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Zusammenfassung Zu den wichtigsten Nebenwirkungen der cholesterinsenkenden Therapie mit Fibraten und den die 3-Hydroxy-3-methyl-glutaryl-Coenzym-A- (HMG-CoA-)Reduktase hemmenden Statinen gehört die Auslösung einer Myopathie, die von Myalgien ohne Creatinkinase- (CK-)Erhöhung über klinisch asymptomatische CK-Anstiege bis hin zu lebensbedrohlichen Rhabdomyolysen mit Nierenversagen reichen kann. Mit Ausnahme des 2001 vom Markt genommenen Cerivastatins sind bedrohliche Rhabdomyolysen unter Therapie mit Statinen mit einer geschätzten Inzidenz von unter 0,2/1 Mio. Verschreibungen sehr seltene Nebenwirkungen. Muskelschmerzen und Muskelkrämpfe ohne CK-Anstiege werden jedoch von bis zu 5% der behandelten Patienten geklagt, sind aber in den Therapiestudien in gleicher Häufigkeit auch in den Plazebogruppen aufgetreten und können so nicht unbedingt der Medikation zugerechnet werden. Wegen des sehr verbreiteten Einsatzes der Statine und Fibrate stellen aber die Differenzialdiagnose und das Management einer durch Lipidsenker ausgelösten Myopathie in den neuromuskulären Spezialambulanzen eine zunehmend häufigere Frage dar.

Es gibt eine Reihe wichtiger Berührungspunkte zwischen Rheumatologie und Neurologie. Zum einen beziehen viele systemische rheumatische Erkrankungen das zentrale und periphere Nervensystem sowie die Muskulatur mit ein, was zu charakteristischen Symptomenkomplexen führt, zum anderen gleichen sich neurologische und rheumatologische Autoimmunerkrankungen, basierend auf einer oft ähnlichen Pathophysiologie. An dieser Stelle sollen die wichtigsten neurologischen Aspekte rheumatischer Erkrankungen auch hinsichtlich ihrer Diagnose und Therapie beleuchtet werden. There are a number of common aspects between rheumatology and neurology. First, many systemic rheumatic diseases also affect the central and peripheral nervous system as well as muscle causing characteristic symptom complexes. Second, there are similarities between neurological and rheumatological autoimmune diseases in terms of underlying pathomechanisms. Here the most important neurological aspects of rheumatological disorders including their diagnosis and therapy are highlighted.

Zusammenfassung Statine sind Inhibitoren des bei der Bildung von Cholesterin notwendigen Enzyms 3-Hydroxy-3-methylglutaryl-Koenzym-A (HMG-CoA)-Reduktase und werden weit verbreitet als Cholesterinsenker verwendet. Sie vermindern Arteriosklerose und damit das kardiovaskuläre Risiko, was in der Vergangenheit hauptsächlich auf ihre Cholesterin senkenden Eigenschaften zurückgeführt wurde. Neuere Forschungsergebnisse zeigen, dass Statine zusätzlich potente immunmodulatorische Effekte haben, die Ausprägung klinischer und pathologischer Veränderungen im Tiermodell der Experimentellen Autoimmunen Enzephalomyelitis vermindern und damit als therapeutische Option für die Multiple Sklerose grundsätzlich infrage kommen. Der genaue Wirkmechanismus ist noch unklar, diskutiert werden HMG-CoA-Reduktase-abhängige Effekte oder auch direkte Einflüsse auf Immunrezeptoren.

Recent data suggest that statins may be potent immunomodulatory agents. In order to evaluate the potential role of statins as immunomodulators in MS, the authors studied their immunologic effects in vitro and compared them to interferon (IFN)-1b.

