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N Neu

Publications and source records attributed to N Neu.

At least 37 records · Page 2Linked to original sources
PubMed1996

Cardiac myosin-induced myocarditis: target recognition by autoreactive T cells requires prior activation of cardiac interstitial cells.

Immunization with cardiac myosin causes T cell-mediated myocarditis in genetically predisposed mice and serves as a model for autoimmune heart disease. The normal heart is not susceptible to T cells autoreactive with cardiac myosin; therefore, we investigated the conditions that are required to facilitate recognition of the target tissue. A.SW mice were immunized with cardiac myosin on Days 0 and 7. Major histocompatibility antigen (MHC Ag) and intercellular adhesion molecule-1 (ICAM-1) expression in the heart tissue was investigated by immunohistochemical techniques shortly before disease onset (ie, on Day 9). At this time point, cardiac interstitial cells expressing class II but not class I MHC Ag were significantly increased. In addition, endothelial ICAM-1 expression was strongly up-regulated. Myofibers did not show expression of these markers, and T cells were virtually absent. Because lipopolysaccaride (LPS) induced a similar distribution of class II MHC Ag and ICAM-1 in the myocardial tissue and because these molecules could be crucial to disease onset, we determined whether treatment with this immunomodulator renders the heart susceptible to passively transferred myosin-reactive T cells. We found that concanavalin A-activated spleen cells from myosin-immunized donors induced myocarditis in LPS-primed recipients, whereas normal mice were resistant to the injection of such cells. Increased class II MHC Ag expression after LPS-treatment was mediated by TNF because LPS-primed mice genetically lacking the TNF receptor failed to increase class II MHC Ag expression in the heart tissue. In summary, these results suggest that in cardiac myosin-induced myocarditis, expression of interstitial class II MHC Ag and/or endothelial ICAM-1 is a prerequisite for target organ recognition by autoreactive T cells.

Animals↗
PubMed1995

Serum cardiac troponin T and creatine kinase-MB elevations in murine autoimmune myocarditis.

BACKGROUND: We used a murine model of autoimmune myocarditis to investigate systematically whether serum markers of myocardial cell injury, that is, cardiac troponin T (TnT) and the MB isoenzyme of creatine kinase (CK-MB) are useful for the diagnosis of inflammatory heart disease. METHODS AND RESULTS: Fifty-two A.SW mice were immunized with cardiac myosin to induce myocarditis. The disease was evident on day 12 after the initial immunization in 14 of 22 immunized mice, on day 16 in 7 of 10 mice, on day 19 in 6 of 10 mice, and on day 23 in 5 of 10. The severity of myocarditis increased between days 12 and 16 and remained constant thereafter. TnT was elevated in a considerable number of mice with myocarditis, resulting in a diagnostic sensitivity (number of marker elevations per number of mice with myocarditis) of 0.43 on day 12, 0.71 on day 16, and 0.50 on day 19. CK-MB elevations were not seen on day 12 but resulted in a diagnostic sensitivity of 0.71 on day 16 and of 0.33 on day 19. No elevations of CK-MB or TnT were observed on day 23. All elevations were specific for the disease, as none of the mice lacking myocarditis showed increased markers. CONCLUSIONS: In murine autoimmune myocarditis, TnT is a more sensitive marker for the disease than CK-MB. Elevations clearly indicate myocarditis, but negative test results do not exclude the presence of the disease. These data suggest that the determination of CK-MB and, in particular, of TnT, can be useful for the diagnostic evaluation of patients with suspected myocarditis.

Animals↗
PubMed1995

Cellular immune mechanisms in myosin-induced myocarditis.

Cardiac myosin-induced myocarditis proved to be a valuable virus-free murine model with which to investigate autoimmunological mechanisms in inflammatory heart disease. The disease was shown to be T cell-mediated. In this contribution the functional role of CD4 and CD8 molecules and the conditions that are required to make the cardiac tissue susceptible to an autoimmune attack are discussed.

Animals↗
PubMed1995

Pallister-Hall syndrome and McKusick-Kaufmann syndrome: one entity?

The Pallister-Hall syndrome is characterised by specific facial anomalies, postaxial polydactyly, imperforate anus, and brain anomalies including a diencephalic hamartoblastoma. The hallmarks of the McKusick-Kaufmann syndrome are hydrocolpos owing to vaginal atresia, postaxial polydactyly, imperforate anus, and congenital heart defects. We report a patient with the unique features of hydrocolpos, postaxial polydactyly, and hypothalamic hamartoblastoma and discuss the different aetiological considerations of both syndromes and implications for clinical management.

