmental Risk Factors for Type 1 Diabetes 274
Viruses 275
Nutrition 276
Childhood Obesity and Rapid Growth Rate 277
Psychosocial Stress 277
Perinatal Factors 277
CONCLUSION 278
REFERENCES 278
Chapter 17: Natural History of Type 1 Diabetes 281
CHANGING GENETIC PROFILE CONFIRMS ENVIRONMENTAL INFLUENCE 282
ISLET CELL ANTIBODIES AND BEYOND 283
TITER, IGG SUBCLASS, AND AFFINITY OF ANTIBODIES: ADDITIONAL PREDICTORS 283
ZINC TRANSPORTER: A NEW ANTIGEN TARGET IN TYPE 1 DIABETES 284
b-CELL DESTRUCTION AND DYSFUNCTION 285
INSULIN RESISTANCE IN PRE-CLINICAL TYPE 1 DIABETES 287
IMPAIRED GLUCOSE TOLERANCE 289
SUMMARY 290
REFERENCES 290
Chapter 18: Immunotherapy of Type-1 Diabetes: Immunoprevention and Immunoreversal 295
INTRODUCTION 295
IMMUNO-PATHOGENESIS: MURINE MODELS, T-CELLS, B LYMPHOCYTES, INNATE IMMUNE SYSTEM 296
IMMUNO-PATHOGENESIS: HUMAN DATA, PREDICTION OF DEVELOPMENT, T-CELL ISLET INFILTRATES 298
IMMUNO-MODULATION: IMMUNO-PREVENTION VS. IMMUNOREVERSAL 299
ANTIGEN SPECIFIC IMMUNO-MODULATION 300
Mechanisms 300
Insulin 301
Glutamic Acid Decarboxylase 65 302
Diapep 277 303
NONANTIGEN SPECIFIC IMMUNO-MODULATION 304
Mechanisms 304
SYSTEMIC IMMUNO-SUPPRESSION: CYCLOSPORINE, AZATHIOPRINE, PREDNISONE 305
BIOLOGICAL IMMUNO-MODULATORS 305
Anti-CD3 mAbs 305
Rituximab (Anti-CD20) 307
Abatacept (CTLA4-Ig) 307
COMBINATION THERAPIES 308
CONCLUSIONS 309
REFERENCES 310
Chapter 19: Latent Autoimmune Diabetes in Adults 317
INTRODUCTION 317
WHAT IS LATENT AUTOIMMUNE DIABETES OF ADULTS? 318
AUTOANTIBODIES 318
Autoantibodies in T1DM and LADA Patients 318
Autoantibodies in T2DM and LADA 320
ISLET REACTIVE T CELLS 321
T Cell Responses to Islet Proteins in T1DM and LADA Patients 321
T-Cell Responses to Islets in T2DM and LADA Patients 322
GENETICS 323
Genetics in T1DM and LADA 323
Genetics in T2DM and LADA 324
BETA CELL FUNCTION 324
INSULIN RESISTANCE AND THE METABOLIC SYNDROME 324
IMPORTANCE OF FAMILY HISTORY IN TYPE 1, TYPE 2, AND LADA 325
TREATMENT 325
CONCLUSIONS 326
REFERENCES 326
Chapter 20: Fulminant Type 1 Diabetes Mellitus 332
INTRODUCTION 332
EPIDEMIOLOGY 334
MECHANISM OF BETA-CELL DESTRUCTION 335
THERAPY AND PROGNOSIS 340
CONCLUSIONS 341
REFERENCES 341
Chapter 21: Insulin Autoimmune Syndrome (Hirata Disease) 344
INTRODUCTION 344
INSULIN AUTOIMMUNE SYNDROME AS THE THIRD LEADING CAUSE OF SPONTANEOUS HYPOGLYCEMIA IN JAPAN 345
ONSET AGE AND SEX DISTRIBUTION, AND DURATION OF HYPOGLYCEMIA OF 330 JAPANESE IAS PATIENTS REGISTERED IN JAPAN FROM 1970 TO 200 345
DRUG EXPOSURE AHEAD OF DEVELOPMENT OF IAS AND ASSOCIATED DISEASES 346
CLINICAL FEATURES OF IAS PATIENTS OUT OF JAPAN 348
INSULIN AND INSULIN AUTOANTIBODY IN THE SERA OF THE PATIENTS WITH IAS 351
TWO GROUPS OF IAS DEFINED BY CLONALITY OF INSULIN AUTOANTIBODIES 352
CRITICAL AMINO ACIDS FOR IAS POLYCLONAL RESPONDER AND IMPORTANCE OF DR GENE PRODUCTS IN THE PRESENTATION OF HUMAN INSULIN AN 357
DIFFERENT AMINO ACIDS FOR IAS MONOCLONAL RESPONDER 359
POSSIBLE ROLE OF THE SPECIFIC AMINO ACIDS ON THE DRb-CHAIN IN IAS PATHOGENESIS 360
A CONCEPT OF DRUG-INDUCED INSULIN AUTOIMMUNE SYNDROME AND DRb1-CHAIN 362
POSTPRANDIAL HYPERGLYCEMIA IN IAS 363
A CONCEPT OF TYPE VII HYPERSENSITIVITY INTRODUCED BY INSULIN AUTOIMMUNE SYNDROME (HIRATA’S DISEASE) 364
NATURAL HISTORY OF IAS 364
REFERENCES 365
