Analysis of the immune-encodrine feedback loop in the avian system and its alteration in chickens with spontaneous autoimmune thyroiditis.

In both mammals and chickens, immunization with exogenous antigens results in a surge of serum glucocorticoid hormone levels concomitant with the antibody response. This effect is mediated by glucocorticoid-increasing factors (GIF) produced by cells of the immune system. In the avian system, GIF appear to act via the hypothalamo-pituitary axis and not directly on the adrenal gland. Interleukin 1 is the main active substance responsible for GIF activity, as shown by molecular sieve and immunoaffinity chromatography studies. In contrast to data from mammals, we found no evidence that interleukin 2 elevates chicken corticosterone. Obese strain chickens with spontaneous Hashimoto-like autoimmune thyroiditis are deficient in their in vivo GIF response. Because no differences were found between autoimmune and healthy chickens in the corticosterone response of the adrenal gland after ACTH administration, and since autoimmune animals are able to react normally to immobilization stress, it is assumed that this deficiency is due to a specific defect rather than a general disturbance in the endocrine system.

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.

Decreased level of thymidine in the serum of obese strain (OS) chickens with spontaneous autoimmune thyroiditis.

We have previously shown that normal chicken serum (NCS) is able to interfere with the IL 2 promoted incorporation of DNA precursors into T lymphoblasts and that serum derived from autoimmunity prone Obese strain (OS) chickens is deficient in this respect. This "defect in non-specific suppression" has been speculated to be one of the causes for T cell hyperreactivity in the OS. In this study we present several lines of evidence that the suppressive effect of normal chicken serum (NCS) on 5-(125Iodo)-2-deoxyuridine (125IUdR) uptake into chicken T blasts is a competition artefact due to cold thymidine (TdR) present in NCS. Inhibition of 125IUdR required the continuous presence of NCS and suppression of 3H-TdR incorporation could be competed for by increasing the dose of the radiolabel. Molecular sieve chromatography followed by reversed phase high performance liquid chromotagraphy revealed the "inhibitory" activity to co-elute with TdR. Moreover, NCS did not suppress protein synthesis by chicken T cells growing with IL 2 and did not affect oxidative metabolism, cell viability, expression of IL 2 receptors, or percentages of cells in the S phase of the cell cycle. In accordance with these data, OS-sera suprisingly contain less TdR than those from normal controls. Experiments involving crosses of the OS with the normal inbred CB strain, revealed that the subnormal serum TdR level of the OS is an autosomally dominant trait which, however, segregates from T cell hyperreactivity. These findings falsify our previous hypothesis that a defect in specific IL 2 antagonists might be involved in T cell hyperfunction of the OS and indicate that NCS is devoid of factors which neutralize IL 2 function.

T cell hyperproliferation in autoimmunity prone obese strain (OS) chickens is independent of abnormal mitogen binding in vitro and can be demonstrated in vivo.

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.

Evidence for a new murine immunoglobulin heavy chain variable region gene family.

In the course of a previous study addressing autoantibody generation in murine models for generalized autoimmune disorders, we observed a nonfunctional immunoglobulin heavy chain transcript in a B cell hybridoma from lupus-prone MRL-Mp-lpr/lpr mice. This transcript, the cDNA sequence of which is presented here, is of general interest for murine immunoglobulin genetics as it cannot be ascribed to any known heavy chain variable region gene (Vh) family by nucleic acid sequence homology criteria and, hence, may represent a new Vh gene family. The sequence showed about equal nucleotide similarity (70-73%) to 3 other Vh gene families (S107, J606, 7183) and less than 65% similarity to members of the remaining 6 Vh gene families. Nucleic acid sequence comparisons with unpublished immunoglobulin sequences uncovered a highly homologous (greater than 95%) functional Vh transcript indicating that the suggested Vh gene family also encodes expressed antibody molecules.

[A follow-up of x-ray-treated tuberous hemangiomas after 15-20 years (author.s transl)]. / Kontrolle röntgenbestrahlter tuberöser Hämangiome nach 15-20 Jahren

The treatment of hemangiomas with X-rays has been sharply criticized because of their tendency to involute spontaneously. It has been the aim of this catamnestic study to re-examine for X-ray injury those patients, whose hemangiomas were irradiated 15-20 years ago. The findings indicate that signs of roentgenoderma can appear already with 800 r and increase rapidly over 1,500 r. The observed irreversible damages, however, were mostly not grave, but admonish a certain amount of restraint. An assessment of the effectiveness of low X-ray doses still requires verification considering a faster spontaneous involution.