Immunology of Clinical and Experimental Diabetes

I. Experimental Diabetes.- 1. Structure and Function of Insulin.- I. Introduction.- II. Three-Dimensional Structure of Insulin in Crystals.- A. Crystal Forms.- B. Insulin in Clinical Preparations.- C. The Structure of Insulin in Crystals.- III. Insulin Structure in Solution.- A. Bovine and Porcine Insulin.- B. Species Variants.- IV. Insulin Biosynthesis.- V. Insulin in Storage Granules.- VI. Evolutionary Differences in Insulin.- A. Evolution of the Insulin Cell.- B. Variations in Insulin Sequences.- C. Proinsulin, Insulinlike Growth Factor, and Relaxin.- VII. Insulin Receptor Binding and Potency.- A. The Active Site of Insulin.- B. The Active Site of Insulinlike Growth Factor.- C. The Negative Cooperative Site of Insulin.- VIII. Immunogenicity and Three-Dimensional Structure.- A. Antigenicity to Clinical Preparations.- B. Antigenicity and the Conformation of Insulin.- References.- 2. Genetic Control of the Immune Response to Insulin in Man and Experimental Animals.- I. Genetic Control of the Immune Response to Insulin in Guinea Pigs and Mice.- A. Guinea Pigs.- B. Mice.- II. Immunity to Insulin in Humans.- References.- 3. Virus and Experimental Diabetes.- I. Introduction.- II. Experimental Model with Polyendocrine Disease and Autoimmunity.- III. Experimental Models with Immunopathological Reactions to the B Cells of Islets of Langerhans.- A. Streptozotocin with Activated Type C Virus.- B. EMC Virus.- IV. Critical Evaluation.- References.- 4. Animal Models of Human Type I Diabetes.- I. Applicability of Animal Models of Diabetes.- II. Experimentally Induced Diabetes.- A. Chemical Agents.- B. Virus-Induced Diabetes.- III. Spontaneous Diabetes.- A. Chinese Hamster (Cricetulus Griseus).- B. South African Hamsters (Mystromys Alb.).- C. Nonobese Diabetic Mouse.- D. Guinea Pig.- E. New Zealand White Rabbit.- F. Canine Models.- G. Nonhuman Primates.- H. BB Rat.- References.- 5. Immune Function in Obese, Diabetic, Hyperinsulinemic C57BL/KsJ-db+/db+ and C57BL/6J-ob/ob Mice.- I. The C57BL/KsJ-db+/db+ Mouse.- A. Introduction.- B. Alterations in Immunological Function.- II. The C57BL/6J-ob/ob Mouse.- A. Introduction.- B. Alterations in Immunological Function.- III. Summary and Conclusions.- References.- 6. The Influence of Sex Hormones on Immunological Processes in the Induction of Diabetes.- I. Introduction.- II. Sex Hormones and Immune Response.- III. Sex Hormones and Diabetes.- IV. Discussion and Conclusion.- References.- 7. Transplantation of Pancreas and Islets.- I. Rationale and Statement of the Problems.- II. Experimental Transplantation.- A. Pancreas with Exocrine Drainage Established.- B. Segmental Pancreas Transplantation without Provision for Exocrine Drainage.- C. Metabolic Efficiency of Pancreatic Transplantation.- D. Immunological Aspects of Pancreatic Allotransplantation.- E. Preservation of the Intact Pancreas.- III. Experimental Transplantation of Free Grafts of Islet Tissue.- A. Source and Preparation.- B. Results in Rodents.- C. Results in Large Animals.- D. Islet Transplantation in Natural Models of Diabetes.- E. Immunological Aspects of Islet Allo- and Xenotransplantation.- F. Preservation of Islet Tissue.- IV. Effect of Transplantation on Secondary Lesions in Experimental Diabetes.- V. Clinical Transplantation: A Brief Summary.- VI. Summary and Prospects.- References.- II. Clinical Diabetes.- 8. Antibodies to Insulin and Insulin Receptors: Mechanisms of Insulin Resistance.- I. Introduction.- II. Insulin Resistance due to Antiinsulin Antibodies.- A. Structure and Antigenicity of Insulin.- B. Genetics of the Immune Response.- C. Clinical Measurements of Insulin Antibodies.- D. Insulin Resistance due to Antiinsulin Antibodies.- E. Therapy.- III. The Insulin Receptor.- A. Clinical Syndrome Associated with Antibodies to the Insulin Receptor.- B. Methods for Detecting Antibodies to the Insulin Receptor.- C. Effects of Antireceptor Antibodies on Insulin Binding.- D. Mechanisms of Insulin Resistance in Patients with Antibodies to Insulin Receptors.- E. Is the Underlying Receptor Normal?.- F. Therapy of Patients with Antireceptor Antibody.- References.- 9. Genetic Basis of Type I (Insulin-Dependent) Diabetes.