Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Randomised and controlled treatment studies of juvenile-onset myasthenia gravis have not been published. We therefore report our retrospective analysis of 79 patients with juvenile-onset myasthenia gravis observed for as long as 30 years. The mean age at onset was 13.7 years and median follow-up 7.7 years. The initial presentation was generalised disease in 90% and ocular disease in the remaining patients. Sixty-five patients (82%) were thymectomised. In 14 of these, treatment consisted of a combination of azathioprine (2-3 mg/kg), corticosteroids (prednisolone up to 60 mg for a maximum duration of 12 months with subsequent tapering) and acetylcholinesterase (AChE) inhibitors, and of azathioprine and AChE inhibitors in 27 patients. One patient received azathioprine and 22 AChE inhibitors only; in another no further medication was necessary. In the severely affected group (n = 16), plasmapheresis was performed additionally before thymectomy and continued for some time after the operation. Treatment was started between 1 and 14 months (mean 2.4 months) after the onset of myasthenic symptoms. No thymectomy was done in 14 patients, and immunosuppressive treatment and AChE inhibitors were given in 9 of these cases. One patient received azathioprine only; 4 patients received AChE inhibitors only. The histology of the thymus gland showed follicular hyperplasia in 89% of the 65 thymectomised patients and normal findings in the remainder. Remission occurred in 60% of patients who underwent thymectomy and in 29% of those who were not thymectomised. Hyperthyroidism (6 patients, 8%), diabetes mellitus (2 patients, 3%) and rheumatoid arthritis (2 patients, 3%) were the most frequent associated immune-mediated diseases. Epileptic seizures and neoplasia were coincident diseases in 2 (3%) and 3 (4%) patients, respectively. There were no deaths from thymectomy or from immunosupression. This open, retrospective analysis suggests that juvenile-onset myasthenia gravis can be treated satisfactorily in most patients by the use of thymectomy and/or immunosupressive medication.
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PMID:Outcome in juvenile-onset myasthenia gravis: a retrospective study with long-term follow-up of 79 patients. 930 59

An unprecedented arsenal of new xenobiotic immunosuppressive agents has been developed recently. Most of the new immunosuppressants have been tested primarily in the treatment of allograft rejection in experimental models of transplantation, and some of the new drugs have already proven their safety and efficiency in extensive clinical trials on transplant patients. Another field for their potential application is the treatment of autoimmune diseases. This review will give an overview of the therapeutic potential of the new xenobiotic drugs in different animal models of rheumatoid arthritis, systemic lupus erythematosus, myasthenia gravis, multiple sclerosis, diabetes mellitus, thyroiditis and uveoretinitis. The new xenobiotics are either inhibitors of the de novo synthesis of nucleotides, for example mycophenolate mofetil, mizoribine, leflunomide, and brequinar, or are immunophilin-binding agents (cyclosporin, FK506 and rapamycin) that inhibit signal transduction and cell cycle progression in lymphocytes. A different mode of action is likely to account for the immunosuppressive effects of deoxyspergualin, which may interfere with intracellular chaperoning by the heat shock protein HSP70 and the activation of transcription factor NF-kappa B.
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PMID:Xenobiotic immunosuppressive agents: therapeutic effects in animal models of autoimmune diseases. 935 1

Failure of distinction between self and non-self is regarded a critical event in the pathogenesis of several human diseases such as systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, myasthenia gravis, uveoretinitis or diabetes mellitus. Autoagressive immune reactions driven by activated autoreactive lymphocytes are a characteristic feature of these autoimmune diseases. The mechanisms by which the pathogenic control of autoreactive lymphocytes deviates from physiology can be studied in appropriate animal models under well-defined experimental conditions. Experimental models of autoimmune diseases in rodent inbred strains allow for the genetic mapping of susceptibility loci and might help to identify candidate genes also relevant to the pathogenesis of human diseases. Finally, the experimental models are valuable tools to develop rational immunotherapeutic strategies. Interesting features of some of the models employed for such research will be introduced in this review.
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PMID:Animal models of autoimmune diseases. 935 2

