Biomedical subjects

N Neu

Publications and source records attributed to N Neu.

46 records · Page 3Linked to original sources

PubMed1987

Autoantibodies specific for the cardiac myosin isoform are found in mice susceptible to Coxsackievirus B3-induced myocarditis.

Several mouse strains are susceptible to immunopathic myocarditis after infection with Coxsackievirus B3 (CB3). This disease is associated with autoantibodies that are directed against myosin. In this study we characterized sera from CB3-infected mice for their reactivity with three different myosin isoforms (heart, skeletal muscle, and brain myosins) and for autoantibody isotype by using an ELISA. Competitive inhibition assays and absorption studies with various myosins demonstrated the presence of two autoantibody populations in sera of susceptible A.CA and A.SW mice. The first was specific for cardiac myosin and was mainly IgG. The second antibody population cross-reacted with heart, skeletal muscle, and brain myosin and was mainly IgM. B10.PL/SgSf and B10.A/SgSf mice, which do not develop immunopathic myocarditis, produced only the IgM autoantibody population cross-reactive with all three myosin isoforms. Because the heart-specific myosin autoantibodies were found exclusively in the mouse strains that developed immunopathic myocarditis, they can be considered a serologic marker for autoimmune heart disease.

Animals↗

PubMed1987

Cardiac myosin and autoimmune myocarditis.

Infection with type 3 of the group B Coxsackieviruses (CB3) sometimes leads to the development of myocarditis in humans. Circumstantial evidence in the form of heart-reactive antibodies in these cases of human myocarditis suggests that the later phases of the disease may be due to autoimmunization. Since human myocarditis is a relatively rare sequel to infection with CB3 virus, we propose that it reflects a genetic predisposition in some individuals. To investigate this possibility we established an experimental murine model of viral myocarditis. By testing a large number of strains of inbred mice infected with CB3 we found that a few strains developed an ongoing myocarditis characterized by diffuse interstitial mononuclear infiltration and by the production of heart-specific IgG autoantibodies. These antibodies reacted with myocardial sarcolemma and myofibrils as well as with muscle striations. The principal myocardial autoantigen, identified by means of postinfectious sera of mice with heart-specific autoantibodies, was found to be the cardiac isoform of myosin. Immunization of susceptible mice with cardiac myosin stimulated the production of heart-specific antibodies reactive with both cardiac muscle striations and sarcolemma, accompanied by mononuclear infiltration of the myocardium. From these results we infer that cardiac myosin is an autoantigen capable of inducing postinfectious myocarditis in genetically predisposed individuals.

Animals↗

PubMed1987

Heart-specific autoantibodies induced by Coxsackievirus B3: identification of heart autoantigens.

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.

Animals↗

PubMed1987

The multi-factorial pathogenesis of autoimmune disease.

Development of organ-specific autoimmune diseases depends on both an abnormal immune regulation and a genetically determined primary susceptibility of the target organ to the autoimmune attack. In addition to the essential genetically determined prerequisites there are also facultative, modulating factors that influence the outcome of an autoimmune disease. This concept is exemplified in the Obese strain (OS) chicken model which develops a spontaneous autoimmune thyroiditis closely resembling human Hashimoto disease. Three modulating factors are specifically addressed, viz. (a) the lower threshold of OS thyroid epithelial cells for the gamma-interferon-induced MHC class II antigen expression as compared to normal controls, (b) the decreased glucocorticoid tonus of the OS and (c) the presence of a new endogenous virus (ev 22) locus in the OS that has so far not been found in any normal strain and which seems to influence the glucocorticoid-mediated immunoregulatory process.

Animals↗

PubMed1987

Coxsackievirus induced myocarditis in mice: cardiac myosin autoantibodies do not cross-react with the virus.

After infection with Coxsackievirus B3 (CB3), H-2 congenic strains of mice on an A-background develop an immunologically mediated myocarditis associated with autoantibodies directed mainly against cardiac myosin. We tested these autoantibodies for cross-reactivity with the virus. Using immunoblotting and virus neutralizing assays with affinity purified antibodies and absorbed sera, we found that the autoantibodies to heart myosin did not cross react with CB3. In addition, myosin autoantibodies induced by immunization with cardiac myosin did not react with the virus. Western immunoblotting revealed that the anti-CB3 antibodies in the infected mice are directed against the capsid protein VP 2. We conclude that CB3 antigens do not stimulate an immune response that cross-reacts with cardiac myosin.

Animals↗

PubMed1986

A monoclonal antibody reacting with a membrane determinant expressed on activated chicken T lymphocytes.

A monoclonal antibody (INN-CH-16) was prepared which reacts with a cell surface antigen termed chicken activated T lymphocyte antigen. This antigen is expressed on antigen- or mitogen-activated T lymphocytes and is not present on nonstimulated lymphocytes. It has an apparent molecular mass of 48-50 kDa under reducing conditions. The value of this antibody for the immunohistochemical characterization of infiltrating cells in the thyroid glands from Obese strain chickens with spontaneous thyroiditis is demonstrated.

