Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Genetic analysis of extrathyroidal features of Obese strain (OS) chickens with spontaneous autoimmune thyroiditis. 305 29

We have recently reported a two-fold defect in glucocorticoid mediated immunoregulation in the Obese strain (OS) of chickens with spontaneous autoimmune thyroiditis (SAT): (i) a decreased basal corticosterone (CN) tonus due to an elevation of plasma corticosteroid-binding globulin (CBG) and (ii) an impaired CN rise in response to antigenic stimuli as well as lymphokines produced after mitogenic stimulation. The aim of the present study was to investigate the pathophysiological relevance of testosterone for the development of SAT. Compared to healthy normal White Leghorn chickens (NWL) the basal sex hormone tonus as well as androgen receptors of bursal tissue are not altered in the OS. Administration of sheep red blood cells (SRBC) or lymphokine containing conditioned media not only increased CN plasma levels but concomitantly modulated testosterone serum concentrations, although in an inverse direction and without significant difference between OS and healthy control chickens. These results suggest that, in contrast to the glucocorticoid system, androgen tonus as well as its modulation by immune signals are normal in the OS. The mode of action by which androgens exert their known beneficial effect on the development of SAT was also studied. According to our findings the capacity of testosterone to prevent SAT when administered during the posthatching period can be attributed to direct effects on bursal epithelial cells as well as indirect mechanisms, namely a fall in CBG levels leading to normalization of the CN tonus.
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PMID:The role of testosterone in spontaneous autoimmune thyroiditis of Obese strain (OS) chickens. 307 54

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.
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PMID:The multi-factorial pathogenesis of autoimmune disease. 312 34

In contrast to systemic autoimmunity, spontaneous autoimmune thyroiditis of Obese strain (OS) chickens is associated with a marked T cell hyperreactivity in vitro, i.e. an increased proliferation and interleukin 2 (IL 2) secretion in response to Concanavalin A (ConA). In the present study we report an enhanced capacity of OS peripheral lymphoid cells (splenocytes and peripheral blood lymphocytes, PBL) to adsorb fluorescein isothiocyante (FITC) labelled ConA, but not phytohemagglutinin (PHA). However, the elevated ConA binding cannot be a prerequisite for in vitro ConA hyperreactivity as OS thymocytes are normal with respect to ConA binding but nonetheless exhibit elevated responses to this mitogen. Moreover, ConA binding does not correlate with the frequency of cells able to express IL 2 receptors upon short term ConA stimulation. The percentage of ConA activatable cells was found to be increased in OS- PBL as compared to normal control PBL, but was unaltered in OS splenocytes. This finding points to a further mechanism of T cell hyperreactivity in OS chicks in addition to the previously reported defects in nonspecific immunosuppression. Finally, enumeration of cells in the S phase revealed that enhanced proliferation of OS T lymphocytes was not restricted to the in vitro response to ConA and phytohemagglutinin (PHA) but also occurs in vivo.
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PMID:T cell hyperproliferation in autoimmunity prone obese strain (OS) chickens is independent of abnormal mitogen binding in vitro and can be demonstrated in vivo. 326 Jan 99

Obese strain (OS) chickens afflicted with spontaneous autoimmune thyroiditis (SAT) display several signs of a general immune dysbalance, some of which may be related to altered endocrine mechanisms such as the glucocorticoid tonus. The latter is the combined result of corticosterone (CN) production, metabolism as well as excretion, and the binding of CN to corticosteroid binding globulin (CBG) and glucocorticoid receptors (GR). The present study deals with the comparative investigation of these parameters in OS and normal White Leghorn (NWL) chickens. The results obtained with radioimmunoassay for CN and radioligand saturation assays for plasma CBG as well as GR in the thymus were as follows: (1) both OS and NWL have equal total CN levels; (2) however, OS chickens exhibit elevated CBG levels, whereas the physicochemical parameters (equilibrium affinity, specificity spectrum) of CBG were equal in OS and NWL; (3) the GR capacities and affinities were equal in both OS and NWL throughout development until thymic involution. Similarly, the specificity, affinity, and sedimentation behaviour were equal in OS and NWL. (4) Furthermore, no differences were found in the response of OS and NWL splenocytes to the suppressive effect of glucocorticoids in vitro, also excluding postreceptor alterations at the cellular level in the OS. From these findings we conclude that the increased CBG levels, which are not compensated for by either increased CN plasma levels or by increased receptor capacities or affinities in lymphatic organs, represent a diminished glucocorticoid tonus in OS chickens. This may have immunoregulatory consequences which, in turn, may contribute to the development of SAT.
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PMID:Diminished glucocorticoid tonus in obese strain (OS) chickens with spontaneous autoimmune thyroiditis: increased plasma levels of a physicochemically unaltered corticosteroid-binding globulin but normal total corticosterone plasma concentration and normal glucocorticoid receptor contents in lymphoid tissues. 326 Mar 12

