Biomedical subjects
Publications and source records attributed to N Neu.
We describe a nosocomial rotavirus outbreak among pediatric cardiology patients and the impact of a prospective, laboratory-based surveillance program for rotavirus in our university-affiliated, quartenary-care pediatric hospital in New York City. Improved compliance with infection control and case-finding among patients and healthcare workers halted the outbreak.
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Since CD4+ lymphocytopenia can be caused by disturbed thymic T-cell maturation, we investigated the T-cell subsets of a 9-year-old boy fulfilling the diagnostic criteria for CD4+ lymphocytopenia in a follow-up period of 4 years. We found (I) reduced CD45RA expression, (II) enhanced CD45RO expression and (III) a significant increase in gamma delta TCR-bearing T cells. An accelerated apoptosis (11%) was observed in the CD45RO+, but not CD45RA+ subset. These findings provide evidence that a disturbed thymic T-cell maturation process might play a role in the pathogenesis of CD4+ lymphocytopenia.
Community projects are a requirement of third-year medical students at three South Dakota clinical campuses. Students identify a community issue, design and implement either a service or research project, and present the project to faculty and peers. Topics include cardiovascular and other disease risk factors, nutrition education, firearm safety and many others. These projects answer a need to advance an understanding of population health, promote community involvement among student physicians, and improve the health of the community.
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BACKGROUND: Dilated cardiomyopathy (DCM) is a major cause of sudden cardiac death. In certain mouse major histocompatibility complex (MHC) backgrounds, myocarditis and inflammatory cardiomyopathy can be triggered by immunization with heart muscle-specific proteins. Similarly, chronic heart disease in humans has been linked to certain HLA alleles, such as HLA-DQ6. However, there is no experimental evidence showing that human MHC class II molecules and peptides derived from human proteins are involved in the pathogenesis of myocarditis and DCM. METHODS AND RESULTS: We generated double CD4- and CD8-deficient mice transgenic for human CD4 (hCD4) and human HLA-DQ6 to specifically reconstitute the human CD4/DQ6 arm of the immune system in mice. Transgenic hCD4 and HLA-DQ6 expression rendered genetically resistant C57BL/6 mice susceptible to the induction of autoimmune myocarditis induced by immunization with cardiac myosin. Moreover, we identified heart-specific peptides derived from both mouse and human alpha-myosin heavy chains capable of inducing inflammatory heart disease in hCD4 and HLA-DQ6 double transgenic mice but not in hCD4 single transgenic littermates. The autoimmune inflammatory heart disease induced by the human heart muscle-specific peptide in hCD4 and HLA-DQ6 double transgenic mice shared functional and phenotypic features with the disease occurring in disease-susceptible nontransgenic mice. CONCLUSIONS: Our data provide the first genetic and functional evidence that human MHC class II molecules and a human alpha-myosin heavy chain-derived peptide can cause inflammatory heart disease and suggest that human inflammatory cardiomyopathy can be caused by organ-specific autoimmunity. The humanized mice generated in this study will be an ideal animal model to further elucidate the pathogenesis of inflammatory heart disease and facilitate the development of rational treatment strategies.
Chlamydia infections are epidemiologically linked to human heart disease. A peptide from the murine heart muscle-specific alpha myosin heavy chain that has sequence homology to the 60-kilodalton cysteine-rich outer membrane proteins of Chlamydia pneumoniae, C. psittaci, and C. trachomatis was shown to induce autoimmune inflammatory heart disease in mice. Injection of the homologous Chlamydia peptides into mice also induced perivascular inflammation, fibrotic changes, and blood vessel occlusion in the heart, as well as triggering T and B cell reactivity to the homologous endogenous heart muscle-specific peptide. Chlamydia DNA functioned as an adjuvant in the triggering of peptide-induced inflammatory heart disease. Infection with C. trachomatis led to the production of autoantibodies to heart muscle-specific epitopes. Thus, Chlamydia-mediated heart disease is induced by antigenic mimicry of a heart muscle-specific protein.
