Neue Untersuchungen über die Innervation der Schilddrüse

Zusammenfassung Mit Hilfe der Osmium-Zinkjodid-Methode vonMaillet wurde die Nervenversorgung der Schilddrüse des Kaninchens untersucht. Diese Methode gestattet es, afferente und efferente Anteile des peripheren Nervensystems gleichzeitig darzustellen, ein Vorgang, der bisher bei Verwendung von Silbermethoden nur in Ausnahmefällen möglich war.Die auffallende, überaus reiche, in anderen Körperregionen meist nicht vorhandene Nervenversorgung des Gefäßsystems wird durch das Vorhandensein zahlreicher rezeptorischer Endigungen erklärt. Solche finden sich als größere traubenförmige Einzelbildungen in der Wand der größeren Gefäße und in kleinerer Ausbildung, jedoch sehr zahlreich, besonders an den Gabelungsstellen des Gefäßbaumes. Im interstitiellen Bindegewebe, jedoch stets in enger Beziehung zur Gefäßwand der Kapillaren, liegen zahlreiche kleine kolben-, zargen- oder traubenförmige Endigungen, welche wir ebenfalls zum Unterschied von anderen Autoren als direkt dem Gefäßsystem zugehörig ansehen.Vereinzelt und nicht jedem Drüsenfollikel zugehörig können kleine kolbenförmige Endigungen festgestellt werden, deren engen plasmatischen Kontakt zu Plasma und Kernen der Drüsenzellen, den einzelne Autoren beschrieben, wir in unseren Präparaten nicht mit Sicherheit feststellen konnten. Inwieweit es sich bei diesen Gebilden um Druck- und Chemorezeptoren handelt, kann auf Grund der neurohistologischen Befunde nicht entschieden werden.Gleichzeitig mit den terminalen Formationen darstellbare Zellen mit stark osmiophilem, teils homogenem, teils granuliertem Protoplasma, wie in allen bisher untersuchten exokrinen Drüsen feststellbar, kommen in der Schilddrüse nicht zur Ansicht. Daraus kann geschlossen werden, daß die rein hormonell gesteuerte Drüse durch die von diesen Zellen produzierten Wirkstoffe (z. B. Histamin, Serotonin usw.) im Gegensatz zu den exokrinen Drüsen nicht beeinflußt wird.Einzelne oder zu Gruppen zusammengeschlossene Ganglienzellen konnten wir bisher nicht feststellen.Die Beziehungen der Schilddrüse zum sympathischen Nervensystem, wie sie klinisch beobachtet werden, können, abgesehen von der direkten allgemein stoffwechselsteigernden Wirkung des Drüsenproduktes, auf Grund der neurohistologischen Befunde als reflektorische Vorgänge im Zuge von Alarmmeldungen und dadurch herbeigeführter Reizüberflutung der nervalen Regulationsstätten angesehen werden.

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Summary With the aid of the osmium zinc-iodide method according toMaillet, the innervation of the thyroid gland of the rabbit was investigated. This method is suited for the simultaneous representation of afferent and efferent portions of the peripheral nervous system which, when silver methods were used, was possible till now only in exceptional cases.The remarkable and extremely rich innervation of the vascular system, which is usually not found to that extent in other regions of the body, is explained by the existence of numerous receptor ends. Such ends are found as larger grapelike single formations in the wall of larger vessels and in a smaller form, but in larger numbers, particularly at the bifurcations of the vascular tree. In the interstitial connective tissue, always, however, in close connection with the wall of the capillaries, there are numerous small ends resembling pistons, edges or grapes, which in our opinion that differs from the one of other authors, pertain directly to the vascular system.Sporadically and not pertaining to every glandular follicle, smaller pistonlike ends could be established. In our preparations, we could not for certain establish their close plasmic contact with plasma and nuclei of the glandular cells as described by other authors. In how far these formations are pressure receptors or chemoreceptors cannot be decided on the grounds of the neurohistological findings.Cells representable simultaneously with the terminal formations which have a strongly osmophil, partly homogenous and partly granulated protoplasma, as could be established in all exocrine glands investigated until now, cannot be seen in the thyroid gland. This leads to the conclusion that the merely hormonally piloted gland is not influenced by the working substances produced by these cells (e. g. histamin, serotonin, etc.), contrary to the exocrine glands.Until now we were unable to establish ganglion cells, either single or in group formations.The connections between thyroid gland and sympathetic nervous system, as they were clinically observed, may be regarded, apart from the direct general effect of the glandular product of increasing metabolism, on the grounds of the neurohistological findings, as reflex processes answering alarm signals and excessive stimulations of the nervous sites of regulation caused thereby.

