Enhanced osteopontin expression and macrophage infiltration in MRL-Fas(lpr) mice with lupus nephritis.

MRL-Fas(lpr) mice spontaneously develop a chronic lupus-like renal disease, characterized by immune complex-mediated glomerulonephritis and abundant mononuclear cell infiltration in the interstitium. In the present study we have examined whether the macrophage chemoattractant osteopontin (Opn) could be important in the recruitment of macrophages in this murine model of autoimmune renal injury. We have examined the expression of Opn in the kidney of MRL-Fas(lpr) mice and have correlated Opn synthesis with the degree of macrophage infiltration. Immunofluorescence staining revealed prominent expression of Opn by proximal tubules in MRL-Fas(lpr) mice but not in MRL-++ control mice. Northern blot analysis demonstrated that steady-state transcript levels for Opn mRNA were also significantly increased in MRL-Fas(lpr) kidneys compared with control kidneys. Furthermore, in situ hybridization showed massive Opn mRNA transcripts in proximal tubules in MRL-Fas(lpr) mice but not in controls. The diffuse macrophage infiltration in the kidney of MRL-Fas(lpr) correlated with the enhanced Opn expression. Opn secretion in vitro by cultured renal tubular epithelial cells was upregulated by TNF-alpha and 1,25(OH)2-vitamin D3, whereas no regulation was observed in a control macrophage cell line. We conclude that the enhanced expression of the chemotactic molecule Opn by tubular cells is a prominent feature of murine lupus nephritis and might be promoted by the proinflammatory cytokine environment in MRL-Fas(lpr). The chronic upregulation of Opn could participate in the recruitment of monocytes in the kidney of MRL-Fas(lpr) mice, thereby contributing to the pathogenesis of autoimmune renal disease.

Characteristic matrix and tubular basement membrane abnormalities in the CBA/Ca-kdkd mouse model of hereditary tubulointerstitial disease.

CBA/CaH-kdkd mice develop hereditary tubulointerstitial disease with mononuclear cell infiltration and cyst formation, possibly representing a model of human nephronophthisis. The purpose of the present investigation was to examine the components of the fibrotic changes which typically develop in the kidneys of these mice. By conventional histology, kdkd mice displayed progressive interstitial fibroblast and matrix accumulation. Immunohistological analysis of kdkd kidneys showed marked deposition of fibronectin in the tubulointerstitial space and revealed prominent irregularities for laminin and collagen type IV in the tubular basement membrane (TBM), including thickening, widening and folding. Electron microscopy confirmed the TBM abnormalities and showed marked undulation and thickening in areas of proximal tubular (PT) degeneration. Immunofluorescence staining analysis for the fibronectin receptors VLA-4 and VLA-5 showed no expression on injured proximal tubules, whereas the expression of the laminin receptor VLA-6 was increased and irregular on altered PT. Analysis of RNA derived from kdkd kidneys revealed marked upregulation of steady-state mRNA levels for the fibrogenic growth factor TGF-beta. We conclude that TBM alterations, matrix accumulation and changes in integrin expression together with enhanced TGF-beta production are typical features of kdkd tubulointerstitial disease and suggest that characteristic TBM or matrix alterations could contribute to the pathogenesis of the disease in these mice.

Autoimmune tubulointerstitial nephritis: insight from experimental models.

Many forms of tubulointerstitial nephritis (TIN) may have an autoimmune origin. To understand the pathogenesis of autoimmune TIN it is important to examine suitable animal models where the initiation and development of tubulointerstitial diseases can be assessed with precision. Experimental models of autoimmune anti-tubular basement membrane (anti-TBM) disease for example have allowed to define the nephritogenic role of antibodies which target tubulointerstitial moieties. Several tubulointerstitial antigens which are recognized by specific anti-TBM antibodies have been characterized at a molecular level in these models. The CBA/CaH-kdkd mouse strain represents another model of TIN where complex T-cell networks are uniquely altered, resulting in cell-mediated interstitial nephritis. Characteristic tubular alterations (up-regulation of adhesion molecules and CD44, cytokine and chemokine secretion) are prominent in several models of experimental TIN, promoting T-cell and monocyte infiltration. The complex interplay between tubular epithelial cells and immune cells is probably a prerequisite for a coordinated immune response in many forms of TIN, resulting in autoimmune renal tubulointerstitial injury and ultimately in renal failure.

Characterisation of cellular infiltration and adhesion molecule expression in CBA/CaH-kdkd mice with tubulointerstitial renal disease.

