myelin-basic-protein and Diabetes-Mellitus--Type-1

In this article, we will examine the roles of transgenic and knockout animals that aid us in understanding two autoimmune diseases-type 1 (insulin-dependent) diabetes and multiple sclerosis. The first sections will focus on studies in type 1 diabetes to show how genetically altered animals have given insight into the role of various immune cell types, autoantigens, co-stimulatory molecules, cytokines and, finally, the role of various effector pathways in the pathogenesis of diabetes. The second section concentrating on the animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), will show how animals that express a T-cell receptor derived from a clone able to cause disease have given insight into the pathogenesis of EAE.

Topics: Animals; Antigen Presentation; Autoantigens; B-Lymphocytes; CD8-Positive T-Lymphocytes; Cytokines; Diabetes Mellitus, Type 1; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Humans; Islets of Langerhans; Mice; Mice, Inbred NOD; Mice, Knockout; Mice, Transgenic; Multiple Sclerosis; Mutation; Myelin Basic Protein

Viruses have often been associated with autoimmune diseases. One mechanism by which self-destruction can be triggered is molecular mimicry. Many examples of cross-reactive immune responses between pathogens and self-antigens have been described. This review presents two transgenic models of autoimmune disease induced by a virus through activation of anti-self lymphocytes. Viral antigens are expressed as transgenes either in beta-cells of the pancreas or in the oligodendrocytes of the CNS. Infection by a virus encoding the same gene activated autoreactive T cells that cleared the viral infection, and as a consequence of transgene expression resulted in organ-specific autoimmune disease. In both transgenic mouse models, autoreactive lymphocytes that escaped thymic negative selection were present in the periphery. Several factors are described that play a role in the regulation of the self-reactive process precipitated by a viral infection. These include the quantity of activated autoreactive T cells, the affinity of these T cells, the number of memory T cells generated following primary infection, costimulation by accessory molecules, and the types and locations of cytokines produced. In addition, unique barriers exist in target tissues that prevent or suppress autoreactive responses and define to a large extent the outcome of disease. Restimulation of autoreactive memory lymphocytes may be required to bypass these barriers and enhance autoimmune disease. Therapy directed at modifying these factors can reduce and even prevent autoimmune disease after it has been initiated.

Topics: Animals; Autoimmune Diseases; Central Nervous System; Central Nervous System Diseases; Diabetes Mellitus, Type 1; Disease Models, Animal; Humans; Insulin; Islets of Langerhans; Lymphocytic choriomeningitis virus; Mice; Mice, Transgenic; Myelin Basic Protein; Self Tolerance; Viruses

Topics: Administration, Oral; Animals; Arthritis, Experimental; Autoantigens; Autoimmune Diseases; Desensitization, Immunologic; Diabetes Mellitus, Type 1; Encephalomyelitis, Autoimmune, Experimental; Humans; Immune Tolerance; Immunity, Mucosal; Immunosuppression Therapy; Mice; Myelin Basic Protein; Peyer's Patches; Rats

Topics: Amino Acid Sequence; Animals; Autoantigens; Autoimmune Diseases; Diabetes Mellitus, Type 1; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Epitopes; Histocompatibility Antigens Class II; Humans; Immunotherapy; Molecular Sequence Data; Myelin Basic Protein; Peptides

Type I diabetes mellitus (DM1) is a widespread metabolic disease ofsocial significance due to early disability in youngpatients and reduced life expectancy. One of the DMI complications is CNS lesions resulting in cognitive dysfunction mediated through metabolic disorders. This condition can be partly or completely reversed if diagnosed and treated'at an early stage. The aim of this study was to determine the level ofneurospecific proteins in 58 patients aged 16-30years with type I diabetes mellitus and cognitive disorders in comparison with 29 healthy controls of simnilar age. All the participants underwent neuropsychological testing based on the Montreal scale for rapid screening of cognitive disorders (MoCA-test). Protein S100, glial fibrillary acidic protein, and myelin basic protein served as early markers of cognitive dysfunction. The study revealed an enhanced level of neurospecific proteins that correlated with hyperglycemia and cognitive deficit (MoCA score 26).

