PubMed Health⌕ Search

Biomedical subjects

R Fässler

Publications and source records attributed to R Fässler.

119 records · Page 7Linked to original sources
PubMed1988

The role of testosterone in spontaneous autoimmune thyroiditis of Obese strain (OS) chickens.

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.

Animals↗
PubMed1987

Disturbed immune-endocrine communication in autoimmune disease. Lack of corticosterone response to immune signals in obese strain chickens with spontaneous autoimmune thyroiditis.

Antigenic challenge as well as injection of lymphokine-containing media lead to a transient increase of serum glucocorticoids, a phenomenon that has been implicated in the regulation of the specificity of immune responses. In the present study we examined the dialogue between the immune and the neuroendocrine systems in Obese strain (OS) chickens, an animal model for human Hashimoto thyroiditis. The following results were obtained: A) OS and normal White Leghorn (NWL) chickens, 5-mo-old, were immunized with sheep red blood cells followed by daily monitoring of corticosterone (CN) serum levels. Whereas in NWL animals CN serum levels markedly increase 3 to 4 days after immunization, OS animals did not respond with CN elevation. B) A single i.v. injection of conditioned medium (CM) from concanavalin A-stimulated spleen cells also led to a transient, dose-dependent peak in plasma CN (maximum after 30 min). This CN response to a given CM preparation was significantly lower in OS than in NWL animals. C) CM, whether obtained from OS or NWL splenocytes, were equally effective to stimulate CN production. D) A single i.v. injection of CM leads--concomitantly to the CN peak--to a decrease of the concanavalin A-mediated proliferative response of peripheral blood lymphocytes in both OS and NWL chickens. This suppression, however, was significantly more pronounced in NWL chickens. In summary, these data suggest a disturbance of the immune-neuroendocrine communication in OS chickens with spontaneous thyroid autoimmunity. The possible implications for the generation of "forbidden" autoimmune responses are discussed.

Animals↗
PubMed1987

Mechanisms of T cell hyperreactivity in obese strain (OS) chickens with spontaneous autoimmune thyroiditis: lack in nonspecific suppression is due to a primary adherent cell defect.

The disturbed homeostasis of the immune system in Obese strain (OS) chickens with spontaneous autoimmune thyroiditis consists in a general T cell hyperreactivity (concanavalin A hyperresponsiveness, interleukin 2 (IL 2) hypersecretion), particularly expressed by those lymphocytes which infiltrate the diseased thyroid gland. This abnormality has been attributed to a defective regulation of both IL 2 production and IL 2 function by low m.w. factors, which are present in serum and splenocyte culture supernatants of normal chickens, but deficient in the OS. In the present study we identified the cellular origin of IL 2 antagonistic activity as a nonlymphoid, adherent cell. Suppressor factor production in vitro was confined to the plastic adherent fraction of spleen cells and preincubation of splenocytes with nylon wool, silica particles, or carbonyl iron significantly reduced the nonspecific suppressive activity of the culture supernatant. Kinetic studies revealed the defect in nonspecific suppression to entail prolonged IL 2 production by concanavalin A-activated OS spleen cells. In vivo treatment of normal White Leghorn chickens with silica led to a decrease in suppressive serum activity down to the OS level, whereas neither neonatal thymectomy nor bursectomy had any effect. The defective suppressor factor production in autoimmune chickens appeared to be due to a functional, but not numeric defect of macrophages as revealed by phenol red staining. The possibility that this aberration in adherent cell function might be a secondary phenomenon to the recently described reduced corticosterone tonus in OS chickens was excluded by in vivo substitution with exogenous glucocorticoids which did not normalize the suppressor defect in serum or in conditioned medium. Finally, we present evidence that T lymphoblasts from OS animals are less susceptible to IL 2 antagonistic regulation than normal cells, which possibly further contributes to the T cell hyperfunction of this autoimmune strain.

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

The genetic origin of murine lupus-associated autoantibodies.

