Advanced Clinician Scientist-Programmteilnehmende

Steckbrief 

Steckbrief

Steckbrief

Autoimmune neuropathies with autoantibodies against paranodal proteins

Autoimmune neuropathies are a heterogeneous disorder and pathogenic autoantibodies against paranodal proteins were recently described in a subset of patients. Some patients develop a chronic course of disease that is cause by autoantibodies of the subclass IgG4, others have a monophasic disease with mostly IgG3 autoantibodies. Our department was significantly involved in the description of this new subtype of autoimmune neuropathies, providing excellent preconditions to establish a database/network to support research on this rare condition. Such a database/network will provide the opportunity of clinical studies as well as biomaterial for experimental research. In continuation of our existing experimental focus, we would like to unravel the pathogenic mechanisms of autoantibodies in their target tissue (A). Another project that focuses on the identification of new autoantigens has just started (B). A new project field is supposed to elucidate mechanisms that induce a chronic course of disease in some patients. As our long-term goal, we aim to identify autoantibodies as a biomarker in as many patients as possible to allow a specific therapy (B) and to identify pathogenic mechanisms at the level of autoantibody binding as well as cause of autoimmunity as a prerequisite for the development of specific therapies in the future. Knowledge on the pathogenesis of IgG3-/IgG4-associated chronic and monophasic autoimmune disorders is supposed to be transferred to other IgG3-/IgG4-related disease and can be used in research groups and collaborations far beyond neuropathy research.

Lymphozyten-vermittelte autoimmune und allergische Reaktionen der Haut

Autoimmune und allergische Hauterkrankungen wie die Psoriasis, der Lichen ruber und das allergische Kontaktekzem sind häufig. Die Psoriasis weist eine Prävalenz von 2-3 % in der deutschen Bevölkerung auf und das allergische Kontaktekzem zählt mit ca. 20% zu den häufigsten Hauterkrankungen. Obwohl T-Lymphozyten bei diesen Erkrankungen unbestritten bei der Auslösung und Aufrechterhaltung eine große Rolle spielen, ist über die molekularen Mechanismen, die zur Progression, Amplifizierung und/oder Kontrolle der Entzündung führen, wenig bekannt. Hinzu kommt, dass die Bedeutung von B-Lymphozyten am Krankheitsgeschehen in der Vergangenheit kaum beachtet wurde. Daher beschäftigt sich unser Labor mit der Rolle des für T- und B-Zellen wichtigen Transkriptionsfaktors „nuclear factor of activated T cells" (NFAT) in anerkannten Mausmodellen jeder einzelnen Entität. Diese Modelle werden in Mauslinien angewandt, die T- oder B-Zellen aufweisen, die gezielt defizient für bedeutsame NFAT-Faktoren (NFATc1, NFATc2 oder NFATc1/NFATc2) sind.

Ein weiterer Schwerpunkt besteht in der Analyse der Toleranzmechanismen der Allergen-spezifischen Immuntherapie (AIT). Die Wespengift-AIT gilt mit einer klinischen Effektivität von bis zu 95% als Paradebeispiel einer therapeutisch induzierten Allergen (Antigen)-Toleranz. Ein im Labor etabliertes Mausmodell zur AIT mit Wespengift soll die zugrundeliegenden Interaktionen von dendritischen Zellen und T-Lymphozyten aufschlüsseln.

Parallel zu allen Mausmodellen sollen die erhobenen Befunde mit humanen Haut- und Blutproben entsprechender Patienten abgeglichen werden. Wir erwarten von den Projekten neue Erkenntnisse zu zellulären Mechanismen und methodischen Optionen für die Therapie allergischer und autoimmuner Reaktionen der Haut.

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Motor adaptive capacity – multimodal quantification and clinical evaluation of a potential prognostic factor in neurodegenerative disease

Neurodegenerative disorders are characterized by loss of specific neuronal populations, along with increasing clinical impairment. The individual disease course may be described as the balance between disease-related pathology and intrinsic mechanisms of adaptation. New treatment strategies should target both sides of this interplay to be most effective. The term “adaptive capacity” refers to the capability of systems to successfully adjust to internal or external changes. Mainly coined in the field of cognitive neuroscience, the underlying concept may be transferable to motor adaptation. However, to date, there is no gold standard as to how the motor adaptive capacity may be quantified. Moreover, it remains undetermined to what extent this parameter contributes to the eventual course of neurological diseases. Therefore, this project aims (i) to quantify motor adaptive capacity and (ii) to put this measure to the test of whether it shows significant association with disease course. In a multimodal approach, behavioral measures, MR imaging, and questionnaires will be used to assess the adaptive capacity in healthy subjects (active/inactive). Subsequently, the optimized parameters will be tested in persons with Parkinson´s disease, ALS, and in a geriatric population on their association with the clinical course. Hand and gait function and clinical scores are recorded at enrollment and will be followed up one year after. An extension of our approach to other neurological conditions is intended. We expect our project to expedite our understanding of differences in individual resiliency towards disease-related challenges. This will eventually contribute to new, individually tailored therapeutic strategies aiming at an early and effective enhancement of the adaptive capacity.

Various brain disorders are based on abnormally oscillating activity within functionally connected circuits, so called oscillopathies. Tremor disorders have a substantial impact on activities of daily living and quality of life and are prime examples of oscillopathies, known to involve cerebello-thalamo-cortical circuits. Non-invasive neurostimulation aims to modulate such oscillations, and circumvents the risk of invasive deep brain stimulation procedures.

It has emerged that phase-specific stimulation in particular can affect neuronal networks and their function. Transcranial alternating current stimulation (tACS) uses weak, exogenous, periodic electric fields to influence neuronal activity by modulating the membrane resting potential. Hence, tACS systems could be adapted into wearable therapeutic devices. Therefore, the combination of tACS with phase-specific stimulation, closely mirroring the endogenous oscillatory activity in involved circuits, poses a means to modulate abnormal network activity.

In previous work, we developed a novel, precise and accurate phase-locking algorithm for non-invasive neurostimulation. The low computational complexity of the devised algorithm allows to be run on light-weight, portable and in-expensive hardware. This phase-locked brain stimulation system synchronizes the electric field with the tremulous activity of tremor-specific networks. Using novel machine-learning based methods, we could show a consistent and reproducible reduction of tremor amplitude in tremor patients.

This project aims to further develop the concept and clinical application of this promising non-invasive stimulation technique towards a clinically relevant therapeutic option by a) exploring the true effect size under longer stimulation, b) establishing advanced adaptive closed-loop stimulation paradigms and c) extend this concept from Essential Tremor to Parkinson´s disease tremor.