CBA/CaH-kdkd mice develop a spontaneous and chronic tubulointerstitial renal disease which is characterised by mononuclear cell infiltration, tubular collapse and cystic dilatation of tubules. The pathogenic mechanisms of renal injury have not been fully elucidated in this model. We have analysed the nature of infiltrating cells and the expression of MHC class II antigens, cytokines and adhesion molecules in CBA/CaH-kdkd kidneys at various disease stages. Using immunohistochemical techniques we found that kdkd kidneys are characterised by abundant macrophage and dendritic cell infiltration with fewer T cells with CD4+ and CD8+ phenotypes. Interestingly, MHC class II antigens were not induced on renal tubules. The proinflammatory cytokine, TNF-alpha, was markedly enhanced in kdkd kidney (up to fourfold), whereas the T cell-specific cytokine, IFN-gamma, increased less (less than twofold). ICAM-1 and VCAM-1 were markedly overexpressed by injured proximal tubules. ICAM-2 and PECAM-1 were constitutively expressed on glomerular capillaries and vascular endothelium in normal kidneys and did not change in CBA/CaH-kdkd mice. In conclusion, tubulointerstitial nephritis in CBA/CaH-kdkd mice is characterised by prominent macrophage infiltration and abundant expression of ICAM-1 and VCAM-1 on injured renal tubules. The lack of MHC class II antigens on injured tubules suggests that the kd gene defect could generate a secondary renal inflammatory response which is characterised by prominent macrophage infiltration and a relative scarcity of T cells.

Upregulated renal tubular CD44, hyaluronan, and osteopontin in kdkd mice with interstitial nephritis.

BACKGROUND: The hyaluronan (HA) receptor CD44 is upregulated on parenchymal cells in various inflammatory lesions and could play a role in immune injury. The purpose of the present study was to examine CD44 and its ligands HA and osteopontin (Opn) in a murine model of tubulointerstitial nephritis (TIN). METHODS: The expression of CD44 was investigated by immunofluorescence staining and RNA analysis in kidneys of kdkd mice with autoimmune TIN. The CD44 expression was then correlated with the location of its ligands HA and Opn. RESULTS: CD44 is expressed de novo by tubular epithelial cells (TEC) in areas of tubular injury in kdkd kidneys, but not in normal control kidneys. CD44 positive lymphocytes and macrophages also infiltrate the kidney to kdkd mice. RT-PCR and Southern blot analysis demonstrate that transcripts encoding standard and variant forms of CD44 are increased in kdkd mice with TIN. In parallel the CD44 ligand HA also accumulates in kdkd kidneys in the interstitial space, particularly in cortical areas of tubular injury. Furthermore, the expression of the chemotactic protein Open is enhanced in kdkd kidney, predominantly in areas of tubular injury. Opn mRNA expression also increases markedly in kdkd kidneys compared with normal kidneys, and correlates with disease severity. CONCLUSIONS: Prominent CD44 expression by TEC in areas of tubulointerstitial lesions is a characteristic feature of kdkd mice. The de novo appearance of CD44 on injured TEC might allow interaction with the ligands HA and Opn in vivo. Interaction of CD44 with these ligands could participate in the tubulointerstitial inflammatory response in kdkd mice.

The effects of continuous light and darkness on the activity of monoamine oxidase A and B in the hypothalamus, ovaries and uterus of rats.

For assessing monoamine oxidase (MAO-A and -B) activities in the hypothalamus, ovaries and uterus, mature female rats were exposed to either continuous light or dark over 6 weeks. Confirming previous studies, continuous light induced constant estrus in all animals. The majority of animals kept under continuous dark during the six weeks remained mostly in diestrus with estrus appearing sporadically. The endocrinological function of the ovaries was disturbed by continuous light, which resulted in the development of polycystic ovaries, their morphological appearance being not significantly affected by continuous dark. Hypothalamic MAO-A activity was markedly reduced under the influence of both light (p < 0.05) and dark (p < 0.01). The activity of hypothalamic MAO-B was reduced only under the influence of dark (p < 0.01). In the ovaries, no significant differences were detected in either MAO-A or -B activity as a result of these environmental manipulations. In the uterus of rats exposed to continuous light which developed polycystic ovaries, MAO-A activity was significantly lower (p < 0.05) in comparison to either intact controls or rats exposed to continuous dark. These results demonstrate that chronic changes in photoperiodicity may considerably influence MAO-A activity and to a lesser extent MAO-B activity dependent on the tissue studied.

The proinflammatory cytokine interleukin-12 occurs as a cell membrane-bound form on macrophages.