Chapter 22: Lessons from Patients with Anti-Insulin Receptor Autoantibodies 369
INTRODUCTION 369
CLINICAL CHARACTERISTICS OF TYPE B INSULIN RESISTANCE 371
METABOLIC CHARACTERISTICS OF TYPE B INSULIN RESISTANCE 373
CHARACTERISTICS OF THE ANTI-INSULIN RECEPTOR AUTOANTIBODY 375
THE PARADOX OF HYPERGLYCEMIA AND HYPOGLYCEMIA 377
TREATMENT OF TYPE B INSULIN RESISTANCE 378
CONCLUSIONS 380
REFERENCES 380
Chapter 23: Islet and Pancreas Transplantation 384
ISLET TRANSPLANTATION 384
Islet Isolation Procedures 385
Islet Infusion Procedure 385
ITX Outcomes 386
Exenatide in ITX 387
Challenges and Future Perspectives in ITX 387
PANCREAS TRANSPLANTATION 389
Hypercoagulable State in T1D/ESRD 390
Pancreas Transplant, Technical Aspects: Exocrine Drainage 391
Pancreas Transplant, Technical Aspects: Venous Drainage 391
Immunosuppression in Pancreas Transplantation 391
Induction with Daclizumab 392
Induction with Daclizumab in Combination with Thymoglobulin 392
Induction with Alemtuzumab 392
Pancreas Transplantation Outcomes 393
Challenges and Future Perspectives in Pancreas Transplantation 393
REFERENCES 394
Chapter 24: Addison’s Disease 398
INTRODUCTION 398
DIAGNOSIS AND CLINICAL MANAGEMENT OF PAI 399
ADRENAL AUTOANTIBODIES AND DIAGNOSIS OF AAD 401
GENETICS OF ISOLATED AND APS-2 ASSOCIATED AAD 404
CELLULAR AUTOIMMUNITY AND AAD 406
SUBCLINICAL AAD 407
REFERENCES 409
Chapter 25: Animal Models of Autoimmune Thyroid Disease 413
INTRODUCTION 413
HISTORY OF ANIMAL MODELS OF AUTOIMMUNE THYROID DISEASES 414
GENETIC FACTORS 415
ENVIRONMENTAL FACTORS 416
CHARACTERI-ZATION OF IMMUNE RESPONSES 417
PERIPHERAL TOLERANCE 419
CENTRAL TOLERANCE 419
CONCLUSIONS 421
REFERENCES 421
Chapter 26: Genetics of Thyroid Autoimmunity 425
INTRODUCTION 425
EPIDEMIOLOGICAL OBSERVATIONS 426
IMMUNE REGULATOR GENES AND SUSCEPTIBILITY TO AITD 426
HLA-DR 427
CTLA-4 427
CD40 429
The Protein Tyrosine Phosphatase-22 Gene 430
THYROID-SPECIFIC GENES IN AITD 431
Thyroglobulin 431
TSH Receptor 432
CONCLUSIONS: FROM GENE MAPPING TO MECHANISMS 432
REFERENCES 434
Chapter 27: Immunopathogenesis of Thyroiditis 441
INTRODUCTION 441
Sec2_27 442
IODINE AND THYROID AUTOIMMUNITY 443
T AND B CELLS IN THYROID AUTOIMMUNITY 445
CD4+CD25+ T REGULATORY CELLS AND THYROID AUTOIMMUNITY 446
APOPTOSIS AND THYROID AUTOIMMUNITY 448
CONCLUSIONS 449
REFERENCES 450
Chapter 28: Immunopathogenesis of Graves’ Disease 454
INTRODUCTION 454
AUTOIMMUNITY AND GRAVES’ DISEASE 455
THE TSH RECEPTOR ANTIGEN OF GRAVES’ DISEASE 455
HUMORAL IMMUNITY TO THE TSHR 455
TYPES OF TSHR ANTIBODIES 457
TSH RECEPTOR ANTIBODY EPITOPES 459
Monoclonal Antibodies to the TSHR 459
Epitopes of Stimulating TSHR-Abs 459
Epitopes of Blocking TSHR-Abs 460
Epitopes for Neutral TSHR-Abs 460
THYROCYTE SIGNAL TRANSDUCTION BY TSHR ANTIBODIES 461
HUMORAL IMMUNITY TO OTHER ANTIGENS IN GRAVES’ DISEASE 462
T CELLS AND GRAVES’ DISEASE 463
Antigen-Specific T Cells 463
Regulatory T Cells 463
Th17 Cells 464
INTRATHYROIDAL ANTIGEN-PRESENTATION IN GRAVES’ DISEASE 464
Thyrocytes as Antigen Presenting Cells 465
Intrathyroidal Dendritic Cells 465
Antigen Presentation by B Cells 466
PRECIPITATING GRAVES’ DISEASE: THE ENVIRONMENT VERSUS GENETIC SUSCEPTIBILITY 466
ENVIRONMENTAL PRECIPITATORS 467
GRAVES’ DISEASE AND THE HYGIENE HYPOTHESIS 468
