Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018799 (heart disease)
 34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

New aspects in the research of myocarditis and dilated cardiomyopathy in West Germany have evolved from molecular biology, immunobiology of the mitochondrion, immunoserology, and immunohistology. Coxsackie B3 virus inoculated into fetal human myocytes induced myocytolysis in the absence of immunologic effector mechanisms. By pretreatment with beta-interferon, the virus yield from the myocytes was reduced significantly. In myocarditis and dilated cardiomyopathy, antibodies against an organ-specific autoantigen of cardiac mitochondria, the adenine nucleotide translocator, were demonstrated. Antibody titers roughly correlated with the ejection fraction using the Elisa technique. It could also be shown that in 13% of cases in myocarditis and 31% in dilated cardiomyopathy heart-associated antimitochondrial antibodies are found, called anti-M7. Most of the patients had an interfibrillary staining pattern in the immunofluorescence test. No correlation with the severity of heart disease could be established. In dilated cardiomyopathy and myocarditis, there has recently been controversy over low suppressor T-cell activity. Whereas other groups have demonstrated a low concanavaldin-A-induced suppressor T-cell activity in both diseases, we have not been able to confirm reduced Con-A-induced or spontaneous T-suppressor cell activity in the different indicator systems used in analysis.
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PMID:Cardiomyopathy and myocarditis--a review of new aspects in research in West Germany. 295 41

Postinfection sera from A.CA/SnJ A.SW/SnJ, B10.S/SgSf, and B10.PL/SgSf mouse strains which varied in their susceptibility to Coxsackievirus B3-induced immunopathology were suspected to contain autoantibodies against cardiac tissue. These sera were used to identify the target myocardial autoantigen(s). Sera pools were made during the peak of the early, virus-induced myocarditis at 5 and 7 days and during the peak of the late, immunopathic phase of myocarditis at Days 15 and 21 after infection. Only the A.CA/SnJ and A.SW/SnJ strains which develop the immunopathic heart disease had heart-specific autoantibodies as determined by indirect immunofluorescence. This panel of sera pools was then tested against solubilized extracts from whole heart and skeletal muscles. Results from Western immunoblotting analyses demonstrated that antibodies to myosin were a prominent feature in the sera of strains which developed immunopathic myocarditis. The immunopathic sera pools were subsequently assayed against low-salt, high-salt, and a number of detergent extracts of heart and skeletal muscle. Anti-myosin was still the most notable reactivity, even though other autoantigens were detected. Absorption with cardiac myosin removed the vast majority of heart reactivity from the pooled sera derived from the A.CA/SnJ and A.SW/SnJ strains as determined within the limitations of the immunofluorescent and immunochemical assays. Both sarcolemmal and A-band staining patterns were abolished by the cardiac myosin absorption. These studies suggest that myosin is one of the major autoantigens in Coxsackievirus B3-induced autoimmune myocarditis.
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PMID:Heart-specific autoantibodies induced by Coxsackievirus B3: identification of heart autoantigens. 303 May 91

The ADP/ATP carrier is an autoantigen in myocarditis and dilated cardiomyopathy, both of which are diseases related to virus infections. Sera of these patients bear carrier-specific autoantibodies inhibiting transmembrane nucleotide transport on isolated mitochondria. To further assess the role of the ADP/ATP carrier in viral heart disease, guinea pigs were immunized with the isolated ADP/ATP carrier protein and A-strain mice were infected with coxsackie B3 virus. Both species generated specific and carrier-inactivating antibodies after immunization/infection. The transport activity of the ADP/ATP carrier-estimated from the cytosolic-mitochondrial difference of the phosphorylation potential of ATP (delta G[cyt-mit])-markedly declined in guinea pig and mice hearts. A close relationship was observed between the magnitude of reduction of delta G(cyt-mit) and the decrease of cardiac function. Therefore, it seems plausible that carrier dysfunction induced by viral infection creates an imbalance in myocardial energy metabolism, and is responsible for the impairment of cardiac function. The underlying mechanism might be an autoimmune reaction triggered via molecular mimicry or a modulation of the expression of ADP/ATP carrier isoforms changing the overall transport capacity of the cardiac ADP/ATP carrier.
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PMID:The role of the ADP/ATP carrier in the pathogenesis of viral heart disease. 868 5

Ag-specific activation of T lymphocytes requires two signals, one by the TCR and a second by costimulatory molecules. In a CD4+ T helper cell-dependent experimental autoimmune myocarditis model, we provide genetic evidence that cardiac myosin-induced autoimmune myocarditis and the production of IgG auto-Abs is dependent on functional T cells and did not occur in mice lacking the tyrosine kinase p56lck or the tyrosine phosphatase CD45. By contrast, animals lacking the T cell-costimulatory molecule CD28 (CD28 -/-) developed autoimmune heart disease, although at significantly lower severity than in heterozygous littermates, and produced IgG auto-Abs depending on the concentration of the autoantigen administered. In addition, the isotypes of IgG auto-Abs specific for cardiac myosin differed between CD28 +/- and CD28 -/- mice. Whereas CD28 +/- mice predominantly produced Th2-mediated IgG1 auto-Abs, CD28 -/- mice produced predominantly IgG2a. These data suggest that CD28 costimulation plays a crucial role in induction and maintenance of autoimmune heart disease and that CD28 expression is required for predominant Th2-IgG1 responses in an autoimmune setting.
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PMID:Induction of autoimmunity in the absence of CD28 costimulation. 875 65

