Descrizione del progetto
Il processo autoimmune guidato dalle cellule T comporta un’infiammazione cronica del cervello con una neurodegenerazione progressiva
Il cervello è un organo che gode di privilegio immunologico in cui le cellule residenti esercitano funzioni immunitarie limitate. Tuttavia, nel caso della sclerosi multipla, una malattia autoimmune cronica indotta dalle cellule T, il tessuto cerebrale si trasforma in un ambiente immunoattivo. Il progetto T-Neuron, finanziato dall’UE, si propone di scoprire i meccanismi della trasformazione neuronale indotta dalle cellule T, concentrandosi in particolare sulle conseguenze funzionali del comportamento invasivo di tali cellule. Studi precedenti hanno dimostrato che le cellule T autoaggressive all’interno delle lesioni autoimmuni sono di solito in contatto diretto con i neuroni o risiedono nel citoplasma degli stessi. I ripetuti attacchi autoimmuni della materia grigia provocano un’infiammazione e una neurodegenerazione costanti. Il progetto verificherà l’ipotesi secondo cui le cellule T contribuiscono direttamente allo sviluppo della malattia cronica, spostando irreversibilmente le cellule residenti nel cervello in uno stato infiammatorio.
Obiettivo
The TOPIC of this proposal is how a T-cell-driven autoimmune process can transform the brain into a chronically inflamed tissue afflicted by progressive neurodegeneration.
The brain is considered to be an immune-privileged organ because immune cells have restricted access to its tissue and its resident cells can only exert limited immune functions. However, in the course of multiple sclerosis, a T-cell-induced chronic autoimmune disease of the brain, such aspects change dramatically and the brain tissue is transformed into an immunoactive milieu. These changes go hand in hand with a gradual degeneration of the neuronal tissue. What steers this transformative process in the brain is not yet understood.
We have developed new experimental models and tools that enable us to follow and functionally test this transition from healthy into degenerating brain tissue in real time. We found that autoaggressive T cells within autoimmune lesions were frequently in direct contact with neurons or were partially or even completely inside the cytoplasm of neurons. Repeated T-cell-mediated autoimmune attacks of the CNS grey matter induce persistent inflammatory lesions with proceeding neurodegeneration. This leads us to the HYPOTHESIS that T cells not only trigger the initiation of autoimmune disease bouts but in addition directly contribute to the chronification of the disease by irreversibly shifting brain resident cells to an inflammatory program. The central AIM of this project is to uncover the mechanisms behind this T-cell-induced neuronal transformation process, particularly the functional consequences of the T-cell invasive behavior.
Our VISION is to shed new light on this previously unknown function of autoaggressive T cells within the CNS tissue and thereby pave the way for new and targeted strategies to prevent autoimmunity-driven degeneration of the central nervous system.
Campo scientifico
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-ADG - Advanced GrantIstituzione ospitante
37075 Goettingen
Germania