Topics: Adolescent; Adult; Biomarkers; Cognition Disorders; Diabetes Mellitus, Type 1; Female; Glial Fibrillary Acidic Protein; Humans; Male; Myelin Basic Protein; S100 Calcium Binding Protein beta Subunit; Young Adult

Humans subjected to diabetes mellitus (DM) and/or hypertension (HTN) develop cognitive decline, cerebral atrophy and white matter abnormalities, but the relative effects of DM and HTN upon myelin and axonal integrity is unknown. We studied models of Type 1 (streptozotocin-induced) and Type 2 DM (ZDF) ± HTN (ZSF-1, SHR) in adult rats using magnetic resonance imaging (MRI) and structural and molecular techniques. Type 1 or 2 DM independently led to loss of myelin associated with changes with MRI T2 and magnetization tensor ratios throughout white matter regions. HTN's effect on myelin loss was minimal. Loss of oligodendroglia and myelin proteins was only identified in either Type 1 or Type 2 DM. Activation of the signal transduction pathways initiated by the receptor for advanced glycation end products (AGEs), RAGE, including upregulation of the signal transducer nuclear factor (NF) κB only occurred with DM. Diabetes is a greater contributor to white matter loss than hypertension in the rat brain, while hypertension only plays a mild additive effect upon neurodegeneration in the presence of diabetes.

Topics: Analysis of Variance; Animals; Blood Glucose; Blotting, Western; Brain; Brain Mapping; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Electrophoretic Mobility Shift Assay; Glycation End Products, Advanced; Hypertension; Image Processing, Computer-Assisted; Immunohistochemistry; Magnetic Resonance Imaging; Male; Myelin Basic Protein; Nerve Fibers, Myelinated; Neurons; Oligodendroglia; Rats; Reverse Transcriptase Polymerase Chain Reaction

Immunization with heat-shock protein (HSP) gp96 elicits protective immunity to the cancer or virus-infected cells from which it is derived. Low doses of gp96 generate immunity, while doses 10 times the immunizing dose do not. We show here that injection of high doses of gp96 generates CD4(+) T cells that down-regulate a variety of ongoing immune responses. Immunization with high doses of gp96 prevents myelin basic protein- or proteolipid protein-induced autoimmune encephalomyelitis in SJL mice and the onset of diabetes in non-obese diabetic mice. The suppression of immune response can be adoptively transferred with CD4(+) cells and does not partition with the CD25 phenotype. The immunomodulatory properties of gp96 (and possibly other HSP) may be used for antigen-specific activation or suppression of cellular immune responses. The latter may form the basis for novel immunotherapies for autoimmune diseases.

Topics: Adoptive Transfer; Animals; Antigens, Neoplasm; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Transplantation; Diabetes Mellitus, Type 1; Encephalomyelitis, Autoimmune, Experimental; Female; Fibrosarcoma; Glycosuria; Immune Tolerance; Immunohistochemistry; Immunologic Factors; Immunotherapy, Active; Insulin; Lipopolysaccharides; Lymphocyte Subsets; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Myelin Basic Protein; Myelin Proteolipid Protein; Pancreas; Paralysis; Peptide Fragments; Receptors, Interleukin-2; Spleen; Time Factors; Tumor Cells, Cultured; Vaccination

Type I diabetes and multiple sclerosis (MS) are distinct autoimmune diseases where T cells target either islet or CNS self-proteins. Unexpectedly, we found that autoreactive T cells in diabetic patients, relatives with high diabetes risk, nonobese diabetic (NOD) mice, and MS patients routinely target classical islet as well as CNS autoantigens. The pathogenic potential of CNS autoreactivity was testable in NOD mice. Pertussis holotoxin, without additional Ags or adjuvants, allowed development of an NOD mouse-specific, autoimmune encephalitis with variable primary-progressive, monophasic, and relapsing-remitting courses. T cells from diabetic donors transferred CNS disease to pertussis toxin-pretreated NOD.scid mice, with accumulation of CD3/IFN-gamma transcripts in the brain. Diabetes and MS appear more closely related than previously perceived. NOD mouse-specific, autoimmune encephalitis provides a new MS model to identify factors that determine alternative disease outcomes in hosts with similar autoreactive T cell repertoires.