Systemic lupus erythematosus and rheumatoid arthritis in human and murine systems are characterized by circulating autoantibodies and immune complex deposition in various organs causing tissue damage and disease. To define the molecular and clonotypic origin of these anti-self responses, and to determine whether abnormalities in Ig genes or somatic mechanisms generating autoantibody diversity may contribute to lupus etiology, we performed molecular analyses of the Ig germline gene organization and the Ig gene segments expressed in monoclonal autoantibodies from autoimmune mice. Comparative restriction fragment length polymorphism analysis of a large number of Ig gene loci from autoimmune and normal mice indicated that (a) lupus can develop in different Ig heavy and kappa light chain variable region gene haplotypes, and (b) the Ig germline genes in lupus mice might be normal. To determine whether autoantibodies are encoded by unique Ig gene segments present in the normal germline repertoire, but not expressed in exogenous responses, we compared nucleic acid sequences encoding lupus autoantibodies and antibodies against foreign antigens. Similar, and in some instances even identical, gene segments were expressed in both types of antibodies, indicating that anti-self and anti-foreign responses use the same, or at least an overlapping, germline gene repertoire. A large variety of Ig variable, diversity, and joining gene segments encoded these autoantibodies with different specificities. Hence, the overall murine lupus-associated anti-self response may be essentially unrestricted. Furthermore, limited evidence has been obtained that both germline genes and somatically mutated genes encode autospecificity, making gross abnormalities in mechanisms for somatic mutation of Ig variable genes unlikely.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Elevation of corticosteroid-binding globulin in obese strain (OS) chickens: possible implications for the disturbed immunoregulation and the development of spontaneous autoimmune thyroiditis.

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.

Animals↗
PubMed1986

Sex steroid and glucocorticoid receptors in the bursa of Fabricius of obese strain chickens spontaneously developing autoimmune thyroiditis.

The female sex develops autoimmune disease far more often than the male. This is claimed to be due to differences in peripheral sex steroid levels. We have examined in the bursa of Fabricius of Obese strain (OS) chickens, which spontaneously develop autoimmune thyroiditis, as well as in their healthy counterparts androgen(AR)-, estrogen(ER)-, progestin(PR)- and glucocorticoid(GR)-receptors in an attempt to elucidate possible further pathomechanisms, namely at the target site of steroid hormones. The characterization (affinity, specificity, association- and dissociation-rate, sedimentation behaviour) of all four types of receptors revealed no difference between sex or strain. Furthermore, the ontogeny study of the receptor capacity and affinity from the 7th embryonic day (i.e. before lymphocyte settlement) until bursa involution, again showed no difference between OS and healthy chickens of either sex. Thus, it can be concluded that the principal sex dependency of the susceptibility to autoimmune disease results predominantly from differences in sex steroid levels per se, although alterations in mechanisms beyond the cytosolic receptor level can presently not be excluded.

Animals↗
PubMed1985

Demonstration of sex hormone binding globulin in human cerebrospinal fluid.

This study demonstrates the existence of sex hormone binding globulin (SHBG) in human cerebrospinal fluid (CSF) by means of a highly sensitive radioligand saturation assay that has been recently described by us for measurement of SHBG in human plasma. The molecular similarity of this 5 alpha-dihydrotestosterone binding protein with plasma-SHBG was substantiated by a number of experiments in which the CSF-protein displayed the same properties as plasma-SHBG with respect to thermolability, affinity, specificity and sedimentation rate. SHBG levels in the CSF of normal women were found to be 0.139 +/- 0.04 nmol/l (mean +/- standard deviation), and in normal men to be 0.083 +/- 0.03 nmol/l respectively. CSF-SHBG in patients with a variety of neurological diseases associated with different degrees of a blood-CSF barrier disturbance, showed a good correlation with commonly determined parameters such as CSF-albumin and CSF-IgG that are known to be of plasma origin. The concept of CSF-SHBG originating from plasma by restricted diffusion is strongly supported by the finding that the CSF/plasma ratio of SHBG is independent of the plasma-SHBG concentration in the entire physiological range. Possible diagnostic and pathophysiological implications of this so far undetected CSF-constituent are discussed with regard to neurological and endocrine abnormalities.

Adolescent↗
PubMedDate not supplied

Incorporation of beta-galactosidase-expressing endothelial cells into the skeletal muscle microvascular bed of mice.

Cloned murine endothelial cells (cEC) were used as a carrier system for introducing a foreign gene into the microvascular bed of the hind limb of inbred mice. cEC were transfected with a beta-galactosidase-neo fusion construct, which enables both selection for DNA uptake in the presence of G 418 and the staining of cells for beta-galactosidase activity. Transfected cEC adhered and integrated readily into confluent monolayers of nontransfected cEC (up to 26% of total cell number). Seeding lacZ-transfected cEC on explanted arteries revealed rapid adhesion of the cells (within minutes) to the intact endothelium. After injection of 10(6) transfected EC via the femoral artery into the microvascular bed of the hind limb their presence was documented by beta-galactosidase staining after various time periods (1 h to 4 wk). Implanted cEC were detected in numerous elements of the microcirculation both in frozen sections and in squash preparations of the hind limb muscle and in the femoral bone up to 4 wk after the injection. The microvascular bed of skeletal muscle of the mouse as a recipient site for transduced syngeneic endothelial cells is, thus, a suitable experimental model to study various strategies for somatic gene therapy.

Animals↗