Dilated cardiomyopathy is a prevalent cause of progressive heart disease and sudden death, and most patients with cardiomyopathy have a history of viral myocarditis. Coxsackie B3 (CB3) picornaviruses can be detected in as many as 50% of these patients and CB3 infections have been epidemiologically linked to chronic heart disease. Several clinical and experimental studies suggest that chronic stages of disease are mediated by an autoimmune response against heart muscle myosin. Human heart disease can be mimicked in mice using cardiac myosin as autoantigen. Murine cardiac myosin-induced myocarditis is an organ-specific autoimmune disease and mediated by CD4+ T cells that recognize a myosin-specific peptide in association with MHC class II molecules. Here, the recent discovery of autoimmune epitopes derived from the alpha isoform of cardiac myosin, the functional roles of surface receptor and signal transduction molecules, and the molecular mechanisms of target organ susceptibility will be discussed.
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PMID:Cellular and molecular mechanisms of murine autoimmune myocarditis. 906 94

Preparation of a pure autoantigen by way of recombinant DNA technology has an important value in an accurate diagnosis or prognosis of an autoimmune disease. BCOADC-E2 subunit, a mitochondrial protein, has been known to be the autoantigen of primary biliary cirrhosis (PBC), a chronic autoimmune liver disease, as well as idiopathic dilated cardiomypathy (IDCM), a chronic autoimmune heart disease. Recombinant form of this molecule had been expressed in E. coli but with low yield and severe degradation. Furthermore, sera from IDCM patients failed to recognized BCOADC-E2 molecule produced in prokaryotic expression system. In this study, a recombinant bovine BCOADC-E2 fusion protein has been expressed in insect cells using baculovirus expression system and analyzed anti-BCOADC-E2 reactivity in sera from patients with PBC or with IDCM. Optimal production of the recombinant fusion protein has been achieved at 20 multiplicity of infection (MOI), and the protein was affinity-purified using metal-binding resins. The affinity-purified BCOADC-E2 protein was successfully recognized by sera from PBC patients, but not by sera from IDCM patients suggesting that the different auto-immune response against BCOADC-E2 is needed to be elucidated in terms of epitope recognition.
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PMID:Expression of a recombinant branched chain alpha-oxo acid dehydrogenase complex E2 (BCOADC-E2) in insect cells and its immunoreactivity to autoimmune sera. 987 25

Molecular mimicry between pathogen and host has been proposed as a mechanism for the development of autoimmune diseases. Evidence suggests that microorganisms contain proteins which are similar enough to host proteins that they can stimulate existing B and T cells to respond to self proteins. The loss of immune regulation during responses against microbial antigens may explain development of pathogenic B and T cell responses in autoimmune diseases associated with infections. The study of B and T cell responses against the group A streptococcal antigens, N-acetyl-glucosamine, M protein and the autoantigen cardiac myosin has led to a better understanding of how molecular mimicry may play a role in disease. Studies of human monoclonal antibodies, T cell responses and animal models in comparison with the immunopathology in the human disease has provided information about the steps leading to inflammatory heart disease in autoimmune post-streptococcal rheumatic carditis. The new data indicate that the steps in pathogenesis of rheumatic heart disease following group A streptococcal infection include the following events. First, the development of crossreactive autoantibodies against the group A streptococcal carbohydrate antigen N-acetyl-glucosamine and cardiac myosin. Second, these antibodies react with valvular endothelium which becomes inflamed with expression of vascular cell adhesion molecule-1 (VCAM-1). After this event, T cells, CD4+ and CD8+, infiltrate through the endothelium/endocardium into the valve which is an avascular structure. Aschoff bodies or granulomatous lesions may form containing macrophages and T cells underneath the endocardium. The T cells are responsive to streptococcal M protein antigen sequences. The valve becomes scarred with eventual neovascularization and progressive, chronic disease in the valve. In the host, the mimicking antigens cardiac myosin and laminin have been involved in the myocardium and valve, respectively. As in other autoimmune diseases, both environmental and genetic factors are involved in the development of rheumatic carditis and inflammatory heart disease, a result of mimicry between the group A streptococcus and heart.
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PMID:Autoimmunity and molecular mimicry in the pathogenesis of post-streptococcal heart disease. 1270 52