Bone marrow transplantation (BMT) is now becoming a powerful strategy for the treatment of patients with autoimmune diseases. Using various animal models for autoimmune diseases, we have previously found that allogeneic BMT (not autologous BMT) can be used to treat autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), immune thrombocytic purpura, insulin-dependent diabetes mellitus (IDDM), chronic glomerulonephritis, and certain types of non-insulin-dependent diabetes mellitus. In contrast, we have found that the transplantation of T-cell-depleted bone marrow cells or partially purified hemopoietic stem cells (HSCs) from autoimmune-prone mice to normal mice leads to the induction of autoimmune diseases in the recipients. These findings have recently been confirmed even in humans; autoimmune diseases such as RA, SLE, multiple sclerosis, and Crohn's disease were resolved after allogeneic BMT. However, there have recently been reports on the rapid recurrence or persistence of autoimmune diseases after autologous BMT. Conversely, the adoptive transfer of autoimmune diseases such as myasthenia gravis, IDDM and Graves' disease by allogeneic BMT from donors to recipients has been reported. Based on these findings, we have proposed that autoimmune disease is 'a stem cell disorder'. To clarify the differences between normal and abnormal HSCs, we have established a new method for purifying HSCs. Using this method, we purified HSCs from normal and autoimmune-prone mice and compared the former with the latter. We have found that a major histocompatibility complex (MHC) restriction exists between normal HSCs and stromal cells, whereas there is no MHC restriction between abnormal HSCs and stromal cells either in vivo or in vitro; abnormal HSCs proliferate even in allogeneic environments. Abnormal HSCs thus appear to be more resilient than normal HSCs. In humans, BMT across MHC barriers has had a low success rate as a consequence of (1) graft-versus-host disease (GVHD), (2) graft rejection and (3) incomplete recovery of T cell functions. However, we have found that such problems can be overcome in mice. GVHD can be prevented if T-cell-depleted bone marrow cells are used. Graft rejection can be prevented by bone grafts to recruit donor stromal cells, since, as we have found, an MHC restriction exists between HSCs and stromal cells. In addition, we have found that stromal cells migrate from the bone marrow to the thymus, where they become engaged in positive selection. Therefore, the bone grafting to recruit donor stromal cells leads to a complete recovery of T cell functions, since T cells, which are positively selected by donor stromal cells in the thymus, can cooperate with donor B cells and antigen-presenting cells. In humans, it is well known that the success rate of BMT in patients more than 45 years old is low. Recently, we have found that the low success rate is due to the aging of the thymus, and that BMT plus embryonal thymus grafts can be used to treat late-onset autoimmune diseases in MRL/+ mice. Based on these findings, we would like to suggest that the transplantation of the embryonal thymus in conjunction with BMT will become a valuable strategy for treating older patients with various intractable diseases, including autoimmune diseases. We believe that similar conditions (to permit successful allogeneic BMT) to those in mice will be realized in humans in the near future.
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PMID:Bone marrow transplantation for autoimmune diseases. 958 93

We report a 36-year-old man with proximal dominant muscle weakness, thymic tumor, diabetes mellitus, hypokalemia, and increased levels of plasma ACTH and cortisol. The diagnosis of carcinoid tumor was made on the basis of pathological findings in the biopsied specimen of the thymic tumor. The proximal muscle weakness was considered to be due to steroid myopathy resulting from the overproduction of cortisol from the adrenal glands induced by the ectopic ACTH secreted by the thymic carcinoid tumor. Although thymoma in frequently associated with myasthenia gravis, we should also consider carcinoid tumors in patients with a thymic tumor presenting with a proximal muscle weakness.
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PMID:[A patient with an ACTH-releasing thymic carcinoid tumor presenting with proximal muscle weakness]. 959 30

