Muenster. For the first time after a longer pandemic-related break, the SFB 128 will host an onsite retreat. On Thursday and Friday, 23 and 24 June, the participating scientists will meet in Muenster to present the current status and developments of their projects. The event is also an opportunity for the exchange and the discussion of future plans and co-operations. Already one day before, the Young Investigators will gather for an internal retreat.

The organisers are particularly pleased that they have been able to secure a guest speaker for the key note lecture: On Thursday, 23rd Prof. Dr. med. Ralf Linker, Head of the Department of Neurology at Regensburg University, will talk about “Environmental factors in MS pathogenesis – what is there beyond EBV?”

This lecture is open for the general public as a webinar. To join the lecture via zoom, please register via email at sarah.khalil@ukmuenster.de

Prof. Luisa Klotz and Marie Liebmann analysed the immune metabolism of cells. (Photo: Anna-Lena Börsch)

Muenster – One person can eat large amounts of pasta and still be a small dress size while another looks at a piece of chocolate and puts on weight: metabolism varies between individuals – and this goes beyond a subjective feeling. What is apparent in the overall organism also applies to each cell: the metabolism of individual cell types differs. It is not surprising that in recent years metabolic immune cell disorders have been observed in connection with several autoimmune diseases, including multiple sclerosis. Now scientists of the transregional collaborative research centre (CRC) 128 have demonstrated: the effectiveness of one particular multiple sclerosis drug is due to its direct interference with cell metabolism. And this is only part of the story: the active ingredient under investigation, dimethyl fumarate (DMF), has a variable effect – depending on how the cells of individual patients metabolize it.
DMF is an approved substance for therapy of relapsing-remitting multiple sclerosis (MS) and reduces the excessive immune reactions in the body. It is known to induce cell death (apoptosis) in immune cells that trigger excessive responses. “It was clear to us that cell death occurs as a result of this drug, but we did not know how,” says Marie Liebmann, a research associate in Prof. Luisa Klotz’s group at the University Hospital for Neurology in Münster. Now it has been proven: The drug specifically targets cells that convert a high amount of energy and thus produce a lot of oxygen. Through a reaction, it leads to even more oxygen being produced, which accumulates in the mitochondria, the powerplants of the cell. This oxygen, however, is highly reactive, putting the cells under high oxidative stress, which eventually kickstarts apoptosis. This type of stress, and even cell death, is to a certain extent desired by nature to enable cell activation.
The mechanism becomes problematic only when it does not happen to the desired extent. In patients with average immune metabolism, just enough cells are killed to maintain a normal immune response. In patients with low cell metabolism, there is the risk of too many T cells dying: leaving immune defenses weakened and infections becoming more likely. This so-called lymphopenia – a drop in T cell count – is a known side effect of DMF and many other drugs used to treat autoimmunity. If the cell counts drop below a certain threshold, therapy must be interrupted as the risk of infection becomes too high. In most cases, the excessive immune response plus inflammation and symptoms of the autoimmune disease will then return.
The latest research from the Münster team – made possible in part by support from the CRC 128 and the Competence Network Multiple Sclerosis – could aid better risk assessment: “We can determine patients’ cell metabolism on an individual level and thus check whether this side effect is likely,” Prof. Klotz explains, who works as a senior physician in the Department of Neurology. “But this is just the beginning,” she says since DMF is not the only drug that works differently in different patients. Already some time ago, Prof. Klotz’s team could prove similar mechanisms underlying multiple sclerosis therapy with the active ingredient teriflunomide. “It is certainly worthwhile to identify cell metabolism types in multiple sclerosis patients to be able to offer individual patient-level treatment,” Prof. Klotz adds looking towards future needs.

Reference:
Liebmann M, Korn L, Janoschka C, Albrecht S, Lauks S, Herrmann AM, Schulte-Mecklenbeck A, Schwab N, Schneider-Hohendorf T, Eveslage M, Wildemann B, Luessi F, Schmidt S, Diebold M, Bittner S, Gross CC, Kovac S, Zipp F, Derfuss T, Kuhlmann T, König S, Meuth SG, Wiendl H, Klotz L. 2021. Dimethyl fumarate treatment restrains the antioxidative capacity of T cells to control autoimmunity. Brain. 144(10):3126-3141.

Münster. Save the date: 12-14 September 2022! We cordially invite you to join this international symposium, jointly organized by the research networks CRC 1450, CRC 1009, CRC 1348, CRU 342, CRC/TR 128 and the Cells in Motion Interfaculty Centre at the University of Münster. At the same time, we will officially open the new research building in which many groups from our networks will be working – the Multiscale Imaging Centre.

A close interaction between gut immune responses and distant organ-specific autoimmunity including the CNS in multiple sclerosis has been established in recent years. This so-called gut-CNS axis can be shaped by dietary factors, either directly or via indirect modulation of the gut microbiome and its metabolites. Here, SFB 128 PI Luisa Klotz and colleagues report that dietary supplementation with conjugated linoleic acid, a mixture of linoleic acid isomers, ameliorates CNS autoimmunity in a spontaneous mouse model of multiple sclerosis, accompanied by an attenuation of intestinal barrier dysfunction and inflammation as well as an increase in intestinal myeloid-derived suppressor-like cells. More . . .