Zusammenfassung: Bei Glatiramer-Azetat (Copaxone®, GA) handelt es sich um eine in der Therapie der schubförmigen Multiplen Sklerose (MS) eingesetzte, seit September 2001 auch in Deutschland zugelassene, standardisierte Mischung synthetischer Polypeptide. Nachdem sich GA in Tierversuchen bei experimenteller autoimmuner Enzephalomyelitis (EAE), dem Tiermodell der MS, als erfolgreich erwiesen hatte, wurde der Wirkstoff in mehreren klinischen Studien untersucht. Dabei konnte für GA eine signifikante Reduktion der Schubfrequenz und auch ein günstiger Einfluss auf die Krankheitsprogression gezeigt werden. Kürzlich konnte in einer großen Multizenterstudie auch eine Reduktion der kernspintomographisch messbaren Krankheitsaktivität nachgewiesen werden. Als tägliche Standarddosis werden 20 mg GA subkutan injiziert. Als Wirkungsmechanismus wird die Induktion von GA-reaktiven T-Helfer-2-(Suppressor-)Zellen angenommen. Häufigste Nebenwirkung sind Hautreaktionen an der Injektionsstelle. Eine seltene, aber erwähnenswerte Nebenwirkung ist die akute, nur vorübergehende Postinjektionsreaktion mit Symptomen wie Herzrasen, Dyspnoe, Urtikaria oder Angstgefühl. Aufgrund der Behandlung mit GA induzierte Antikörper zeigen keine Interferenz mit der klinischen Wirksamkeit von GA.

Copolymer-1 (Copaxone or COP) inhibits experimental allergic encephalomyelitis and has beneficial effects in multiple sclerosis. There is presently no practical in vitro assay for monitoring the immunological effects of COP. We used an automated, computer-assisted enzyme-linked immunoadsorbent spot assay for detecting COP-induced interferon-gamma (IFN-gamma)- and interleukin-4 (IL-4)-producing cells and a standard proliferation assay to assess the immunological response to COP in peripheral blood mononuclear cells from 20 healthy donors, 20 untreated multiple sclerosis patients and 20 COP-treated multiple sclerosis patients. Compared with untreated and healthy controls, COP-treated patients showed (i) a significant reduction of COP-induced proliferation; (ii) a positive IL-4 Elispot response mediated predominantly by CD4 cells after stimulation with a wide range of COP concentrations; and (iii) an elevated IFN-gamma response partially mediated by CD8 cells after stimulation with high COP concentrations. All three effects were COP-specific as they were not observed with the control antigens, tuberculin-purified protein or tetanus toxoid. The COP-induced changes were consistent over time and allowed correct identification of COP-treated and untreated donors in most cases. We propose that these criteria may be helpful to monitor the immunological response to COP in future clinical trials.

Adult male rats were given injections of oestradiol-17β (50 μg/100 g body wt per day) for 7 days. When they were killed 14 days after the last injection, serum levels of gonadotrophins and testosterone and weights of accessory sex organs were less, testicular 17β-hydroxysteroid dehydrogenase 17β-HSD activity was suppressed and spermatogenesis was inhibited. Administration of α2u-globulin (1·5 mg/day) for 14 days to oestrogen-treated rats and for 10 days to control rats resulted in increased concentrations of gonadotrophins and testosterone in the serum. Accessory sex organ weight and spermatogenesis appeared to be normal while 17β-HSD activity increased in oestrogen-treated rats after treatment with α2u-globulin. It was concluded that α2u-globulin has an effect on testicular function in oestrogenized rats by inducing gonadotrophin and testosterone synthesis.

Numerous microbial pathogens, including Listeria monocytogenes, enter the host through the intestine. Although relatively little is known about the biological functions of intestinal intraepithelial lymphocytes (i-IEL), they are generally considered a first line of defense against intestinal infections. In the mouse, the vast majority of i-IEL express the CD8 coreceptor either as a CD8 alpha/alpha homodimer or as a CD8 alpha/beta heterodimer. The CD8 receptor of T-cell receptor TcR gamma/delta i-IEL is exclusively homodimeric, whereas the CD8-expressing TcR alpha/beta i-IEL segregate into equal fractions of CD8 alpha/alpha and CD8 alpha/beta cells. We infected beta 2-microglobulin (beta 2m)+/- mice (possessing all i-IEL populations) and beta 2m -/- mutant mice (lacking all CD8 alpha/beta + i-IEL and having few CD8 alpha/alpha + TcR alpha/beta i-IEL) with L. monocytogenes per os and determined their biological functions after TcR ligation with monoclonal antibodies. Cytolytic activities of TcR alpha/beta and TcR gamma/delta i-IEL from beta 2m +/- mice were not influenced by intestinal listeriosis. Cytolytic activities of TcR alpha/beta i-IEL were impaired in uninfected beta 2m -/- mice, but this reduction was reestablished as a consequence of intestinal listeriosis. Frequencies of gamma interferon (IFN-gamma)-producing TcR alpha/beta i-IEL in uninfected beta 2m -/- mice were reduced, compared with that in their heterozygous controls. Equally low frequencies of IFN-gamma-producing TcR gamma/delta i-IEL in beta 2M +/- and beta 2m-/- mutants were found. Listeriosis increased frequencies of INF-gamma-producing TcR alpha/beta and TcR gamma/delta i-IEL in both mouse strains. Most remarkably, the proportion of IFN-gamma-producing TcR gamma/delta i-IEL was elevated 10-fold in listeria-infected beta 2M -/- mice. Our findings show that the beta 2m-independent CD8 beta- i-IEL expressing either TcR alpha/beta or TcR gamma/delta are stimulated by intestinal listeriosis independent of regional beta 2m expression. We conclude that the three major CD8+ i-IEL populations are stimulated by intestinal listeriosis and that CD8 beta- i-IEL compensate for the total lack of CD8 beta+ i-IEL in beta 2M -/- mutant mice. Hence, in contrast to the peripheral immune system, which crucially depends on CD8 alpha/beta + TcR alpha/beta lymphocytes, the mucosal immune system can rely on additional lymphocytes expressing the CD8 alpha/alpha homodimer.

