Biomedical subjects

Noel R Rose

Publications and source records attributed to Noel R Rose.

At least 37 records · Page 2Linked to original sources

PubMed2005

Increased thyroidal fat and goitrous hypothyroidism induced by interferon-gamma.

Summary Hashimoto's thyroiditis is associated with a diffuse lymphocytic infiltration of the stroma and a production of several cytokines, such as interferon-gamma (IFN-gamma). We previously reported that transgenic mice expressing IFN-gamma under the control of the thyroglobulin promoter develop primary hypothyroidism. In order to determine the long-term changes induced by IFN-gamma in the thyroid gland, we analysed cross-sectionally 202 mice (96 transgenic mice and 106 controls) of 0-650 days of age. Multiple linear regression analysis showed that, after adjusting for age and sex, thyr-IFN-gamma transgenic mice were 14% (3 g) smaller (P < 0.0001) and had a 5- to 6-fold bigger thyroid (P < 0.0001) than wild-type littermates. Transgenic thyroids showed striking histopathological changes in follicles, thyrocytes and stroma. Follicles were enlarged, irregular and were lined by thickened, granular and oxyphilic thyrocytes. The stroma contained a moderate and diffuse mononuclear infiltrate--mainly composed of macrophages--and, interestingly, a clear increase in the content of fat. These findings indicate that, in addition to hypothyroidism, chronic exposure of the thyroid to IFN-gamma leads also to macrophage infiltration and subsequent adipocyte expansion, suggesting a link between inflammation and fat accumulation.

Adipose Tissue↗

PubMed2005

Complement receptors regulate lipopolysaccharide-induced T-cell stimulation.

Complement receptors type 1 and 2 (CR1 (CD35)/CR2 (CD21)) are known to enhance the adaptive immune response. In mice, CR1/CR2 are expressed on B cells, follicular dendritic cells, and activated granulocytes. Recently, we showed that a subset of CD44high and CD62Llow T cells also expresses CR1 and CR2. We now report that CR1/CR2 are detectable on both CD4+ and CD8+ subsets of T cells. Lipopolysaccharide (LPS) from Gram-negative bacteria causes polyclonal activation of B cells and stimulation of macrophages and other antigen-presenting cells. We further demonstrate that LPS induced marked up-regulation of CD25 and CD69 on T cells from CR1/CR2 sufficient (Cr+/+), but significantly lower up-regulation on T cells from CR1/CR2 deficient (Cr-/-) mice. These findings point to a novel mechanism by which CR1/CR2 modulates the activation of T cells by LPS.

Animals↗

PubMed2004

Impaired up-regulation of CD25 on CD4+ T cells in IFN-gamma knockout mice is associated with progression of myocarditis to heart failure.

Inflammation has been recognized increasingly as a critical pathologic component of a number of heart diseases. A mouse model of autoimmune myocarditis was developed to study the role of immune mediators in the development of cardiac dysfunction. We have found previously that IFN-gamma deficiency promotes inflammation in murine myocarditis. It has been unclear, however, how IFN-gamma deficiency in myocarditis affects cardiac function and what underlying immune mechanisms are responsible for these effects. In this work, we show that IFN-gamma knockout (KO) mice have more pronounced systolic and diastolic dysfunction and greater frequency of progression to dilated cardiomyopathy and heart failure compared with WT mice. Cardiac dysfunction in the KO mice is associated with the expansion of activated (CD44(high)) CD3+ T cells due to reduced apoptosis of CD4+, but not CD8+, T cells. CD4+ T cells in the KO mice show impaired up-regulation of CD25 upon activation, resulting in the expansion of CD4+CD44+CD25- T cells and their infiltration into the heart. CD4+CD25- T cells are less apoptosis-prone compared with the CD25+ population, and their infiltration into the heart is associated with greater severity of myocarditis. We conclude that IFN-gamma deficiency in autoimmune myocarditis is associated with preferential expansion of CD4+CD44+CD25- T cells resulting in increased cardiac inflammation. An exaggerated inflammatory response in IFN-gamma KO mice causes cardiac dysfunction, leading to dilated cardiomyopathy and heart failure.