BACKGROUND: Correctly diagnosing tuberculosis (TB) in children is critical to provide appropriate treatment and to detect undiagnosed source cases. However, diagnosing TB in children may be difficult. OBJECTIVE: We sought to determine whether Amplicor, a Food and Drug Administration-approved polymerase chain reaction (PCR) assay used to detect Mycobacterium tuberculosis in sputum and computerized tomography (CT) would facilitate the diagnosis of TB in children. We also examined the applicability of the Centers for Disease Control and Prevention clinical case definition for TB. SETTING: A university-affiliated pediatric hospital in New York City. SUBJECTS: From March, 1995, to November, 1997, 27 children < 15 years of age (mean age, 3.9 years) were evaluated for suspected TB. RESULTS: M. tuberculosis was cultured from 5 of 76 (6.6%) gastric aspirate specimens, and PCR detected M. tuberculosis DNA in 3 (4.1%) of these specimens. There was poor correlation between culture and PCR because 6 specimens were discordant. CT scans were diagnostic of mediastinal or hilar adenopathy in 6 children with equivocal or negative chest radiographs and confirmed adenopathy in 8 others. Six children received alternative diagnoses. CONCLUSIONS: We conclude that the commercially available PCR technology had very limited utility in detecting M. tuberculosis from gastric aspirates, but CT scans were useful in assessing pediatric patients with suspected TB.
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Indinavir sulfate is a protease inhibitor used in the treatment of the human immunodeficiency virus (HIV). This case report describes the radiographic and urologic manifestations of indinavir urolithiasis in two pediatric patients with acquired immunodeficiency syndrome (AIDS). Management involves aggressive hydration and surgical intervention when indicated.
To contribute to the understanding of the role of the thymus in humans in the reconstitution of naive (CD45RA+) T cells after bone marrow transplantation (BMT), we compared T-cell regeneration in a unique situation, namely a thymectomized cancer patient (15 years old), with that of thymus-bearing patients after allogeneic BMT. These cases shared features of transplantation (total body irradiation, HLA-matched donors, and graft-versus-host disease prophylaxis with cyclosporine A) and all had an uncomplicated post-transplantation course. As shown by fluorescence-activated cell sorting analyses, the thymectomized host failed to reconstitute CD45RA+ T-helper cells even 24 months after BMT (11% CD45RA+ of CD4+ cells). In this patient, preferentially CD45RO+ cells contributed to the recovery of CD4+ cells (206 of 261/microL at 6 months and 463 of 558/microL at 24 months after BMT, CD45RA+ of CD4+ cells), whereas CD45RA+ cells remained low (<60/microL). In contrast, nine thymus-bearing hosts (5 children and 4 adults) examined between 6 and 24 months after BMT effectively reconstituted CD4+/CD45RA+ cells according to their normal age-related range (> or = 28% in adults and > or = 50% in children). Five of these were analyzed sequentially at 6 and 9 months after BMT. Within this period, CD45RA+ cells increasingly contributed to the recovery of CD4+ cells (median, +21%), even when total CD4+ cells decreased. With respect to T-cytotoxic/suppressor cells, the thymectomized host retained the capacity to recover CD45RA+ cells (137 of 333/microL at 6 months and 596 of 1,046/microL at 24 months after BMT, CD45RA+ of CD8+ cells), a proportion similar to that seen in thymus-bearing hosts. These findings suggest that a thymus-independent pathway exists to regenerate CD45RA+ T-cytotoxic/suppressor cells, but residual thymus is essential to reconstitute naive (CD45RA+) T-helper cells after BMT in humans.
BACKGROUND: Production of NO by inducible NO synthase (iNOS) has been implicated in the pathology of spontaneous and antigen-induced autoimmune diseases, and iNOS is expressed in the myocardium of patients with heart failure. It is not clear whether inflammatory murine autoimmune heart disease, an experimental model for human postviral heart disease, is characterized by increased iNOS expression within the heart and whether iNOS and NO are essential in the pathogenesis of autoimmune myocarditis. METHODS AND RESULTS: In the murine model of cardiac myosin-induced myocarditis, we demonstrate that iNOS expression was elicited in inflammatory macrophages and in distinct cardiomyocytes. Autoimmune heart disease was accompanied by formation of the NO reaction product nitrotyrosine in inflammatory macrophages as well as in cardiomyocytes. iNOS expression and nitrotyrosine formation were strictly dependent on myocardial inflammation. Focal myocarditis was sufficient to induce nitrotyrosine formation throughout the whole heart muscle. Mice defective for the interferon regulatory transcription factor-1 (IRF-1(-/-)) after gene targeting failed to induce iNOS expression and nitrotyrosine formation in the heart but developed cardiac myosin-induced myocarditis at prevalence and severity similar to those of heterozygous littermates (IRF-1(+/-)). CONCLUSIONS: These data provide the first in vivo evidence that iNOS expression and NO synthesis in macrophages and distinct cardiomyocytes are elicited in experimental murine inflammatory heart disease. The transcription factor IRF-1 controls iNOS expression and NO synthesis in disease. Because autoimmune myocarditis can develop in animals lacking IRF-1, these mice will be useful to elucidate the link between iNOS expression in inflammatory heart disease and the development of dilated cardiomyopathy and heart failure.