Topics: Acute Disease; Adoptive Transfer; Adult; Amino Acid Sequence; Animals; Autoantigens; Cell Division; Cytokines; Diabetes Mellitus, Type 1; Encephalomyelitis, Autoimmune, Experimental; Female; Follow-Up Studies; Humans; Islets of Langerhans; Lymphocyte Activation; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Inbred NZB; Mice, SCID; Molecular Sequence Data; Multiple Sclerosis; Myelin Basic Protein; Organ Specificity; Prospective Studies; Recurrence; Species Specificity; T-Lymphocyte Subsets

Linomide (quinoline-3-carboxamide), a well tolerated, orally administered compound was recently shown to be effective in the prevention and treatment of several autoimmune diseases in experimental animal models. We have investigated its effect on specific humoral immune responses directed to T-cell-dependent soluble or particulate antigens and to a T cell-independent antigen in several mouse strains. Linomide administered after antigen priming did not affect primary and secondary antibody responses directed to T-cell particulate antigens (SRBC) or soluble antigens given with or without complete Freund's Adjuvant (CFA). Linomide treatment given prior to antigen priming did not affect the antibody response to a soluble antigen (TNP-KLH) given with an adjuvant. In contrast, dose-dependent down regulation of primary antibody responses was observed when T cell-dependent (BSA-dextran) or T-cell-independent (TNP-Ficoll) antigens were administered in an immunogenic form without adjuvant after starting Linomide treatment. The primary anti-SRBC antibody response was also suppressed by high dose Linomide given prior to immunization although normal secondary responses were retained. It is worth noting that no immunosuppressive effects on antibody responses were found at low dose ranges which effectively reversed T cell dependent autoimmune manifestation.

Topics: Animals; Antibody Formation; Antigen Presentation; Antigens, T-Independent; Autoantibodies; Autoantigens; Autoimmune Diseases; Dextrans; Diabetes Mellitus, Type 1; Drug Administration Schedule; Encephalomyelitis, Autoimmune, Experimental; Female; Ficoll; Freund's Adjuvant; Haptens; Hemocyanins; Hydroxyquinolines; Immunization; Immunologic Factors; Mice; Mice, Inbred BALB C; Mice, Inbred DBA; Mice, Inbred NOD; Myelin Basic Protein; Peptide Fragments; Serum Albumin, Bovine; Solubility; Trinitrobenzenes

The nature (Th1 versus Th2) and dynamics of the autoimmune response during the development of insulin-dependent diabetes mellitus (IDDM) and after immunotherapy are unclear. Here, we show in nonobese diabetic (NOD) mice that the autoreactive T cell response starts and spreads as a pure Th1 type autoimmunity, suggesting that a spontaneous Th1 cascade underlies disease progression. Surprisingly, induction of antiinflammatory Th2 responses to a single beta cell antigen (betaCA) resulted in the spreading of Th2 cellular and humoral immunity to unrelated betaCAs in an infectious manner and protection from IDDM. The data suggest that both Th1 and Th2 autoimmunity evolve in amplificatory cascades by generating site-specific, but not antigen-specific, positive feedback circuits. Determinant spreading of Th2 responses may be a fundamental mechanism underlying antigen-based immunotherapeutics, explaining observations of infectious tolerance and providing a new theoretical framework for therapeutic intervention.

Topics: Animals; Autoantigens; Autoimmunity; Diabetes Mellitus, Type 1; Female; Glutamate Decarboxylase; Interferon-gamma; Interleukin-4; Interleukin-5; Islets of Langerhans; Mice; Mice, Inbred AKR; Mice, Inbred BALB C; Mice, Inbred NOD; Myelin Basic Protein; T-Lymphocytes; Th2 Cells