F. Zipp
University Medical Center of the Johannes Gutenberg University MainzAuthor Of 2 Presentations
PL02.01 - New Insights on Immunopathogenesis
Abstract
Abstract
Multiple sclerosis is a complex disease in which the innate and adaptive immune systems play a fundamental role. Treatment with disease-modifying therapies reduces relapses of neurologic symptoms (Bittner and Zipp, Nat Rev Neurol 2018). However, it does not stop overall disease progression and most patients eventually develop the secondary chronic progressive form of the disease (Larochelle et al., Trends Neurosci 2016). Immune modulatory therapies have given us novel insights into disease pathology, for example, that long-neglected B cells play a relevant role or that early consequent treatment in the relapsing phase of the disease is able to prevent a later conversion into a secondary progressive disease course. Novel blood-based biomarkers such as neurofilaments might not only facilitate patient treatment stratification (Bittner et al., EBioMedicine 2020), but also illustrate the relevance of axonal damage starting from the very first phases of MS. This highlights a need for new avenues of research that address the problem of progression in a fundamentally different way. We will critically discuss current pathophysiological models of progressive disease, e.g., the involvement of the adaptive versus innate immune system, immune-independent neurodegenerative pathways, repair mechanisms and higher network alterations. A special focus will be put on CNS-intrinsic pathways, the complex interplay between immune cells, glial cells and neurons within the CNS parenchyma, and its impact on brain function in health and disease.
PS06.04 - GlcNAc-signaling as a new target to reduce T cell pathogenicity in the CNS
Abstract
Background
Both adaptive and innate immune cells infiltrate the CNS during multiple sclerosis (MS) and in its animal model experimental autoimmune encephalomyelitis (EAE). Pathogenic T cells are known as key drivers of the disease while treatment strategies specifically targeting inflammatory processes directly within the CNS parenchyma behind the blood-brain-barrier are still missing.
Objectives
In this project we aimed to unravel CNS-internal mechanisms to counteract the disease in both the murine and the human system by modulating T cell pathogenicity in the CNS.
Methods
We used intravital 2-photon microscopy to visualize T cells and their interactions with neurons and microglia in the CNS of EAE-diseased animals and in organotypic slice cultures. Using immunohistochemistry and flow cytometry we further analyzed surface molecules on T cells and myeloid cells to gain a deeper understanding of the molecular pathways behind the CNS-response to T cell infiltration. Human T cells isolated from blood and cerebrospinal fluid of MS patients were analyzed ex vivo to allow translation to the human system.
Results
We discovered that detrimental effects of pathogenic Th17 cells can be mediated via a cell-to-cell-interaction-dependent vesicular glutamate release pathway that induces damage in neurons. In a counteractive mechanism, microglia attempted to remove fully viable invaded pathogenic T cells from the CNS tissue during the disease. This T cell engulfment was mediated by expression of activation-dependent lectin and its T cell-binding partner, N-acetyl-D-glucosamine (GlcNAc) and enhancement of GlcNAc signaling in the CNS ameliorated disease outcome. In human subjects, we could show that GlcNAc was highly exposed on T cells in the CNS of MS patients. Of note, this GlcNAc exposure on CNS-infiltrated T cells was significantly increased as compared to peripheral T cells.
Conclusions
Myeloid cells are able to directly react to pathogenic T cell infiltration by engulfing living T cells in a GlcNAc-dependent manner. Increased GlcNAc-exposure on T cells in the human CNS reflects high susceptibility of infiltrated T cells to get eliminated by myeloid cells, suggesting that pharmacological enhancement of T cell engulfment could particularly affect T cells in the target organ of MS.