BACKGROUND: Interleukin (IL)-2 is an important growth and survival factor for T cells and plays a crucial role in inflammation. Myosin-induced myocarditis is strictly dependent on activated T cells and is a model for postinfectious inflammatory heart disease in humans. To explore the role of IL-2 in myocarditis, we injected mice genetically deficient for IL-2 with cardiac myosin. Because it is conceivable that the lack of IL-2 either promotes or ameliorates the disease, we selected mouse strains that differ in their susceptibility to cardiac myosin-induced myocarditis. METHODS AND RESULTS: Mice from a susceptible strain (C3H) that were rendered IL-2 deficient by gene targeting (IL-2-/- mice) and littermate controls were immunized twice with purified cardiac myosin at a 7-day interval. Three weeks after the first immunization, hearts were obtained for histopathological and immunohistochemical analysis. Sera were tested for autoantibodies to the cardiac myosin isoform by enzyme-linked immunosorbent assay. The majority of C3H IL-2-/- mice developed severe myocarditis accompanied by high-titer myosin autoantibodies. In C57BL/6 mice, which develop only little myocarditis on myosin immunization, lack of IL-2 did not increase susceptibility to the disease. Moreover, the composition of the inflammatory infiltrate in C3H IL-2-/- mice was virtually identical to that seen in the wild-type strain. CONCLUSIONS: Our data provide the first genetic evidence that in cardiac myosin-immunized mice, IL-2 has no essential role for the development of autoimmune heart disease and the generation of myosin autoantibodies.
BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) is involved in the pathogenesis of myocarditis and can bind to either tumor necrosis factor receptor (TNF-R) p55 or TNF-Rp75. However, it is not known which TNF-R mediates the specific functions of TNF in disease. To determine the role of the TNF/TNF-R system in chronic heart disease, we used a murine model of cardiac myosin-induced myocarditis that closely resembles the chronic stages of virus-induced myocarditis in humans. METHODS AND RESULTS: Mice lacking TNF-Rp55 expression after targeted disruption of the TNF-Rp55 gene were backcrossed into a genetic background susceptible to the induction of myocarditis with cardiac myosin. Here, we demonstrate that TNF-Rp55 gene-deficient mice did not develop any inflammatory infiltration into the heart after autoantigen injection, whereas control littermates showed autoimmune myocarditis at high prevalence and severity. Despite the absence of autoimmune heart disease, TNF-Rp55-/- mice produced cardiac myosin-specific IgG autoantibodies, indicating that activation of autoaggressive T and B lymphocytes had occurred. However, heart interstitial cells failed to express major histocompatibility complex (MHC) class II molecules in TNF-Rp55-/- animals, and adoptive transfer of autoreactive T cells resulted in heart disease only in TNF-Rp55-/- but not in TNF-Rp55-/- littermates. CONCLUSIONS: Cardiac myosin-induced myocarditis is dependent on autoaggressive T cells and on autoantigen presentation in association with MHC class II molecules within the heart. Thus, lack of TNF-Rp55 expression could interfere with either lymphocyte activation or target organ susceptibility. The data presented here show that the TNF-Rp55 is a key regulator for the induction of autoimmune heart disease by its controlling target organ susceptibility.
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.
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.
Immunization with cardiac myosin induces T cell-mediated myocarditis in genetically predisposed mice and serves as a model for autoimmune heart disease. This study was undertaken to identify pathogenic epitopes on the myosin molecule. Our approach was based on the comparison of the pathogenicity between cardiac (alpha-)myosin and soleus muscle (beta-)myosin. We show that alpha-myosin is the immunodominant isoform and induces myocarditis at high severity and prevalence whereas beta-myosin induces little disease. Therefore the immunodominant epitopes of alpha-myosin must reside in regions of different amino acid sequence between alpha- and beta-myosin isoforms. Cardiac myosin peptides corresponding to these regions of difference were synthesized and tested for their ability to induce inflammatory heart disease. Three pathogenic peptides were identified. One peptide that is located in the head portion of the molecule induced severe myocarditis, whereas two others that reside in the rod portion possessed only minor pathogenicity. The identification of pathogenic epitopes on the cardiac myosin molecule will allow detailed studies on the recognition of this antigen by the immune system and might be used to downmodulate ongoing heart disease.