Abnormalities, Multiple↗
PubMed1994

Persistence of virus and viral genome in myocardium after coxsackievirus B3-induced murine myocarditis.

Following infection with Coxsackievirus B3 (CVB3), A-strain mice develop ongoing myocarditis that persists after the virus ceases to be cultivatable from heart tissue. We studied the natural history of this virus-induced but apparently autoimmune inflammation by means of in situ hybridization (ISH) and by polymerase chain reaction (PCR). Both ISH and culture allowed detection of virus up to 2 weeks post-infection in virtually all heart tissues. In contrast, PCR revealed the presence of viral genome for a substantially longer period of time, i.e. at least 34 days after CVB3 infection. Similarly, the majority of mice showed myocardial inflammation at this time point. However, the persistence of virus did not correlate with ongoing myocarditis, and vice versa. Most mice with ongoing myocarditis produced heart myosin autoantibodies, most probably as a result of tissue damage. The lack of correlation between presence of ongoing inflammation and persistence of virus supports our previous view that the late phase of CVB3-induced myocarditis is mediated by autoimmunological mechanisms.

Animals↗
PubMed1993

The induction of experimental autoimmune myocarditis in mice lacking CD4 or CD8 molecules [corrected].

Experimental induction of most autoimmune diseases appears to depend on the activation of CD4+ T helper cells, while CD8+ lymphocytes may have a role in disease progression. To study the role of CD4+ and CD8+ T cell subsets in T cell-dependent autoimmunity, mice lacking CD4 or CD8 molecules after gene targeting were injected with cardiac myosin to induce organ specific autoimmune myocarditis. Mice homozygous for the CD8 mutation (CD8-/-) developed significantly more severe disease as compared to CD4+/-CD8+/- controls. Surprisingly, CD4-/- mice developed autoimmune myocarditis with infiltration of TCR alpha beta +CD4-CD8- T cells in the heart tissue and appearance of autoantibodies. These data demonstrate that the lack of CD4+ or CD8+ T cells has no significant influence on the initiation of autoimmune myocarditis. CD4+ and CD8+ cells regulate disease severity and these results may explain the occurrence of autoimmunity in CD4 immunodeficiencies.

Animals↗
PubMed1993

T cells in cardiac myosin-induced myocarditis.

Autoimmune myocarditis induced by immunization with cardiac myosin can be seen as a virus-free system to analyze the immunopathological mechanisms of certain forms of postinfectious heart disease. Immunodepletion studies have shown that in A.SW mice myosin-induced myocarditis is mediated by both CD4+ and CD8+ cells. The CD4+ subset is at least required for the induction of the autoimmune response, whereas the CD8+ subset seems to play a key role in mediating the myocardial injury. In addition, we found a bias concerning the TCR repertoire, because T cells within the inflammatory heart infiltrate almost exclusively use V beta 8 elements. Furthermore, recent serologic and immunohistologic studies indirectly suggest that the cardiac myocyte is not the target for the anti-myosin response. Rather, the primary target might consist in dendritic cells presenting myosin epitopes even under normal conditions.

Animals↗
PubMed1992

Target organ susceptibility and autoantibody production in an animal model of spontaneous autoimmune thyroiditis.

F1-hybrids of Obese strain (OS) chickens, afflicted with spontaneous autoimmune thyroiditis (SAT), and normal, inbred CB chickens, do not develop severe thyroiditis. About 50% of these crosses show circulating autoantibodies to thyroglobulin (TgAAb), but the thyroid glands are only slightly infiltrated, suggesting that the target organ is not susceptible to autoimmune attack. In the present study we show that despite this mild infiltration TgAAb are only synthesized by lymphoid cells within the thyroid gland. Furthermore, we demonstrate that immunization with chicken thyroglobulin (Tg) in complete Freund's adjuvant causes severe experimental autoimmune thyroiditis (EAT) in F1(OSxCB) hybrids.

Animals↗
PubMed1991

Cardiac myosin-induced myocarditis as a model of postinfectious autoimmunity.

Immunization with purified cardiac myosin induces autoimmune myocarditis in A strain mice. Because this disease parallels Coxsackievirus B3 (CB3)-induced myocarditis in many respects, we are now using the immunization model as a virus-free system to study certain forms of immunologically-mediated heart disease. In the present article we will describe several characteristics of the humoral and cellular autoimmune response acting in myosin-induced myocarditis. Furthermore, we discuss hypotheses which might explain how myosin-reactive T cells recognize and attack the heart tissue.

Animals↗
PubMed1991

Experimentally-induced autoimmune myocarditis: production of heart myosin-specific autoantibodies within the inflammatory infiltrate.