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Résumé A l'aide de la méthode à de l'osmium et du zinc iodique d'aprèsMaillet, l'innervation de la glande thyroïde du lapin était étudiée. Cette méthode est capable de représenter simultanément des parties afférentes et efférentes du système nerveux périphérique ce qui, en employant des méthodes à de l'argent, n'était possible que dans des cas exceptionnels.L'innervation remarquable et extrêmement riche du système vasculaire que, pour l'ordinaire, on ne trouve pas à ce degré dans d'autres régions du corps, est expliquée par l'existence de nombreux bouts récepteurs. De tels bouts sont trouvés comme des formes isolées plus larges en forme de grappes dans la paroi de vaisseaux plus grands et dans une forme plus petite, mais en plus grand nombre, surtout dans les bifurcations de l'arbre vasculaire. Dans le tissu connectif interstitiel, toujours, cependant, en connexion étroite avec la paroi des vaisseaux capillaires, il y a de petits bouts ressemblant à des pistons, des bords ou des grappes qui, d'après notre avis qui diverge de l'opinion d'autres auteurs, appartiennent directement au système vasculaire.Sporadiquement et non appartenant à tous les follicules, on pouvait constater des bouts plus petits en forme de pistons. Dans nos préparations, nous n'avons pas réussi à constater avec certitude leur contact plasmique étroit avec le plasma et les noyaux des cellules glandulaires, comme il a été décrit par d'autres auteurs. Jusqu'à quel point ces formations sont des récepteurs de pression ou des récepteurs chimiques ne peut pas être décidé en considération des résultats neurohistologiques.Des cellules représentables simultanément avec les formations terminales qui ont un protoplasma très osmophile, en partie homogène et en partie granulé, comme on l'a pu constater dans toutes les glandes exocrines étudiées jusqu'à présent, ne peuvent pas être vues dans la glande thyroïde. Cela mène à la conclusion que la glande dirigée seulement par des hormones n'est pas influencée par les substances efficaces produites par ces cellules (p.e. l'histamine, la sérotonine etc.), contrairement aux glandes exocrines.Jusqu'à présent nous ne pouvions pas constater des cellules ganglionnaires isolées ou en groupes.Les connexions entre la glande thyroïde et le système nerveux sympathique, comme elles étaient observées cliniquement, peuvent être regardées, abstraction faite de l'effet général direct du produit glandulaire d'augmenter le métabolisme, d'après les constatations neurohistologiques, comme des processus réflexes répondant à des signaux d'alarme et à des stimulations excessives des sites nerveux de régularisation causées de cette manière.

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Blood-brain barrier in chronic relapsing experimental allergic encephalomyelitis: A correlative study between cerebrospinal fluid protein concentrations and tracer leakage in the central nervous system

Summary Blood-brain barrier (BBB) permeability in chronic relapsing experimental allergic encephalomyelitis was studied morphologically in tracer studies with horseradish peroxidase (HRP) as well as by quantitative determination of HRP, albumin, and IgG in serum and cerebrospinal fluid (CSF), BBB damage was found to be localized in demyelinating plaques and in blood vessels with vasculitis. Actively demyelinating lesions showed massive increase in BBB permeability, whereas in inactive or remyelinated lesions BBB damage was either minimal or absent. Determination of serum proteins in the CSF of animals with severe disease and a high incidence of actively demyelinating lesions showed evidence of BBB damge (reduction of Q-albumin) and an IgG-index in the normal range. In animals with only inactive lesions the Q-albumin was normal, the IgG index, however, was elevated. This finding indicates intrathecal IgG synthesis.A correlation between morphologically visualized tracer leakage in the central nervous system (CNS) with serum protein concentrations in the CSF revealed that elevated CSF albumin is a reliable indicator for BBB damage in lesions, located near the inner or outer surface of the brain and spinal cord. However, singular focal lesions with BBB damage located in the depth of the CNS parenchyma may not be accompanied by CSF protein alterations. The invariable presence of BBB damage in active inflammatory demyelinating lesions and its absence in inactive plaques or in the unaffected nervous tissue may be important in therapy, not only in experimental allergic encephalomyelitis but also in multiple sclerosis (MS).Supported by Fonds zur Förderung der wissenschaftlichen Forschung, Austria, Project no. S25/07     