Animals↗

PubMed1986

Genetic background of spontaneous autoimmune thyroiditis in the obese strain of chickens studied in hybrids with an inbred line.

To determine the number and function of genes which are responsible for spontaneous autoimmune thyroiditis (SAT) in the obese strain (OS) of chickens we crossed birds of this strain (B15/B15) with those of the inbred CB line (B12/B12). The progeny was analyzed for autoantibodies to thyroglobulin (TgAAb) and for histopathological changes in the thyroid glands. In F1 (OS X CB) hybrids only those animals which derived from CB mothers had circulating TgAAb, the progeny from the reverse combination female OS X male CB was negative. Since the disease is not inherited by OS males only, we conclude that maternal TgAAb, which are transferred from the egg yolk to the embryo, might prevent the immune system of the F1 chickens from TgAAb formation via blocking or eliminating the respective antigens. Those F1 hybrids which have high TgAAb levels in the serum show only little or no thyroiditis. Together with other observations, these data lead to the conclusion that the thyroid gland of the F1 hybrids is not susceptible to TgAAb. This supports previous findings that a genetically determined thyroid abnormality is a prerequisite for the full development of SAT. The low degree of SAT in backcross (F1 X OS) animals and F2 hybrids suggests that several genes are involved in the disease. MHC typing of these generations revealed that the B haplotype affects the time of SAT onset.

Animals↗

PubMed1985

Spontaneous autoimmune thyroiditis in obese strain chickens: a genetic analysis of target organ abnormalities.

In this study we investigated the genetic background of primary abnormalities found in the thyroid gland of Obese strain (OS) chickens with spontaneous autoimmune thyroiditis (SAT), i.e., susceptibility to passively transferred antibodies to thyroglobulin (TgAb) and incomplete suppression of iodine uptake by thyroxine (T4). Several crosses between the B15/B15 subline of OS chickens and the inbred CB line (B12/B12) were done and the progeny was analyzed for thyroiditis after injection of OS serum containing high titers of TgAb. It was found that passive transfer of TgAb increased the lymphoid infiltration in the thyroids of OS chickens, but had no effect on CB birds. A genetic analysis of backcrosses revealed that this trait is, in the case of simple Mendelian inheritance, encoded by at least three recessive genes. The thyroidal 131I uptake of these crosses under T4 was also determined and we found that this trait is most probably encoded by only one recessive gene.

Animals↗

PubMed1985

In vitro T cell hyperreactivity in Obese strain (OS) chickens is due to a defect in nonspecific suppressor mechanism(s).

Spontaneous autoimmune thyroiditis of OS chickens is associated with a marked hyperreactivity of the T cell system. The purpose of the present study was to investigate the underlying regulatory mechanisms. Co-cultivation experiments between Con A-stimulated OS and NWL lymphocytes in communicating cultures revealed soluble regulatory factors to be responsible for the observed functional differences: the high proliferative response to Con A and hyperproduction of IL 2 of OS cells was found to be due to a deficiency in the conditioned medium of dialyzable inhibitory factor(s) that regulate IL 2 secretion of NWL lymphocytes. Furthermore, sera of young NWL chickens were found to profoundly inhibit the IL 2-promoted lymphoblast proliferation. This IL 2 antagonizing activity is lost with age (3 to 6 yr) and was found to be significantly diminished in OS birds throughout ontogeny, thus pointing to possible parallels between immune regulatory dysfunction in autoimmunity and in physiologic aging. Both enhanced T cell response and the defect in serum suppressor were inherited by (OS X CB)F1 animals, indicating that these two aberrations may be related to each other.

Animals↗

PubMed1984

"Natural" chicken antibodies to red blood cells are mainly directed against the B-G antigen, and their occurrence is independent of spontaneous autoimmune thyroiditis.

Using an indirect hemagglutination assay we tested sera from 94 healthy normal White Leghorn (NWL) and 117 Obese strain (OS) chickens with spontaneous autoimmune thyroiditis for the presence of "natural" antibodies against major histocompatibility complex (MHC) antigens expressed on red blood cells (RBC). In both groups older animals had a significantly increased frequency of such antibodies, but the titer was age-independent. OS chickens showed almost the same frequency of natural antibodies as NWL, and a comparison between OS birds with high antithyroglobulin autoantibody (TgAAb) titers and those with low titers also did not reveal a significant difference. We conclude that the occurrence of natural antibodies has no relation to TgAAb. The specificity of natural antibodies for MHC-encoded antigens was investigated in indirect immunofluorescence tests including absorption experiments with RBC and white blood cells (WBC). This analysis revealed that of 14 MHC-specific sera 13 were reacting with the B-G antigen, which is present on RBC only. One serum reacted with the B-F antigen, expressed on all somatic cells, i.e., both on RBC and WBC.

Age Factors↗