INFECTIONS AND GRAVES’ DISEASE 469
INFECTIOUS MECHANISMS IN GRAVES’ DISEASE 469
A NOTE ON THE FEMALE SEX AND SUSCEPTIBILITY TO GRAVES’ DISEASE 471
DRUGS PRECIPITATING GRAVES’ DISEASE 471
Iodine 471
Anti–viral Therapy 471
Immunomodulation 472
CONCLUDING REMARKS AND FUTURE DIRECTIONS 472
REFERENCES 473
Chapter 29: Graves’ Ophthalmopathy 479
INTRODUCTION 479
EPIDEMIOLOGY 481
CLINICAL PRESENTATION 482
RELATIONSHIP WITH THYROID DISEASE 485
IMMUNOPATHO GENESIS 486
MANAGEMENT 490
FURTHER DEVELOPMENTS 492
REFERENCES 493
Chapter 30: Hypoparathyroidism 497
INTRODUCTION 497
CAUSES OF HYPOPARATHY-ROIDISM 498
Antibody-Mediated Inhibition/Destruction of Parathyroid Function/Anatomy 498
General Overview 498
Historical Perspective of Anti-Parathyroid Antibodies 498
The CaSR as an Antigenic Target in Autoimmune Hypoparathyroidism 499
Inactivating Antibodies to the CaSR- A Cause of Autoimmune Hyperparathyroidism or Hypocalciuric Hypercalcemia 500
Anti-CaSR Antibodies and Human Leukocyte Antigen Associations 502
Other Causes of Hypoparathyroidism 502
Abnormal Development of the Parathyroid Gland 502
Hypoparathyroidism Due to Abnormalities of the PTH Gene Product 503
Hypoparathyroidism Related to Disorders of Magnesium Homeostasis 503
Iatrogenic and Infiltrating Causes of Hypoparathyroidism 504
Autosomal Dominant Hypoparathyroidism (OMIM) (601298) 505
Pseudohypoparathyroidism 505
DIAGNOSIS OF HYPOPARA THYROID SYNDROMES 507
TREATMENT OF HYPOPARA THYROIDISM 508
REFERENCES 509
Chapter 31: Premature Gonadal Insufficiency 514
INTRODUCTION 514
PREMATURE OVARIAN INSUFFICIENCY: OVERVIEW 516
Etiology of Premature Ovarian Failure 516
Iatrogenic Including Surgical, Post Chemotherapy or Radiotherapy 516
Surgical 516
Radiation and Chemotherapy-Induced Ovarian Dysfunction 516
Genetic 516
Turner’s Syndrome 516
Fragile X Syndrome 517
Genetic Metabolic Disorders Resulting in POI 518
AUTOIMMUNE POI 518
Support for an Autoimmune Etiology in POI 518
Immune System Errors 519
Association of POI with Other Autoimmune Disorders 520
Autoimmune POI and Ovarian Cysts 521
TREATMENT CONSIDERATIONS WITH POI 521
Hormonal Therapy 521
Fertility Issues 522
Prevention of or Treatment of Osteoporosis 522
PREMATURE TESTICULAR FAILURE 522
Overview of Early Testicular Failure 522
Etiology of Testicular Failure 523
Early Testicular Failure from Surgery, Chemotherapy or Radiotherapy 523
Genetic 523
Premature Testicular Failure and Other Autoimmune Disorders 524
TREATMENT OPTIONS FOR EARLY TESTICULAR FAILURE 525
Androgen Replacement for Early Hypogonadism 525
Fertility 525
Osteoporosis 525
SUMMARY 526
REFERENCES 526
Chapter 32: Celiac Disease and Intestinal Endocrine Autoimmunity 530
GENOMEWIDE ASSOCIATION STUDIES IN CD 536
INTESTINAL ENDOCRINE AUTOIMMUNITY 537
REFERENCES 539
Chapter 33: Pituitary Autoimmunity 541
INTRODUCTION 542
HISTORICAL NOTES 542
EPIDEMIOLOGY 543
CRITERIA OF AUTOIMMUNITY 544
ANIMAL MODELS 546
ANTIPITUTARY ANTIBODIES 546
INDIRECT IMMUNOFLUORE-SCENCE METHOD 547
OTHER METHODS TO DETECT ANTIBODIES DIRECTED TO PUTATIVE PITUITARY ANTIGENS 549
HISTOPATHO-LOGICAL OBSERVATIONS 550
ASSOCIATION WITH OTHER AUTOIMMUNE DISEASES AND WITH OTHER ORGAN-SPECIFIC ANTIBODIES 550
LYH AND PREGNANCY 552
DIAGNOSIS 553
THERAPEUTIC STRATEGIES 556
References 557
Index 562