Animals↗

PubMed2004

Expression of class II major histocompatibility complex molecules on thyrocytes does not cause spontaneous thyroiditis but mildly increases its severity after immunization.

Class II major histocompatibility complex (MHC) molecules are classically expressed on antigen-presenting cells of the hematopoietic lineage but have also been described on epithelial cells in association with autoimmunity. In this context, however, it remains debatable whether class II MHC molecules are the initiating event or rather the consequence of the autoimmune attack. In addition, the role of epithelial class II expression once the autoimmune attack has begun is unknown. We generated transgenic mice expressing in the thyroid follicular cells the class II transactivator, the master regulator of all the genes in the class II MHC pathway. The study used a cohort of 245 CBA/J mice (127 wild-type and 118 transgenic), both in basal conditions (n = 63) and at different time points after immunization with mouse thyroglobulin (n = 182). In basal conditions, transgenic mice were similar to wild-type controls and did not develop spontaneous autoimmune thyroiditis, despite the aberrant expression of class II MHC molecules on thyrocytes. After immunization, thyroiditis was 8% more severe in transgenics than controls (95% confidence interval from 1.8-13.4%; P = 0.033), especially during the florid stages of disease. These findings suggest that expression of class II MHC molecules on epithelial cells is not sufficient to initiate autoimmunity but mildly modulates an already established autoimmune attack against the target organ.

Animals↗

PubMed2004

Mercury exposure, malaria, and serum antinuclear/antinucleolar antibodies in Amazon populations in Brazil: a cross-sectional study.

BACKGROUND: Mercury is an immunotoxic metal that induces autoimmune disease in rodents. Highly susceptible mouse strains such as SJL/N, A.SW, B10.S (H-2s) develop multiple autoimmune manifestations after exposure to inorganic mercury, including lymphoproliferation, elevated levels of autoantibodies, overproduction of IgG and IgE, and circulating immune complexes in kidney and vasculature. A few studies have examined relationships between mercury exposures and adverse immunological reactions in humans, but there is little evidence of mercury-associated autoimmunity in humans. METHODS: To test the immunotoxic effects of mercury in humans, we studied communities in Amazonian Brazil with well-characterized exposures to mercury. Information was collected on diet, mercury exposures, demographic data, and medical history. Antinuclear and antinucleolar autoantibodies (ANA and ANoA) were measured by indirect immunofluorescence. Anti-fibrillarin autoantibodies (AFA) were measured by immunoblotting. RESULTS: In a gold mining site, there was a high prevalence of ANA and ANoA: 40.8% with detectable ANoA at > or =1:10 serum dilution, and 54.1% with detectable ANA (of which 15% had also detectable ANoA). In a riverine town, where the population is exposed to methylmercury by fish consumption, both prevalence and levels of autoantibodies were lower: 18% with detectable ANoA and 10.7% with detectable ANA. In a reference site with lower mercury exposures, both prevalence and levels of autoantibodies were much lower: only 2.0% detectable ANoA, and only 7.1% with detectable ANA. In the gold mining population, we also examined serum for AFA in those subjects with detectable ANoA (> or =1:10). There was no evidence for mercury induction of this autoantibody. CONCLUSIONS: This is the first study to report immunologic changes, indicative of autoimmune dysfunction in persons exposed to mercury, which may also reflect interactions with infectious disease and other factors.

Adult↗

PubMed2004

Novel model of constrictive pericarditis associated with autoimmune heart disease in interferon-gamma-knockout mice.