Immunization with cardiac myosin in complete Freund's adjuvant (CFA) induces severe autoimmune myocarditis in A H-2 congenic mouse strains. The disease shares a variety of characteristics with Coxsackie-virus B3 (CB3)-induced myocarditis and is strongly associated with high-titered autoantibodies to cardiac myosin. Using the spot ELISA-technique, we demonstrate here that in cardiac myosin-immunized mice myosin autoantibodies were not only produced within the spleen, but also at the site of the autoimmune attack, i.e., within the inflammatory heart infiltrate. At the level of single plasma cells we further showed that a substantial part of the myosin autoantibodies was specific for the cardiac myosin isoform, thereby supporting previous serologic data. The finding that cells of the inflammatory heart infiltrate significantly contribute to autoantibody production might explain why the occurrence of high-titered myosin autoantibodies is restricted to mice which develop the disease.

Animals↗
PubMed1991

Cellular infiltrate, major histocompatibility antigen expression and immunopathogenic mechanisms in cardiac myosin-induced myocarditis.

Immunization with cardiac myosin induces severe myocarditis in genetically predisposed mice. The disease closely parallels that seen after infection with Coxsackievirus B3 and is characterized by a diffuse interstitial cellular infiltrate. To analyze the immunopathologic events in the heart tissue of cardiac myosin-immunized A/J and A.SW mice, the phenotype of inflammatory cells and the expression of class I and class II major histocompatibility (MHC) antigens (Ag) was examined at different time points using the immunoperoxidase method. On day 14 after the initial immunization, very few inflammatory cells were seen, whereas on day 21 the lesions were severe and extended over the whole ventricular wall. At both time points tested, the inflammatory infiltrate was composed of Mac-1+ cells, representing 70 to 80% of the infiltrate, and Thy-1.2+ cells, representing 20 to 25%. These Thy-1.2+ cells consisted of CD4+ cells and to a lesser extent of CD8+ cells. Essentially, no B cells were found on day 14, and on day 21 their frequency was only 1 to 2%. Furthermore, massive Ig deposits were observed along the infiltrated myofibers. Both on day 14 and 21, MHC class II Ag expression was associated with cells of the inflammatory infiltrate, but no aberrant I-A Ag expression was found on endothelial cells of coronary vessels or on myofibers. Similarly, no increased MHC class I Ag expression was seen on myofibers on day 14. However, on day 21 the infiltrated myofibers did show an increase in surface MHC class I Ag expression, thereby suggesting that this phenomenon is a consequence of the inflammatory process. Furthermore, in vivo administration of monoclonal antibodies to either CD4 or CD8 protected cardiac myosin-immunized mice from myocarditis, and a similar effect was achieved by monoclonal antibody to I-A Ag. Thus, cardiac myosin-induced myocarditis is mediated by a cooperation between CD8+ cells and MHC class II restricted, i.e., CD4+ cells.

Animals↗
PubMed1990

Cardiac myosin-induced myocarditis. Heart autoantibodies are not involved in the induction of the disease.

We recently demonstrated that cardiac myosin is capable of inducing autoimmune myocarditis in genetically predisposed mice. This disease parallels coxsackievirus B3-induced autoimmune myocarditis in many respects and is associated with high-titer autoantibodies specific for cardiac myosin. The following lines of evidence suggest that these autoantibodies are not involved in the induction of autoimmune myocarditis: 1) immunoperoxidase staining of heart sections from cardiac myosin-immunized A/J and A.SW mice revealed IgG depositions only along damaged muscle fibres in infiltrated areas, but not in intact tissue; 2) myosin autoantibodies did not bind to the surface of viable cardiac myocytes isolated from mice, but only reacted with myocytes permeabilized with detergent; 3) mice treated with a single high dose of cyclophosphamide, which reduces the humoral immune response, still developed severe myocarditis, despite the fact that their autoantibody titers were reduced to the level of adjuvant-injected controls; and 4) passive transfer of high-titer myosin autoantibodies failed to induce myocarditis, although the titers in the recipients were comparable to those found in mice with cardiac myosin-induced disease. Together, the results suggest that high-titer myosin autoantibodies are secondary rather than primary to the disease.

Animals↗
PubMed1990

[Virus demonstration and pathologic changes in different phases of coxsackievirus B myocarditis in mice].

