Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Schnabl, A.
Immunometabolic biomarkers and therapeutic targets in multiple sclerosis.
[ Diplomarbeit/Master Thesis (UNI) ] Universität Graz; 2025.
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Angiari Stefano
- Altmetrics:
- Abstract:
- Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) affecting approximately 2.9 million people worldwide. The pathogenesis of MS is closely linked to the inflammatory potential of activated immune cell populations. In particular, T cells control the development of local inflammation in the CNS and mediate the autoimmune attack against the myelin sheath. Pyruvate Kinase (PK) is the enzyme that catalyzes the final step in glycolysis. There are four identified PK isoforms and immune cells preferentially express the PK isoenzymes M1 (PKM1) and M2 (PKM2). Apart from its canonical enzymatic activity, PKM2 can translocate into the cell nucleus, where it performs ‘moonlighting’ functions including regulation of gene expression. Interestingly, several pre-clinical studies have recently demonstrated that PKM2 moonlighting activity controls T cell pathogenicity in the CNS in experimental autoimmune encephalomyelitis (EAE), the mouse model of MS. Nevertheless, no studies have analyzed the role of PKM2 in T cells of MS patients. Moreover, while soluble PKM2 has been detected in body fluids and correlates with disease activity in cancer patients and individuals with autoimmune diseases, whether soluble PKM isoforms can represent biomarkers of MS onset or progression is unknown. The goal of this master thesis was to evaluate the role of PKM2 in T cell inflammatory potential in MS patients, and if PKM isoforms might serve as biomarkers in MS. We first confirmed the presence of PKM2 in various circulating T cell subsets, with antigen- triggered T cells showing higher levels of PKM2 compared to naïve T cells. We could not detect differences between healthy control individuals and MS individuals, nevertheless, some MS patients show very high PKM2 levels. We further evaluated whether targeting PKM2 with the allosteric activator TEPP-46 had an impact on T cell pathogenic potential. We show that TEPP-46, which blocks PKM2 moonlighting activity, decreased pro- inflammatory cytokine production and inhibited proliferation in T cells of MS patients. Finally, we investigated the presence of PKM1 and PKM2 in the cerebrospinal fluid (CSF) of healthy controls and identified a striking distribution of PKM isoforms in the CSF. Overall, our data indicate that targeting PKM2 may represent a new therapeutic approach to limit T cell pathogenicity in MS. Additionally, we confirm the presence of PK isoforms in the CSF, which may potentially represent novel biomarkers in MS.