Since Morton and Siegel's epochal experiments 30 years ago animal models have been successfully utilized both for transfer and resolution of autoimmune diseases (AID). More recently human lymphocyte xenografts have reproduced clinical AID in SCID mice. Allogeneic stem cell transplantation demonstrated therapeutic potential in fully developed autoimmune disease. Mixed allogeneic chimerism induced by a sublethal approach has also been shown to prevent and even reverse autoimmune insulitis in nonobese diabetic (NOD) mice. More unexpectedly it was found that experimental adjuvant arthritis (AA) and experimental allergic encephalomyelitis (EAE) could be cured by means of total body irradiation (TBI) followed by autologous hemolymphopoietic stem cell (HSC) transplantation. It was postulated that the newly developing T cells might be tolerant to self antigens. The transfer of AID from affected donors to recipients of allogeneic HSC transplants has been reported for many organ-specific AID, including diabetes (IDDM), thyroiditis, myasthenia gravis and thrombocytopenic purpura (AITP); rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) were not transferred. Conversely patients with the combination of AID and a severe blood disease (leukemia, aplasia) were cured of both diseases following allogeneic BMT, with the notable exception of a relapse in a patient with RA despite full donor engraftment. Allogeneic transplants are certainly more promising as far as concerns a resolution of AID, because they may also exert a graft-versus-autoimmunity effect by gradually eradicating the recipient's lymphopoiesis, but transplant related mortality (TRM) is considered still too high to employ this procedure consistently. New non-myeloablative conditioning regimens, designed to allow the donor's immune system to take over, are already utilized for malignant and non-malignant hematologic diseases, and may become an attractive option for severe, refractory AID. For the time being, however, autologous procedures are still safer, and are being utilized in many projects worldwide. The EBMT/EULAR Registry has collected over 70 patient reports. The more numerous and favorable results have been obtained up to now in multiple scleosis and in systemic lupus erythematosus; the worst in refractory autoimmune thrombocytopenic purpura. No definite conclusions as to the efficacy of autologous HSC transplantation, from marrow or from blood, with or without T-cell depletion, may be drawn at this time, but the feeling is that real cures will be very difficult to obtain by this approach, and that corticosteroid-free remissions and a general lowering of the autoimmune potential will be more realistic goals. Accurate comparisons with already existing aggressive immunosuppressive protocols will become necessary, if possible by means of prospective randomized clinical studies.
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PMID:Stem cell transplantation for severe autoimmune diseases: progress and problems. 979 58

Using three reference disease models--insulin-dependent diabetes mellitus (IDDM) as a prototype of T-cell mediated organ-specific autoimmune disease, myasthenia gravis (MG) as a prototype of autoantibody-mediated organ-specific autoimmune disease and systemic lupus erythematosus (SLE) as a prototype of non-organ-specific autoimmune disease--we have reached several conclusions: 1) All three diseases are associated with the presence of multiple autoantibodies and/or autoreactive T cells that recognize a large number of antigenic molecules. The apparent predominant role of certain antibodies in some diseases could relate to their functional properties such as acetylcholine receptor (AChR) blockade for anti-AChR autoantibodies in MG or anti-dsDNA in SLE. 2) Major target antigens are clustered in the target cell affected by organ-specific autoimmune diseases: beta cells in IDDM, striated-muscle cells in MG, or apoptotic cells in the case of SLE. 3) Antibodies and T cells recognize multiple epitopes in these molecules. 4) The most evident explanation for the observed clustering and diversity is autoantigen spreading. Spreading probably involves T cells secreting proinflammatory cytokines but also possibly antibodies as in the case of nucleosome autoantibodies in SLE. 5) The counterpart of antigen spreading is bystander suppression in which regulatory cytokines deviate the immune response towards a protective response. 6) The mechanisms underlying the initiation of the autoimmune response and antigen spreading are still undetermined. They could imply a direct abnormality of the target cell in the case of organ-specific autoimmune diseases (e.g. infection with a virus showing a selective tropism for the target cell in organ-specific autoimmune diseases, or loss of physiological regulation of major histocompatibility complex molecule expression) or could be consequence of a ubiquitous cell abnormality such as increased apoptosis in SLE. The respective roles of genetic and environmental factors in these triggering events remain to be determined.
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PMID:Are there unique autoantigens triggering autoimmune diseases? 979 72