A/J mice between 15 days and 10 weeks of age were infected intraperitoneally with Coxsackievirus B3 (CVB3). To search for virus in the myocardium various methods were applied: virus isolation from the myocardium, RNA extraction for dot blot hybridization and in situ hybridization. Two different RNA probes, one specific for CVB3 the other cross-reacting with other enteroviruses, were radioactively labeled with 35S or 32P by in vitro transcription. In paraffin sections histological alterations were assessed semiquantitatively. The animals developed acute myocarditis with myolysis and virus in the myocardium until 14 days after infection. The second stage of the disease was characterized by a persistent inflammatory infiltrate. At this stage no virus could be shown in the myocardium. Antibodies against cardiac myosin appeared 16 days after infection. Autoimmune mechanisms thus seem to be a most relevant factor for persistent inflammation after the acute viral phase of the disease.

Animals↗
PubMed1989

Immunogenetic analysis of spontaneous autoimmune thyroiditis of obese strain chickens.

A variety of immunological, endocrinological, and virological abnormalities have been implicated in the etiopathogenesis of spontaneous autoimmune thyroiditis (SAT) of Obese strain (OS) chickens, e.g., a general T cell hyperreactivity, an increased uptake of iodine into the thyroid gland, a diminution of the glucocorticoid tonus, and an OS-specific endogenous virus. In crosses of the close-bred OS B15/B15 subline with the inbred normal CB B12/B12 strain we have studied the mode of inheritance of these aberrations and their putative association with SAT. The results indicate that none of these OS-specific characteristics alone is an absolute prerequisite for the development of thyroid infiltration, which appears to be governed by one autosomal recessive gene.

Animals↗
PubMed1988

Genetic analysis of extrathyroidal features of Obese strain (OS) chickens with spontaneous autoimmune thyroiditis.

The Obese strain (OS) of chickens, which is afflicted with Hashimoto-like spontaneous autoimmune thyroiditis (SAT), displays elevated T cell proliferation, interleukin (IL)2 production and IL2 receptor expression upon mitogen stimulation, and defects in the neuroendocrine control of the immune system including elevated corticosteroid-binding globulin (CBG) and a deficient increase of serum corticosterone (CN) upon cytokine injection. Recently this strain has further been shown to harbor retrovirus-related sequences (endogenous virus no. 22, ev22) absent in healthy control strains. To determine the number of genes responsible for SAT-associated immunodysregulation and to unravel possible ev22 associations, we analyzed the above immune and endocrine parameters in F1 hybrids and backcrosses of the autoimmune OS B15B15 with healthy inbred CB B12B12 chickens. OS-like T cell hyperproliferation and IL2 hypersecretion in response to both concanavalin A and phytohemagglutinin were transmitted as autosomal dominant traits and co-segregated in backcross animals. In vivo hyporesponse of the OS to the corticosterone-inducing effect of cytokine preparations was inherited dominantly and the elevated CBG serum levels recessively. None of these traits appeared to be major histocompatibility complex (MHC) linked. However, while T cell abnormalities and elevated CBG serum levels were not associated with the autosomal ev22 locus, in vivo hyporesponsiveness to glucocortocoid-inducing cytokines co-segregated with this OS-specific provirus. These results add to the concept of SAT as a polyetiological and plurigenetic disease and do not support our previous hypothesis that T cell hyperreactivity and immunoendocrine dysfunction might be functionally related.

Animals↗
PubMed1987

Cardiac myosin induces myocarditis in genetically predisposed mice.

After infection with coxsackie virus B3 (CB3), H-2 congenic mice on an A- background develop immunologically mediated myocarditis associated with an increased titer of myosin autoantibody, part of which is specific for the cardiac myosin isoform. The present study demonstrates that cardiac myosin itself induces severe myocarditis and high titers of myosin autoantibodies in A/J, A.SW/SnJ, and A.CA/SnJ mice. As in CB3-induced myocarditis, one population of these autoantibodies was specific for cardiac myosin. A.BY/SnJ and B10.A/SgSnJ mice also developed the disease after immunization, but the prevalence and the myosin autoantibody titers were lower. In contrast, C57BL/6J and C57BL/10J mice were resistant to myocarditis induced by cardiac myosin and did not develop increased myosin autoantibodies or cardiac myosin-specific autoantibodies. Immunization with skeletal muscle myosin had no effect compared with controls injected with complete Freund's adjuvant, thereby suggesting that the immunogenic epitopes are unique to the cardiac myosin isoform. Furthermore, we found that susceptibility to myocarditis induced by cardiac myosin is influenced by the major histocompatibility complex and by genes not closely linked to the major histocompatibility complex. Because there are parallels between myocarditis induced by cardiac myosin and that induced by CB3, this new animal model can be used to analyze the pathologic mechanisms in autoimmune heart disease.

Animals↗