The review presents a concept for the pathogenesis of spontaneous, organ-specific autoimmune diseases that take into account an altered immune regulation, modulating hormonal influences and a genetically determined primary susceptibility of the target organ for the autoimmune attack. The concept is exemplified by means of the Obese strain (OS) chicken model which develops a spontaneous hereditary autoimmune thyroiditis. In respect to the the altered function of the immune system both, MHC associated (Ir) and non-MHC associated genes are involved. The MHC, i.e. a certain haplotype, only plays a modulatory role in determining the frequency and severity of spontaneous autoimmune thyroiditis, while the presence of certain non-MHC associated genes is a absolute prerequisite for the emergence of the disease. The latter is also true for the genetically determined target organ susceptibility, while hormonal factors, notably sex-steroids and glucocorticoids, again only have a facultative, modulatory effect. Only if an appropriate genetic constellation concerning the non-MHC encoded aberrant immunological function and genes coding for the susceptibility of the thyroid gland for the autoimmune process is present, severe autoimmune thyroids develops.
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PMID:Concept of a multigenic basis for the pathogenesis of spontaneous autoimmune thyroiditis. 330 94

Basal plasma levels of corticosterone and corticosteroid-binding globulin (CBG) have been investigated in Obese strain (OS) chickens afflicted with spontaneous autoimmune thyroiditis (SAT). Corticosterone was determined radioimmunologically, and CBG by using a highly sensitive radioligand saturation assay. OS chickens displayed total corticosterone levels not different from healthy normal White Leghorn (NWL) chickens. CBG, however, was found to be twice as high in OS chickens as compared with their healthy counterparts, irrespective of sex or age. This quantitative difference in the CBG level is not compensated for by either altered affinity or specificity of the molecule. Furthermore, no differences were found in the response of OS and NWL lymphocytes to the suppressive effect of glucocorticoids in vitro. We therefore assume that OS animals are deficient in free, hormonally active corticosterone. An additional indication for such a diminished glucocorticoid tonus was that in vivo treatment of OS chickens with glucocorticoid hormones, thus increasing the free and active hormone fraction, normalizes the T cell hyperreactivity and significantly reduces thyroid infiltration. Possible pathophysiological implications of a diminished glucocorticoid tonus for spontaneous autoimmunity, as well as possible explanations for the beneficial effects of glucocorticoid treatment on the development of SAT, are discussed.
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PMID:Elevation of corticosteroid-binding globulin in obese strain (OS) chickens: possible implications for the disturbed immunoregulation and the development of spontaneous autoimmune thyroiditis. 348 17