BACKGROUND: Constrictive pericarditis represents a serious hemodynamic syndrome that may lead to heart failure. Studies of its pathophysiological mechanisms have been impeded by the lack of an animal model. METHODS AND RESULTS: Cardiac myosin-induced experimental autoimmune myocarditis in interferon (IFN)-gamma-knockout (KO) mice results in increased cardiac inflammation and development of severe grossly detectable pericarditis. Using in vivo pressure-volume studies, we found that the acute phase of experimental autoimmune myocarditis in IFN-gamma-KO mice was characterized by reduced left ventricular (LV) volumes compared with wild-type mice. The KO mice exhibited a classic restrictive/constrictive phenotype with decreased cardiac output, increased chamber stiffness, preserved ejection fraction, and impaired diastolic filling, characterized by reduced deceleration time and pressure tracings showing the square root sign similar to that observed in clinical cases of constrictive pericarditis. This phenotype was not associated with the severity of myocarditis but correlated with the presence of grossly detectable adhesive pericarditis present only in the KO group and characterized by increased pericardial inflammation and fibrosis. Comparison of IFN-gamma-KO and wild-type mice matched for the severity of myocardial disease further confirmed that pericarditis, and not myocarditis, was responsible for smaller LV volumes, reduced cardiac output, increased cardiac stiffness, and increased peak filling rate adjusted for end-diastolic volumes in KO mice. CONCLUSIONS: Autoimmune heart disease in IFN-gamma-KO mice results in increased pericardial inflammation and fibrosis, leading to constrictive phenotype during the acute phase of disease. It represents a novel animal model of constrictive pericarditis.

Animals↗

PubMed2004

Autoimmune myocarditis: cellular mediators of cardiac dysfunction.

Immune mediators play a critical role in the pathogenesis and outcomes of a number of cardiac diseases. This review summarizes recent findings on the composition of the inflammatory infiltrate and the role of different types and subtypes of immune cells and their products in mediating cardiac dysfunction in experimental autoimmune myocarditis (EAM). CD4+ T cells are required for initiation of myocarditis and their numbers in the heart infiltrate correlate with systolic dysfunction during disease progression. Other immune cells, including CD8+ T cells, granulocytes, and mast cells, can directly affect cardiomyocyte function. When regulatory mechanisms fail, the local damage leads to cardiomyocyte death, replacement fibrosis and overall cardiac dysfunction. EAM provides insights into the role of the immune system in the development of dilated cardiomyopathy (DCM) and heart failure and may serve as a general paradigm for autoimmune organ-specific tissue damage.

Animals↗

PubMed2004

Early chemokine expression induced by interferon-gamma in a murine model of Hashimoto's thyroiditis.

Chemokines represent a group of small, secreted proteins mainly involved in navigating leukocytes towards site of inflammation. Some chemokines have been implicated in the pathogenesis of autoimmune diseases, which are characterized by an ectopic retention of leukocytes within the target organ, ultimately leading to loss of function. To determine the chemokines profile expressed in the thyroid gland upon chronic exposure to interferon-gamma (IFNgamma), we analyzed C57BL6 transgenic mice that aberrantly express IFNgamma under control of the thyroglobulin promoter. We compared by reverse transcriptase PCR the thyroidal expression of 10 chemokines (CCL1 through 5 and CXCL9 through 13) in thyr-IFNgamma transgenics and wild-type littermates. We found that transgenics exclusively expressed CCL4, CXCL9, and CXCL11, and showed increased expression of CCL5 and CXCL10. This chemokine profile was associated with moderate mononuclear cell infiltration of the thyroid stroma that, however, decreased significantly after 2 months of age and did not organize into lymphoid structures. Our findings indicate that the isolated expression of IFNgamma is capable of recruiting mononuclear cells but they do not progress to full lymphoid transformation of the thyroid.

Animals↗

PubMed2004

Quantitative analysis of myocardial inflammation by flow cytometry in murine autoimmune myocarditis: correlation with cardiac function.