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Transient Axonal Injury in the Absence of Demyelination: A Correlate of Clinical Disease in Acute Experimental Autoimmune Encephalomyelitis

Axonal degeneration contributes to the transient and permanent neurological deficits seen in multiple sclerosis, an inflammatory disease of the central nervous system. To study the immunological mechanisms causing axonal degeneration, we induced experimental autoimmune encephalomyelitis (EAE) in wildtype Lewis rats and Lewis rats with a slowly progressive myelin degeneration due to proteolipid protein (PLP) overexpression. EAE was triggered either by the transfer of encephalitogenic T-cells alone or by the co-transfer of T-cells with demyelinating antibodies. Inducible nitric oxide synthase (iNOS) expression in perivascular macrophages was associated with a transient functional disturbance of axons, reflected by the focal and reversible accumulation of amyloid precursor protein. Clinical disease correlated with the numbers of APP positive axon spheroids. Demyelination was associated with a further increase of iNOS expression in macrophages and with a higher degree of axonal injury. Our studies suggest that nitric oxide and its metabolites contribute to axonal pathology and possibly also to subsequent neurological dysfunction in EAE.     

A transgenic mouse model for T-cell ignorance of a glial autoantigen

The fate of autoreactive CD4+T cells was investigated in HNT-TCR x GFAP-HA double transgenic mice, in which the majority of CD4+T cells is specific for a neo-selfantigen expressed under a glial cell-specific promoter. These mice do not develop any clinical or histological signs of central or enteric nervous system autoimmunity. Although HA is transcribed in the thymus of GFAP-HA mice, similar numbers of CD4+ CD8- thymocytes, expressing comparable levels of the transgenic TCR, developed in HNT-TCR x GFAP-HA double transgenic and HNT-TCR single transgenic mice, indicating that HA-specific thymocytes are not negatively selected. In the periphery, the HA-specific T cells remained similarly unaffected as they displayed a na?ve phenotype and were neither deleted nor anergized. Finally, immunization of HNT-TCR x GFAP-HA mice with the HNT peptide in CFA and/or in vivo depletion of CD25+ cells did not reverse this state of immune ignorance as judged by the lack of clinical manifestations of intestinal and neurological disease in these mice. Taken together these data demonstrate a profound state of immune ignorance towards a self-antigen expressed in the enteric and central nervous system.     

Pivotal advance: HMGB1 expression in active lesions of human and experimental multiple sclerosis

Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the CNS, most frequently starting with a series of bouts, each followed by complete remission and then a secondary, progressive phase during which the neurological deficit increases steadily. The underlying molecular mechanisms responsible for disease progression are still unclear. Herein, we demonstrate that high mobility group box chromosomal protein 1 (HMGB1), a DNA-binding protein with proinflammatory properties, is evident in active lesions of MS and experimental autoimmune encephalomyelitis (EAE) and that HMGB1 levels correlate with active inflammation. Furthermore, the expression of the innate HMGB1 receptors--receptor for advanced glycation end products, TLR2, and TLR4--was also highly increased in MS and rodent EAE. Additionally, in vitro activation of rodent CNS-derived microglia and bone marrow-derived macrophages demonstrated that microglia were equally as capable as macrophages of translocating HMGB1 following LPS/IFN-gamma stimulation. Significant expression of HMGB1 and its receptors on accumulating activated macrophages and resident microglia may thus provide a positive feedback loop that amplifies the inflammatory response during MS and EAE pathogenesis.