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Immunologische Aspekte bei schizophrenen Störungen

Immunology in schizophrenic disorders

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Zusammenfassung

Der vorliegende Beitrag beschäftigt sich mit der Frage, inwieweit immunvermittelte Mechanismen eines entzündlichen Geschehens zur Pathogenese der Schizophrenie beitragen können. Es wird ein Modell vorgestellt, das psychoneuroimmunologische Befunde mit aktuellen Ergebnissen aus pharmakologischen, neurochemischen und genetischen Studien bei Schizophrenie zusammenführt. Eine zentrale Rolle in der Neurobiologie der Schizophrenie spielt die dopaminerge Neurotransmission, die durch Einflüsse des Glutamatsystems entscheidend moduliert wird. Die bei Schizophrenie beschriebene Hypofunktion des Glutamatsystems ist funktionell vor allem durch einen NMDA-Rezeptor-Antagonismus vermittelt. Kynureninsäure ist der einzige bisher nachgewiesene endogene NMDA-Rezeptor-Antagonist. Zusätzlich blockiert Kynureninsäure bereits in geringeren Konzentrationen den nikotinergen Acetylcholinrezeptor, der für kognitive Funktionen eine wichtige Bedeutung hat. Ein Anstieg des Kynureninsäurespiegels kann neurobiologisch also sowohl psychotische Symptome als auch kognitive Einschränkungen erklären. Eine Reihe von Befunden legen nahe, dass eine (pränatale) Infektion, verbunden mit einem frühen Sensibilisierungsprozess des Immunsystems, in einem Ungleichgewicht der Immunantwort (Typ-1- vs. Typ-2-Immunantwort) resultiert. Diese Immunkonstellation führt zur Hemmung des Enzyms Indoleamin-Dioxygenase, das den Abbau von Tryptophan zu Kynurenin reguliert. Diese Immunkonstellation spiegelt sich im ZNS vor allem im Aktivierungsstatus von Mikroglia und Astrozyten wider. Die bei Schizophrenen bestehende Astrozytenaktivierung führt vermutlich zu einer weiteren Akkumulation von Kynureninsäure, die dann nicht weiter abgebaut werden kann. Deshalb kann Kynureninsäure im ZNS Schizophrener akkumulieren und als NMDA-Antagonist kognitive Einbußen und schließlich psychotische Symptome hervorrufen. Dieses Modell kann erklären, auf welchem Weg die immunmediierte glutamaterg-dopaminerge Dysregulation zu den klinischen Symptomen der Schizophrenie führen kann. Therapeutische Konsequenzen (z. B. Cyclooxygenase-II-Inhibitoren) werden diskutiert.

Summary

This manuscript deals with whether immune-mediated mechanisms of inflammation contribute to the pathogenesis of schizophrenia. A model is presented which integrates psychoneuroimmunologic findings and actual results from pharmacological, neurochemical, and genetic studies in schizophrenia. A pivotal role in the neurobiology of schizophrenia is played by dopaminergic neurotransmission, which is modulated by influences of the glutamatergic system. The decreased function of the glutamate system described in schizophrenia seems primarily mediated by N-methyl-D-aspartate (NMDA) receptor antagonism. Kynurenine acid is the only known endogenous NMDA receptor antagonist. In higher concentrations it blocks the NMDA receptor, but in lower concentrations it blocks the nicotinergic acetylcholin receptor, which has a prominent role in cognitive functions. Therefore, higher levels of kynurenine acid may explain psychotic symptoms and cognitive dysfunction. Several findings point out that prenatal infection, associated with an early sensitisation of the immune system, may result in an imbalance of the immune response (type 1 vs type 2) in schizophrenia. This immune constellation leads to inhibition of the enzyme indoleamin dioxigenase (IDO). It and tryptophane 2,3-dioxygenase (TDO) both catalyse the degradation from tryptophan to kynurenine. Due to the inhibition of IDO, tryptophan is metabolised to kynurenine primarily by TDO. In the CNS, TDO is located only in astrocytes, which are in particular activated in schizophrenia and in which kynurenine acid is the final product and can not be further metabolised. Therefore kynurenine acid accumulates in the CNS of schizophrenics and – due to its NMDA-antagonistic properties – leads to cognitive dysfunction and psychotic symptoms. This model describes the pathway of immune-mediated glutamatergic-dopaminergic dysregulation, which may lead to the clinical symptoms of schizophrenia. Therapeutic consequences (e.g. cyclo-oxygenase-2 inhibitors) are discussed.

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Interessenkonflikt

N.M. hat die therapeutische Anwendung der COX-2-Inhibition bei psychiatrischen Indikationen zum Patentschutz eingereicht. Er erhielt Honorare der Firmen Pfizer, Pharmacia und Janssen-Cilag. Die Firmen Pfizer und Pharmacia unterstützen Forschungsprojekte von N.M. Trotz des möglichen Interessenkonfliktes ist der Beitrag unabhängig und produktneutral.

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Dieser Artikel ist Manfred Ackenheil gewidmet, einem Pionier der Psychoneuroimmunologie.

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Müller, N., Schwarz, M.J. Immunologische Aspekte bei schizophrenen Störungen. Nervenarzt 78, 253–263 (2007). https://doi.org/10.1007/s00115-006-2108-9

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