Phagocyte-derived interleukin-12 (IL-12) is a proinflammatory cytokine promoting cell-mediated immune responses in inflammatory and infectious disorders. Based on sequence homology of the p40 subunit with the interleukin-6 receptor it has been speculated that IL-12 could also exist as a membrane-bound form, but thus far only soluble (secreted) IL-12 has been identified. We have therefore analyzed human monocytic U937 and mouse P388D1 macrophages for membrane-bound IL-12 by flow cytometry. IL-12 is constitutively expressed on the cell surface of both cell lines. IL-12 cell surface staining is enhanced in response to stimulation with IFN-gamma plus LPS. IL-12 is also present in the supernatant of cultured P388D1 macrophages. Thus, in addition to a soluble form IL-12 occurs as a membrane-bound molecule on monocyte/macrophage cell lines.

[Not Available]. / Die Geschichte der Psychiatrischen Klinik St. Pirminsberg.

The psychiatric clinic St. Pirminsberg, a house with an impressive history. The early days of its existence were turbulent. At that time, medical care of the mentally disordered was neglected, patients being misunderstood and mistreated. The search for an appropriate place, that could house those "mad" people, met with a lot of difficulties. The government's, the doctors' and the people's views on the necessity of such an institution were too varied to make decisions easy. However, thanks to untiring initiative, the canton St. Gallen can now consider itself the proud owner of a wonderful psychiatric clinic. In Switzerland, St. Pirminsberg its the oldest institute for mental treatment after Munsterlingen and Geneva. At the same time, there were also a few private houses where the mentally sick were accommodated. Although these patients were usually relatives of wealthy families, they did, in fact, receive insufficient medical care. St. Pirminsberg's methods in therapy describe the development and modernization of psychiatry. The resident staff constantly endeavoured to satisfy the highest demands. In this respect, the work of famous personalities made a large contribution to the clinic. Each director and senior consultant has engraved his personal style on the institute. Some were primarily concerned with construction work to the building, others had to economize due to the financial situation. A few vested their interests exclusively in the science of psychiatry. All, however, had to cope with a shortage of staff, due to the rather remote situation of the clinic, the unsatisfactory remuneration and the demanding nursing care needed, often coupled with a great deal of responsibility. Cooperation with foreign clinics and those of other cantons was fruitful in human, medical and also financial aspects. Experiences were exchanged, decisions were made concerning education and schools for staff were founded. St. Priminsberg received recognition as an institute for further education towards specializing in psychiatry. A walk through today's clinic does not only mean seeing, but also experiencing history. Situated between the walls of the former monastery of St. Pirmin, the old part of the building, with its splendid ornamentation, can transport the visitor back to former times. Life in the clinic must have been difficult: massive, cold walls, mostly badly-lit rooms and corridors temporarily filled with beds must surely have had a very unfavourable effect on the disposition of the patients. Pavilions, erected later in a more useful but nonetheless pleasing style of architecture are equally impressive - new and old harmoniously united. Even in earlier times, people praised the beautiful countryside in which Pfäfers is situated. The outward appearance of the village has not changed in years. Its high location offers a wonderful view over the valley and provides a fresh, cool climate - an advantage which will always be held in great esteem by the clinic St. Pirminsberg.

Development of monoamine oxidase activity during postnatal development of the ground squirrel (Citellus citellus).

1. Monoamine oxidase (MAO) activity in the brain and peripheral tissues of newborn ground squirrel, as well as its evolution during postnatal development were studied. 2. Monoamine oxidase activity in the brain stem and liver, at the day of birth is significantly higher (P less than 0.01; P less than 0.005) than in adults. 3. After that, enzyme activity decreases, but at the 25th day, e.g. at the day of the opening of the eyes, still remains significantly above the adult's value (P less than 0.01). 4. The results indicate some species specificity concerning the level and the evolution of cerebral and hepatic MAO activity as compared to the rats.

Adrenal dopamine-beta-hydroxylase activity in the ground squirrel Citellus citellus--effect of hibernation, arousal, and continuous light.

In the hibernating ground squirrel activity of adrenal dopamine-beta-hydroxylase was significantly lower as compared with the active animals (P less than 0.01). The highest activity of this enzyme was found in animals tested immediately after arousal from hibernation (P less than 0.01). The adrenal weight was higher in hibernating animals than in the active or aroused ones. The difference between the active and aroused animals was significant (P less than 0.01). Extremely high enzyme activity was found in the adrenals of animals exposed to continuous light for 3 weeks as compared with active animals kept in continuous darkness or with controls subjected to a regime of 12 hr light - 12 hr darkness (P less than 0.01). The weight of the adrenals in the three groups was about the same level.