Inflammation has been increasingly recognized as an important pathological component of heart failure. Existing methods of assessing myocardial infiltrate are labor-intensive and provide data that are difficult to quantify and not representative of the whole heart. As a result, little effort has been made to systematically assess the components of myocardial inflammation. We established an alternative method of quantitative assessment of myocardial inflammation by flow cytometry after enzymatic digestion of hearts to characterize the infiltrate and study the association between inflammation and cardiac function in murine experimental autoimmune myocarditis. The severity of acute myocarditis uniquely correlated with the proportion of neutrophils, but not T cells, B cells, or macrophages. Both acute and chronic phases were characterized by the presence of CD44high (activated) T cells in the heart, whereas T cells trafficking through normal hearts exhibited CD44low phenotype. During the chronic phase, the proportion of CD4+ T cells was associated with increased left-ventricular volumes and deterioration of systolic function, the hallmarks of dilated cardiomyopathy. We conclude that flow cytometry on uniformly digested mouse hearts provides sensitive and reproducible assessment of myocardial infiltrate and can be used to dissect out the specific role of individual immune components from the overall inflammatory response in the heart.

Animals↗

PubMed2004

Interferon-gamma protects against chronic viral myocarditis by reducing mast cell degranulation, fibrosis, and the profibrotic cytokines transforming growth factor-beta 1, interleukin-1 beta, and interleukin-4 in the heart.

Inflammatory fibrosis is a characteristic feature of myocarditis, dilated cardiomyopathy (DCM), and congestive heart failure. Th1-type immune responses, mediated by interleukin (IL)-12-induced interferon (IFN)-gamma, are believed to exacerbate autoimmune diseases including myocarditis. In this study, we examined the effect of IL-12R beta 1 and IFN-gamma deficiency on the development of chronic CB3-induced myocarditis using knockout mice. We found increased chronic CB3-induced myocarditis (14.1 to 43.1%, P < 0.001); pericarditis (1.5 to 7.6%, P < 0.001); fibrosis (9.7 to 27.4%, P < 0.05); and the profibrotic cytokines transforming growth factor-beta(1), IL-1 beta, and IL-4 in the hearts of IFN-gamma-deficient mice. All mice infected with CB3 developed DCM, but IFN-gamma-deficient mice developed a fibrous, adhesive pericarditis associated with increased numbers of degranulating mast cells (MCs) in the pericardium (26.6 to 45.9%, P < 0.01), increased histamine levels (716 to 1930 ng/g of heart, P < 0.01), and reduced survival (100 to 43%). In contrast, IL-12R beta 1 deficiency did not significantly alter the development of chronic myocarditis. Thus, IFN-gamma protects against the development of severe chronic myocarditis, pericarditis, and DCM after CB3 infection by reducing MC degranulation, fibrosis, and the profibrotic cytokines transforming growth factor-beta(1), IL-1 beta, and IL-4 in the heart.

Animals↗

PubMed2004

Cardiomyopathies.

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Autoantibodies↗

PubMed2004

Mast cells and innate cytokines are associated with susceptibility to autoimmune heart disease following coxsackievirus B3 infection.

The development of autoimmune disease involves a combination of genetic and environmental factors. Many autoimmune diseases are believed to be triggered by viral infections. Since the early, natural immune response to infection can determine the later development of the adaptive immune response, innate immunity likely influences the progression from viral immunity to autoimmunity. To investigate the role of the innate immune response on susceptibility to autoimmune disease, we compared the early cytokine response of mice susceptible or resistant to the development of autoimmune heart disease following viral infection. We found that susceptible BALB/c mice produced elevated levels of TNF-alpha, IL-1beta, and IL-4 within hours of Coxsackievirus B3 (CB3) infection. These cytokines are known to be critical for the development of autoimmune heart disease, and are also rapidly produced from activated mast cells (MC). Degranulating MC were observed as early as 6 h following CB3 infection in the heart, and significantly higher numbers of MC were found in the spleen of susceptible BALB/c mice at this time. Thus, susceptibility to autoimmune heart disease can be determined as early as 6 h following viral infection in susceptible strains of mice.