Numerous microbial pathogens, including Listeria monocytogenes, enter the host through the intestine. Although relatively little is known about the biological functions of intestinal intraepithelial lymphocytes (i-IEL), they are generally considered a first line of defense against intestinal infections. In the mouse, the vast majority of i-IEL express the CD8 coreceptor either as a CD8 alpha/alpha homodimer or as a CD8 alpha/beta heterodimer. The CD8 receptor of T-cell receptor TcR gamma/delta i-IEL is exclusively homodimeric, whereas the CD8-expressing TcR alpha/beta i-IEL segregate into equal fractions of CD8 alpha/alpha and CD8 alpha/beta cells. We infected beta 2-microglobulin (beta 2m)+/- mice (possessing all i-IEL populations) and beta 2m -/- mutant mice (lacking all CD8 alpha/beta + i-IEL and having few CD8 alpha/alpha + TcR alpha/beta i-IEL) with L. monocytogenes per os and determined their biological functions after TcR ligation with monoclonal antibodies. Cytolytic activities of TcR alpha/beta and TcR gamma/delta i-IEL from beta 2m +/- mice were not influenced by intestinal listeriosis. Cytolytic activities of TcR alpha/beta i-IEL were impaired in uninfected beta 2m -/- mice, but this reduction was reestablished as a consequence of intestinal listeriosis. Frequencies of gamma interferon (IFN-gamma)-producing TcR alpha/beta i-IEL in uninfected beta 2m -/- mice were reduced, compared with that in their heterozygous controls. Equally low frequencies of IFN-gamma-producing TcR gamma/delta i-IEL in beta 2M +/- and beta 2m-/- mutants were found. Listeriosis increased frequencies of INF-gamma-producing TcR alpha/beta and TcR gamma/delta i-IEL in both mouse strains. Most remarkably, the proportion of IFN-gamma-producing TcR gamma/delta i-IEL was elevated 10-fold in listeria-infected beta 2M -/- mice. Our findings show that the beta 2m-independent CD8 beta- i-IEL expressing either TcR alpha/beta or TcR gamma/delta are stimulated by intestinal listeriosis independent of regional beta 2m expression. We conclude that the three major CD8+ i-IEL populations are stimulated by intestinal listeriosis and that CD8 beta- i-IEL compensate for the total lack of CD8 beta+ i-IEL in beta 2M -/- mutant mice. Hence, in contrast to the peripheral immune system, which crucially depends on CD8 alpha/beta + TcR alpha/beta lymphocytes, the mucosal immune system can rely on additional lymphocytes expressing the CD8 alpha/alpha homodimer.

The urinary proteinα2ustimulates adrenalΔ5-3βdehydrogenase activity and prevents adrenal enlargement in estrogen-treated adult male rats.

Treatment of adult male rats with oestradiol-17β (50 μg/100g body wt per day for 7 days) resulted 14 days later in reduced levels of α2u-globulin in serum and inhibition of spermatogenesis. Administration of corticosterone (2 mg/day) for 14 days to oestrogen-treated rats raised the concentration of α2u-globulin in the serum and prevented spermatogenic degeneration. It is concluded that endogenous α2u-globulin induced by corticosterone may play a role in spermatogenesis in oestrogenized rats.