Neuroimmunology research group:
Cecilie Ammitzbøll, Sophie Buhelt, Lars Börnsen, Marina Rode von Essen, Poul Erik Hyldgaard Jensen, Ditte Jonesco, Annette Bang Oturai, Eva Rosa Petersen, Rikke Ratzer, Birgitte Romme Nielsen, Jeppe Romme Christensen, Helle Bach Søndergaard, Per Soelberg Sørensen, Finn Sellebjerg
Neuroimmunology of MS
The extent to which inflammation is involved in the pathogenesis of MS remains controversial. There is compelling evidence that treatment strategies targeting systemic immune activation or migration of immune cells to the brain and spinal cord prevent relapses in MS. Some researchers do, however, argue that primary neurodegenerative processes are more important, and that inflammation and relapses have no major impact on the long-term evolution of the disease.
In our research we focus on the role of immune activation and inflammation in the pathogenesis of MS. This is achieved by studying the activation of blood cells, cerebrospinal fluid (CSF) cells and soluble inflammatory mediators in blood and CSF. We compare these in patients with relapsing-remitting, primary and secondary progressive MS, study how treatment alters these factors, and whether they are influenced by genetic, environmental and lifestyle factors associated with the risk of developing MS. Furthermore, we study whether immune activation correlates with clinical and magnetic resonance imaging measures of disease activity. In order to investigate these processes in detail, we combine molecular biology studies with flow cytometry studies of leukocyte phenotypes and functional studies of antigen reactivity, migration and cytokine secretion.
The overall aim of the neuroimmunology research at DMSC is to identify immune activation processes that drive the disease evolution in MS and to understand differences between the different subtypes of MS, in this way describing the effects of MS treatment on the immune system, and how genetic and environmental factors increase the risk of MS and influence immune activation and inflammation.
Molecular biology studies
In the molecular biology studies we investigate mRNA and protein expression and measure the expression and function of microRNAs, which are small, non-coding RNA molecules that regulate the degradation and translation of mRNA. In 2013 we published a study on the expression of microRNA in blood cells, serum and plasma in relapsing-remitting MS. This study showed that several microRNAs are differentially expressed in blood cells and plasma, and that one specific molecule (miR-145) may be a useful biomarker for diagnosing MS. In another study we compared gene expression by Affymetrix DNA arrays, and found that gene expression is quite comparable in patients with relapsing-remitting, primary and secondary progressive MS. Differentially expressed genes were associated with immunoinflammatory processes, arguing for a role of these processes in all subtypes of MS.
Ongoing studies further investigate the role of microRNAs in MS and investigate how MS-associated genetic variants influence gene expression and immune cell functions in MS. These studies include:
- Studies of microRNA and immune activation in pregnant patients with MS Studies of microRNA biomarkers in serum and CSF
- Studies of microRNA effect of treatment with interferon-beta and glatiramer acetate
- Studies of the effects of an MS-associated genetic variant in the gene encoding the interleukin-2 receptor alpha-chain in patients with MS and healthy control subjects Studies of the effects of MS-associated genetic variants on the expression of pro-inflammatory and immunoregulatory cytokines
Immune activation in MS
We have conducted a series of studies addressing the immune activation in blood cells and CSF in patients with relapsing-remitting, primary and secondary progressive MS. These studies complement our microarray studies, and implicate several subtypes of T lymphocytes in the pathogenesis of MS. Interestingly, a recently discovered T lymphocyte subset (follicular helper cells), which are important drivers of antibody responses, seems to be particularly important in patients with relapsing-remitting onset of the disease. We are now exploring these findings further in a series of ongoing studies:
- Activation of naïve, central memory and effector T cells in MS
- The effect of smoking and other exogenous risk factors on immune activation in MS The effect of genetic risk factors on immune activation in MS
- Immune activation and autoreactive T cells in relapsing-remitting MS
- Immune activation and autoreactive T cells in progressive MS Cytokine effects on T cells in MS
Effects of MS therapy and biomarkers
The development of biomarkers that can be used as surrogate outcomes in clinical trials and identify patients with different responses to specific treatments is an important research area in MS. We have sought to identify biobarkers for the response to treatment with glatiramer acetate and interferon-beta for several years, and published studies in 2012 and 2013 suggesting that flow cytometry may be useful to identify effects associated with an insufficient resonse to treatment. We have also tried to identify genetic variants associated with the response to treatment with natalizumab and interferon-beta, but until now these attempts have not been successful. In parallel, we have studied CSF biomarkers for use in early trials in progressive MS, and have identified factors that are associated with tissue damage and which are inhibited by treatment with natalizumab in progressive MS.
We recently completed a study investigating the effect of monthly pulse methylprednisolone treatment in progressive MS, and are currently analysis these results in detail. Other ongoing studies investigate the effects of treatment with mesenchymal stem cells as part of an ongoing, multicentre phase 2 study, and we continue our attempts to identify biomarkers for treatment response for other MS therapies. These studies investigate:
- Effects of mesenchymal stem cell treatment on immune activation and autoreactive T cells in MS
- Immune activation and autoreactive T cells in MS patients treated with natalizumab
- Immune activation and autoreactive T cells in MS patients treated with fingolimod
- Immune activation and autoreactive T cells in MS patients treated with dimethyl fumarate
- Chemokines and gene expression in patients treated with interferon-beta
- Gene expression and disease activity in patients treated with glatiramer acetate