Inflammatory heart diseases such as myocarditis and rheumatic heart disease result from the infiltration of the myocardium or valve with T cells and macrophages that result in scarring of the myocardium or valve and alteration in cardiac function. Our studies of T cells from these diseases have identified cardiac myosin in both rheumatic carditis and myocarditis as an important autoantigen. In rheumatic heart disease, streptococcal M protein specific T cells migrate to valves. By investigating streptococcal M protein and cardiac myosin in the Lewis rat model of myocarditis and valvulitis, T cell mimicry is supported as a potential mechanism in disease. Structural and immunological mimicry between the streptococcal M protein and cardiac myosin is shown directly in the Lewis rat model. Rat T cell lines demonstrate mimicry between cardiac myosin and M protein, and T cells isolated directly from inflammatory lesions in myocarditis respond to streptococcal M protein peptides. Studies in BALB/c mice also support the immunological crossreactivity of T cells primed against cardiac myosin with streptococcal M protein peptides containing cardiac myosin homologies. T cell lines produced from the Lewis rat specific to the cardiac myosin like sequences of streptococcal M protein migrated to the valves after passive transfer of the M protein specific T cell lines. In coxsackieviral myocarditis in the MRL mouse strain, cardiac myosin mimicking M protein peptide NT4 was found to induce tolerance and prevent coxsackieviral induced myocarditis, suggesting T cell mimicry between coxsackievirus and streptococcal M protein, both of which are associated with inflammatory heart disease. T cell mimicry between cardiac myosin and microbial antigens such as the streptococcal M protein may prime the immune system for inflammatory heart disease.
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PMID:T cell mimicry in inflammatory heart disease. 1503 18

Autoimmune diseases such as type 1 diabetes and multiple sclerosis pose a significant health burden on our society. As a whole, autoimmune diseases affect approximately 6% of the population and are the third largest disease burden after heart disease and cancer. Such pathologic manifestations arise by way of damaging reactions of B-cell derived antibodies and/or T-cells to self-antigens and are triggered by genetic and environmental factors. Currently there is no known cure, with treatment restricted to toxic, long-term immunosuppressive regimes, replacement therapy and in intractable cases, transplantation of autologous or allogeneic haematopoietic stem cells. In experimental models of autoimmunity, gene therapeutic approaches have demonstrated promise in treating the autoimmune diseases. These include delivery of anti-inflammatory cytokines and exploitation of regulatory T cells. However, none of these approaches provide lasting, long-term benefit. We hypothesise that therapeutically transduced haematopoietic stem cells followed by transplantation is an alternative strategy to establish permanent immune tolerance that can not only prevent autoimmunity but also cure these diseases. Our approach is focused on directing autoimmune disease-specific autoantigen expression in the thymus by genetic manipulation of haematopoietic stem cells to establish molecular chimeras. Our hypothesis originates from experimental studies with a mouse model of experimental autoimmune gastritis (EAG) and more recently with the non-obese diabetic (NOD) mouse model for type 1 diabetes (T1D).
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PMID:Gene therapy strategies towards immune tolerance to treat the autoimmune diseases. 1647 45

Dilated cardiomyopathy (DCM), a leading cause of heart failure and heart transplantation in younger adults, is characterized by dilatation and impaired contraction of the left or both ventricles; it may be idiopathic, familial/genetic (20-30%), viral, and/or immune. On endomyocardial biopsy there is chronic inflammation in 30-40% of cases. Mutations in genes encoding myocyte structural proteins, cardiotoxic noxae and infectious agents are known causes; due to high aetiologic and genetic heterogeneity, the gene defects identified so far account for a tiny proportion of the familial cases. In at least two thirds of patients, DCM remains idiopathic. Myocarditis may be idiopathic, infectious or autoimmune and may heal or lead to DCM. Circulating heart-reactive autoantibodies are found in myocarditis/DCM patients and symptom-free relatives at higher frequency than in normal or noninflammatory heart disease control groups. These autoantibodies are directed against multiple antigens, some of which are expressed only in the heart (organ-specific); some autoantibodies have functional effects on cardiac myocytes in vitro as well as in animal models. Depletion of nonantigen-specific antibodies by extracorporeal immunoadsorption is associated with improved ventricular function and reduced cardiac symptoms in some DCM patients, suggesting that autoantibodies may also have a functional role in humans. Immunosuppression seems beneficial in patients who are virus-negative and cardiac autoantibody positive. Prospective family studies have shown that cardiac-specific autoantibodies are present in at least 60% of both familial and non familial pedigrees and predict DCM development among asymptomatic relatives, years before clinical and echocardiographic evidence of disease. Animal models have shown that autoimmune myocarditis/DCM can be induced by virus as well as reproduced by immunization with a well-characterized autoantigen, cardiac myosin. Thus, in a substantial proportion of patients, myocarditis and DCM represent different stages of an organ-specific autoimmune disease, that represents the final common pathogenetic pathway of infectious and noninfectious myocardial injuries in genetically predisposed individuals.
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PMID:Clinical implications of anti-heart autoantibodies in myocarditis and dilated cardiomyopathy. 1817 63


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