The enhanced T cell reactivity (ConA hyperresponsiveness and IL 2 hypersecretion) of spleen lymphocytes of Obese strain (OS) chickens with spontaneous autoimmune thyroiditis has recently been shown to be due to a defect in macrophage-derived non-specific suppressor factors that regulate IL 2 secretion and IL 2-promoted T lymphoblast proliferation in normal healthy animals. In the present study, we present several lines of evidence that the increased T cell response of peripheral blood lymphocytes (PBL) of OS chickens is due to mechanisms entirely different from the described dysregulation of splenic T cells: 1) In contrast to the splenic macrophages, peripheral blood monocytes of OS animals are not deficient in the production of IL 2 antagonistic activity (IAA); 2) therefore, cocultivation of PBL from OS and Normal White Leghorn (NWL) chickens in communicating culture chambers did not abrogate the difference in Con A response as previously observed with spleen lymphocytes. 3) Immunofluorescence with a monoclonal antibody (INN CH 16) against the chicken IL 2 receptor revealed enhanced numbers of mitogen activatable T cells in OS PBL but not OS spleen lymphocytes. 4) After prolonged Con A stimulation of PBL, OS and NWL lymphoblasts did not differ from each other in functional aspects. In contrast to this, Con A lymphoblasts from OS spleens exhibited enhanced staining with INN CH 16 in parallel with an increased proliferative response to IL 2. Thus, the primary T cell dysfunction involved in the development of autoimmune disease in OS chickens is the result of at least two separate regulatory defects.
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PMID:T cell hyperreactivity in obese strain (OS) chickens. Different mechanisms operative in spleen and peripheral blood lymphocyte activation. 350 Jan 18

Mouse monoclonal antibodies (MCAs) were prepared against chicken inflammatory macrophages for the purpose of analyzing macrophage heterogeneity. Macrophage-rich adherent peritoneal exudate cells harvested from Cornell K-strain chickens 42 hr after stimulation with Sephadex were used as immunogens in the production of the monoclonal antibodies. Eight hybridoma clones producing antibodies reactive with chicken peritoneal macrophages were subjected to characterization. While six of the monoclonal antibodies cross-reacted with various hematopoietic cell types, two MCAs (CMTD-1 and -2) were restricted in reactivity to macrophages. CMTD-1 was found to react with activated peritoneal macrophages generated by several irritants. In contrast, CMTD-2 identified a subpopulation of macrophages elicited by specific carbohydrate-based stimulants. This presumably was based on the cross-reaction of this MCA with specific carbohydrate linkages. Analysis using flow cytometry revealed the time-dependent appearance of CMTD-2-positive peritoneal macrophages between 24 and 52 hr after ip Sephadex injection. This subpopulation of peritoneal macrophages was found to be heterogeneous for the ability to undergo in vitro phagocytosis of sheep erythrocytes. CMTD-2-positive cells were also detected in the thyroids of 2-week-old Obese strain chickens with spontaneous autoimmune thyroiditis and at a low incidence in the spleens of normal chickens.
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PMID:Monoclonal antibodies reactive with chicken peritoneal macrophages: identification of macrophage heterogeneity. 352 1

In Obese strain (OS) chickens the role of maternal antibodies, passively transferred through the egg to the developing chick, was evaluated as a causative factor in the early development of spontaneous autoimmune thyroiditis (SAT). In the egg, passive antibody titers were highest in the yolk and lower in the allantoic fluid and sera of developing embryos. This passage of antibodies was documented by use of radiolabeled antibodies. In dams with high antibody titers, antibodies could be found in the sera of chicks at the time of hatch. Thyroglobulin was absent in the yolk of OS eggs during embryonal life, as compared with its detection in normal eggs. Immune complexes (thyroglobulin-autoantibody) detected in the thyroids of OS, but not CS, chicks at the time of hatch, or earlier, appear to reflect the presence of the maternally transferred antibodies. A pair of crosses between OS chickens, with thyroiditis, and the C strain (CS), without thyroiditis, was made to evaluate the role of transferred antibodies in the pathogenesis of autoimmune disease. When an OS chicken was the dam, maternal antibodies could be passively transferred; when a CS chicken was the dam, no maternal antibodies were present to be transferred. Nevertheless, both hybrids developed full-blown thyroiditis, demonstrating that binding of transferred maternal antibody to thyroglobulin is not a prerequisite for the induction of SAT. However, presence of maternal antibodies precipitated the onset of disease. Immune complexes formed in the embryonic thyroid are likely to participate in early autoimmune disease, although the development of full-blown thyroiditis may await the competency of the chick's immune system to provide the characteristic cellular infiltrate.
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PMID:Materno-embryonally transferred antibodies precipitate autoimmune thyroiditis in obese strain (OS) chickens. 372 17


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