- I. Introduction.- II. The Size of the Problem.- III. The HLA System.- A. Population Studies.- B. Family Studies.- IV. Possible Evidence for Non-HLA Susceptibility.- V. Genetic Heterogeneity.- VI. Complement Factors.- A. Bf.- B. C2.- C. C4.- VII. Conclusions.- References.- 10. Virus and Insulin-Dependent Diabetes Mellitus.- I. Introduction.- II. General Aspects of Insulin-Dependent Diabetes Mellitus.- A. Epidemiological Studies.- B. Family Studies.- C. Histopathological Features of IDDM.- III. Insulin-Dependent Diabetes Mellitus and Viral Infections.- A. Mumps.- B. Picornaviruses.- C. Rubella Virus.- D. Herpesviruses.- E. Miscellaneous Viruses.- IV. Mechanisms of Virus-Induced Beta Cell Injury.- A. Virus-Mediated Cytolysis.- B. Immune Mechanisms of Injury.- V. Conclusions.- References.- 11. Lymphocyte Response in Diabetes Mellitus.- I. Introduction.- II. Surface Markers of Major Subpopulations.- III. Functions of Major Subpopulations.- IV. Human T-Cell Subsets Defined by the Fc Receptors for Immunoglobulin Isotypes.- V. Monoclonal-Antibody-Defined Lymphocyte Subpopulations.- A. Differentiation Antigens on Cells of T-Cell Lineage.- B. Functions of T-Cell Subsets.- C. B-Cell Subsets.- D. Natural Killer (NK) Cells.- VI. Insulin Receptors.- VII. Morphology of Lymphoid Tissues in Diabetes.- VIII. Lymphocyte Subpopulations in Diabetes.- IX. Blastogenic Response in Diabetes.- A. Response to Mitogens.- B. Response to Alloantigens and Autoantigens.- X Immune Response to Pancreatic Antigens.- XI. Cell-Mediated Immunity to Insulin.- XII. Serum Immunglobulins and Specific Antibody Response.- XIII Immunoregulation.- XIV. Cytotoxic Response.- XV. Summary.- References.- 12. Autoimmunity.- I. Insulitis.- II. Clinical and Immunological Associations of IDDM with Autoimmune Endocrinopathies.- III. Relation to Other Autoimmune Phenomena.- IV. Antipancreatic Cell-Mediated Autoimmunity (APCI).- V. Islet Cell Antibodies.- A. Islet Cell Cytoplasmic Antibodies.- B. Islet Cell Surface Antibodies.- C. Complement-Dependent Cytotoxic Antibodies.- D. Antibody-Dependent Cellular Cytotoxicity.- VI. Circulating Immune Complexes.- VII. Monoclonal Antibodies.- VIII. Conclusions and Clinical Perspectives.- References.- 13. Phagocytic Cell Functions in Diabetes Mellitus.- I. Introduction.- II. Infections.- A. Urinary Tract Infections.- B. Tuberculosis.- C. Fungal Infections.- D. Cutaneous Infections.- E. Osteomyelitis.- F. Nonclostridial Gas Gangrene.- G. Malignant Pseudomonas External Otitis.- III. Phagocytic Activities.- A. Normal Movement of Phagocytes.- B. Normal Phagocytosis.- C. Normal Bactericidal Activity.- IV. Disorders of Movement.- V. Disorders of Phagocytosis.- VI. Disorders of Bactericidal Activity.- VII. Summary and Speculations.- References.- 14. Circulating Immune Complexes.- I. Introduction.- II. Determinants of Circulating Immune Complexes.- III. Methods of Detection.- IV. Evidence of Circulating Immune Complexes in Diabetes Mellitus.- V. Nature of Immune Complexes.- A. Insulin—Insulin-Antibody Complexes.- B. Idiotypic Antibodies.- C. Immune Complexes and Islet Cell Antibodies.- D. Organ-Specific Antibodies.- VI. Role of Immune Complexes in Diabetic Complications.- A. Diabetic Retinopathy.- B. Diabetic Nephropathy.- C. Necrobiosis Lipoidica.- D. Lipoatrophy.- E. Insulitis.- VII. Immune Complexes and Metabolic Control.- VIII. Summary.- References.- 15. Insulin Hypersensitivity: Pathogenesis, Diagnosis, and Management.- I. Introduction.- II. Classification.- III. Local Reactions to Insulin.- A. Cutaneous.- B. Subcutaneous.- IV. Generalized, Immediate-Type IgE-Mediated Reactions.- A. Clinical Manifestation.- B. Differential Diagnosis.- C. Symptomatic Management.- D. Insulin Therapy.- E. Continued Insulin Therapy.- F. Antiallergic Therapy during Continued Insulin or Desensitization Therapy.- G. Insulin Desensitization.- V. Insulin as an Antigen.- A. Noninsulin Protein Contaminants.- B. Antigenicity of Native Insulins.- C. Antigenicity of Altered Insulins.- D. Mechanism of Desensitization.- E. Allergic Reactions to Nonprotein Materials.- F. Mechanism of Serum Sickness.- G. Immunological Insulin Resistance.- VI. Summary.- References.