The hepatitis C virus (HCV) infection is characterized by a variety of extra-hepatic manifestations in many individuals. Among these, diabetes mellitus (DM) can be included, as such a metabolic disorder has been demonstrated to be more frequent in chronic hepatitis C than in liver disease due to other causes. Recently, we have observed that most patients affected with HCV-associated mixed cryoglobulinemia (13 out of 15, 86.7%), that were at baseline normoglycemic, developed DM following corticosteroid treatment (prednisone > 25 mg/daily) for at least three months. Conversely, when we consider a control group including 36 HCV negative patients affected with various immunomediated disorders, i.e., systemic lupus erythematosus, myasthenia gravis, poly/dermatomyositis and chronic inflammatory demyelinating polyneuropathy, that were initially normoglycemic, corticosteroid induced DM (prednisone > 25 mg/daily for at least three months) occurred only in 16.7% of subjects. Moreover, in other two HCV positive patients suffering from myasthenia gravis, prolonged corticosteroid treatment was complicated by DM. These data, that are still unclear from a pathophysiologic viewpoint, seem to indicate corticosteroid induced DM as a further, unusual extra-hepatic manifestation of the HCV infection.
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PMID:[Frequent occurrence of diabetes mellitus after corticosteroid treatment in mixed cryoglobulinemia. An HCV-related complication?]. 982 89

It is well known that individuals positive for particular HLA-class II alleles show high risks for the development of Takayasu arteritis and other diseases caused by immunological disorders such as autoimmune diseases and allergies. HLA class II molecules present antigenic peptides to CD4+ T cells. Their extensive polymorphism affects the structures of peptides bound to HLA class II molecules to create individual differences in immune responses to antigenic peptides. To better understand the mechanisms for association between HLA class II alleles and susceptibility to autoimmune diseases, it is important to identify self-peptides presented by disease-susceptible HLA class II molecules and triggering disease-causative T cells. Many autoimmune diseases are observed in all ethnic groups, whereas the incidences of diseases, clinical manifestations and disease-susceptible HLA class II alleles are different among various ethnic groups for some autoimmune diseases. These phenomena suggest that differences in autoimmune self-peptide(s) in the context of disease-susceptible HLA class II molecules may cause these differences. Therefore, comparisons among disease-susceptible HLA class II alleles, autoimmune self-peptides and clinical manifestations of autoimmune diseases in different ethnic groups would be helpful in determining the pathogenesis of the diseases. In this paper, we describe our recent findings on: (1) the uniqueness of both clinical manifestations and HLA-linked genetic background of Asian-type (optico-spinal form) multiple sclerosis; (2) the structural characteristics of peptides bound to HLA-DQ molecules susceptible to insulin-dependent diabetes mellitus; (3) the identification of a disease-related autoantigenic peptide presented by disease-susceptible HLA-DQ molecules in Asians-specific infant onset myasthenia gravis; and (4) a manipulation of human T cell response by altered peptide ligands, as a possible candidate for new and antigen-specific immuno-suppressive therapy against autoimmune diseases.
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PMID:Molecular analyses of HLA class II-associated susceptibility to subtypes of autoimmune diseases unique to Asians. 995 8

An individual's major histocompatibility complex (MHC) ancestral haplotype (AH) is the clearest single determinant of susceptibility to MHC associated immunopathological disease, as it defines the alleles carried at all loci in the MHC. However, the direct effects of any of the 150-200 genes that constitute the MHC are difficult to determine since recombination only occurs at defined hotspots. This review concerns the 8.1 AH (HLA-A1, C7, B8, C4AQ0, C4B1, DR3, DQ2), which is carried by most Caucasians with HLA-B8. It is associated with accelerated human immunodeficiency virus (HIV) disease, and susceptibility to insulin-dependent diabetes mellitus (IDDM), systemic lupus erythematosus, dermatitis herpetiformis, common variable immunodeficiency and IgA deficiency, myasthenia gravis and several other conditions. We have mapped susceptibility genes for HIV, IDDM and myasthenia gravis to the central MHC between HLA-B and the tumour necrosis factor or complement genes. Here we consider which of the remaining 8.1-associated diseases are more closely associated with HLA-DR3 and/or DQ2. Several candidate genes in the central MHC have the potential to modulate immune or inflammatory responses in an antigen-independent manner, as is seen in studies of cultured cells from healthy carriers of the 8.1 AH. Hence these genes may act as a common co-factor in the diverse immunopathological conditions associated with the 8.1 AH.
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PMID:The genetic basis for the association of the 8.1 ancestral haplotype (A1, B8, DR3) with multiple immunopathological diseases. 1031 67


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