Animals↗

PubMed2004

Autoimmune disease 2002: an overview.

Autoimmune disease includes a large spectrum of clinically distinct entities that share a common etiology, a misguided, self-directed immune response. Collectively, they are major contributors to morbidity and mortality. Normally, the body utilizes a number of strategies to avoid the pathologic consequences of autoimmune reactions, but these defenses may fail for a combination of hereditary and environmental factors. Infection has long been regarded as a common environmental trigger of autoimmune disease. Our laboratory has developed a mouse model of myocarditis induced by Coxsackievirus B3 infection and demonstrated some of the steps involved in the transition from an infection to an autoimmune disease. Such basic studies may suggest improved treatment or preventive measures for this group of diseases.

Autoimmune Diseases↗

PubMed2004

Animal models for autoimmune myocarditis and autoimmune thyroiditis.

This chapter describes four murine models of autoimmune diseases: two related to autoimmune myocarditis and two related to autoimmune thyroiditis. The first model, Coxsackie virus B3 (CB3)-induced myocarditis, results in the development of acute myocarditis in susceptible as well as resistant mouse strains, whereas chronic myocarditis develops only in genetically susceptible mice. CB3-induced myocarditis closely resembles the course of human myocarditis, which is believed to be initiated by viral infection. Mouse cardiac myosin heavy chain has been identified as the major antigen associated with the late chronic phase of viral myocarditis. The second model is cardiac myosin-induced experimental autoimmune myocarditis (EAM) and, in a modification, cardiac alpha-myosin heavy chain peptide-induced myocarditis. In the EAM model, cardiac myosin or the relevant peptide in Freund's complete adjuvant (FCA) is injected subcutaneously into mice. The immune response, the histological changes, and the genetic susceptibility seen in EAM are similar to those of CB3-induced myocarditis. The third model is experimental autoimmune thyroiditis (EAT). EAT can be induced in genetically susceptible strains of mice by immunization with mouse thyroglobulin in FCA or lipopolysaccharide. Mice susceptible to EAT have the H-2A(k), H-2A(s), or H-2A(q) alleles. We describe here a standard technique for the induction of EAT; it was developed in our laboratory and is widely used as a model for studying Hashimoto's thyroiditis. The fourth model presented in this chapter is that of spontaneous autoimmune thyroiditis in NOD.H2h4 mice. These mice express the H-2A(k) allele on an NOD genetic background and develop spontaneous thyroiditis, which is exacerbated with dietary iodine.

Amino Acid Sequence↗

PubMed2004

Women and autoimmune diseases.

Autoimmune diseases affect approximately 8% of the population, 78% of whom are women. The reasons for the high prevalence in women are unknown, but circumstantial evidence links autoimmune diseases with preceding infections. Animal models of autoimmune diseases have shown that infections can induce autoimmune disease. For example, coxsackievirus B3 (CB3) infection of susceptible mice results in inflammation of the heart (myocarditis) that resembles myocarditis in humans. The same disease can be induced by injecting mice with heart proteins mixed with adjuvant(s), which indicates that an active infection is not necessary for the development of autoimmune disease. We have found that CB3 triggers autoimmune disease in susceptible mice by stimulating elevated levels of proinflammatory cytokines from mast cells during the innate immune response. Sex hormones may further amplify this hyperimmune response to infection in susceptible persons, which leads to an increased prevalence of autoimmune diseases in women.

Animals↗

PubMed2003

Thyroid-specific expression of IFN-gamma limits experimental autoimmune thyroiditis by suppressing lymphocyte activation in cervical lymph nodes.

The role of IFN-gamma in the pathogenesis of autoimmune disease is controversial, being described as immunostimulatory in some studies and immunosuppressive in others. To determine the contribution of local expression of IFN-gamma, we derived NOD.H-2(h4) transgenic mice overexpressing IFN-gamma in a thyroid-restricted manner. Transgenic mice, which had serum IFN-gamma levels similar to wild-type littermates, showed up-regulation of MHC class II on thyrocytes, but did not develop spontaneous thyroiditis. Upon immunization with murine thyroglobulin, transgenic mice developed milder disease and reduced IgG1 responses compared with wild type. The milder disease was associated with decreased frequency of activated CD44(+) lymphocytes in the cervical lymph nodes. This suppressive effect was confirmed by showing that blockade of systemic IFN-gamma with mAb enhanced disease and increased IgG1 responses. The study supports a disease-limiting role of IFN-gamma in autoimmune thyroiditis. Furthermore, it provides the first evidence that local IFN-gamma activity in the thyroid is sufficient for disease suppression.

Animals↗

PubMed2003

IL-12 receptor beta 1 and Toll-like receptor 4 increase IL-1 beta- and IL-18-associated myocarditis and coxsackievirus replication.

Th1-type immune responses, mediated by IL-12-induced IFN-gamma, protect the host from most viral infections. To investigate the role of IL-12 and IFN-gamma on the development of Coxsackievirus B3 (CB3)-induced myocarditis, we examined the level of inflammation, viral replication, and cytokine production in IL-12Rbeta1- and IFN-gamma-deficient mice following CB3 infection. We report that IL-12Rbeta1 deficiency results in decreased viral replication and inflammation in the heart, while IFN-gamma deficiency exacerbates CB3 replication. Importantly, decreased IL-1beta and IL-18 levels in IL-12Rbeta1-deficient hearts correlated directly with decreased myocardial inflammation. Because IL-1beta and IL-18 were associated with myocardial inflammation, we examined the effect of TLR4 deficiency on CB3 infection and myocarditis. We found that TLR4-deficient mice also had significantly reduced levels of myocarditis, viral replication, and IL-1beta/IL-18, just as we had observed in IL-12Rbeta1-deficient mice. This is the first report that TLR4 influences CB3 replication. These results show that IL-12Rbeta1 and TLR4 exacerbate CB3 infection and myocarditis while IFN-gamma protects against viral replication. The remarkable similarities between the effects of IL-12Rbeta1 and TLR4 suggest that these receptors share common downstream pathways that directly influence IL-1beta and IL-18 production, and confirm that IL-1beta and IL-18 play a significant role in the pathogenesis of CB3-induced myocarditis. These findings have important implications not only for the pathogenesis of myocarditis, but for other autoimmune diseases triggered by viral infections.

Acute Disease↗

PubMed2003

Kinetics of mononuclear cell infiltration and cytokine expression in iodine-induced thyroiditis in the NOD-H2h4 mouse.

Mononuclear cell infiltration of the thyroid gland is a common histologic feature of chronic lymphocytic thyroiditis. Although the infiltrating mononuclear cells have been implicated in the destruction of the thyroid, information concerning the progression of infiltration into the thyroid is limited. In this report, we examine the composition and kinetics of mononuclear cell infiltration in the thyroid and the expression of major histocompatibility complex class II (I-Ak), IL-12, and IFN-gamma in the thyroid of the NOD-H2h4 mouse, a model of spontaneous autoimmune thyroiditis accelerated by the administration of excess dietary iodine. Mice were given a low dose of 0.015% NaI in their drinking water for 2, 4, 6, 8, and 16 weeks, and thyroids were removed, serially sectioned, and stained in an avidin-biotin peroxidase assay. The thyroid infiltrate included CD4+ and CD8+ T cells, F4/80+ macrophages, and B220+ B cells. After 2 weeks of iodine treatment, CD4+ T cells were the first seen in the thyroid, followed by CD8+ T cells and F4/80+ macrophages. B220+ B cells entered the thyroid after 4 weeks of iodine treatment. IL-12 and IFN-gamma positive cells were located in the thyroid early in disease and were up-regulated in the focal accumulations of infiltrating cells. Thyrocytes clearly expressed I-Ak after 4 weeks of iodine treatment near the location of mononuclear cell infiltration.

Animals↗