BioNTech SE (Nasdaq: BNTX, “BioNTech” or “the Company”) announced the publication of preclinical data on its novel mRNA vaccine approach against autoimmune diseases in the peer-reviewed journal Science. The publication titled “A non-inflammatory mRNA vaccine for treatment of experimental autoimmune encephalomyelitis” co-authored by SFB principal investigator Ari Waisman summarizes the findings on the disease-suppressing effects of a non-inflammatory, nucleoside-modified mRNA vaccine in several clinically relevant mouse models of multiple sclerosis (MS). More . . .

Patients suffering from COVID-19 can develop concomitant and long-term symptoms in their nervous system. The most common symptom in this context is the loss of the sense of smell and taste, while more severe symptoms such as stroke, cerebral seizures, or meningitis are possible. A team of scientists from the medical faculties at the Universities of Münster and Duisburg-Essen investigated this phenomenon, termed Neuro-COVID. They could demonstrate that immune and interferon responses are weakened in COVID-19 patients. These results were recently published in the journal Immunity.

The research teams applied state-of-the-art single-cell transcription technologies, which help visualize the expression of thousands of genes on a single-cell level. “This allowed us to characterize in detail the immune response of Neuro-COVID in the cerebral fluid at a location near the brain”, says PD Dr. Gerd Meyer zu Hörste, a senior physician in the Department of Neurology at the University Hospital Münster and senior author of the study publication. “From a group of 102 COVID-19 patients, we identified those who developed neurological symptoms and required a cerebral fluid extraction for further diagnosis”, says PD Dr. Dr. Mark Stettner, who is a senior physician in the Depart

Priv.-Doz. Dr-Gerd Meyer zu Hörste (left) and Dr. Michael Heming investigated “Neuro-Covid”.

ment of Neurology at the University Hospital Essen and led the study together with Meyer zu Hörste.

Samples from eight Neuro-COVID patients were collected and sent to Münster for analysis. “An increased number of T cells in the patients’ cerebral fluid had reached a stage of exhaustion”, says Dr. Michael Heming, first author of the study and assistant physician in the Department of Neurology at the University Hospital Münster. Also, the interferon answer of Neuro-COVID patients was reduced compared with viral brain inflammation. Interferons are an essential early defense mechanism for viral diseases. The researchers further found an increased number of dedifferentiated phagocytes in the cerebral fluid.

“These findings indicate a reduced antiviral immune response in Neuro-COVID patients”, says Prof. Christoph Kleinschnitz, Director of the Department of Neurology at the University Hospital Essen. A more detailed understanding of the Neuro-COVID phenomenon is the basis for faster disease detection and improved treatment. “Publication of the study results in a high-class journal such as Immunity is the result of intensive and hard work. Our researchers achieved impressive results within a short time”, says Prof. Wiendl, Director of the Department of Neurology at the University Hospital Münster.

It has long been acknowledged that multiple sclerosis disease risk is associated with reduced sun-exposure, and subsequent low vitamin D levels. The study by Ostkamp et al. now assessed the relationship between measures of sun exposure and MS severity. For this, the researchers analyzed data of around 2,000 patients from the German NationMS- and the French BIONAT cohort. To approximate a patients’ sunlight exposure, the researchers used serum vitamin D measurements, the geographical latitude of residence, and UV-light estimates extracted from the recordings of NASA satellites. As expected, high serum vitamin D could be shown to be associated with a reduced MS severity score, reduced risk for relapses, and lower disability accumulation over time. Furthermore, low latitude associated with higher vitamin D levels, a lower MS severity score, fewer gadolinium-enhancing lesions, and lower disability accumulation over time. As an exception, no association between latitude and disability was found in patients who were treated with IFN-β before the start of the study. This lined up with a finding from an RNA-sequencing analysis, in which the researchers could show an induction of the type I interferon-pathway in a small cohort of patients, who were treated with narrowband UVB-light for six weeks.

Patrick Ostkamp was in the team of scientists who analysed the cohort data. (Photo: Leßmann)

Therefore, as UVB potentially initiates an interferon response itself, it might be possible that no effect of UVB can be observed in patients whose blood is already saturated with interferons. Although the study shows that sunlight exposure has a beneficial effect on MS severity, the researchers argue against excessive sun exposure, as the observed effects of UV-light were of comparably low magnitude, and photosensitive patients who carried a genetic variant of the melanocortin-1-receptor (an important factor for pigmentation) even seemed to worsen upon increased sunlight exposure, according their MRI activity.

Reference: Ostkamp P, Salmen A, Pignolet B, Görlich D, Andlauer TFM, Schulte-Mecklenbeck A, Gonzalez-Escamilla G, Bucciarelli F, Gennero I, Breuer J, Antony G, Schneider-Hohendorf T, Mykicki N, Bayas A, Then Bergh F, Bittner S, Hartung H-P, Friese MA, Linker RA, Luessi F, Lehmann-Horn K, Mühlau M, Paul F, Stangel M, Tackenberg B, Tumani H, Warnke C, Weber F, Wildemann B, Zettl UK, Ziemann U, Müller-Myhsok B, Kümpfel T, Klotz L, Meuth SG, Zipp F, Hemmer B, Hohlfeld R, Brassat D, Gold R, Gross CC, Lukas C, Groppa S, Loser K, Wiendl H, Schwab N, German Competence Network Multiple Sclerosis (KKNMS) and the BIONAT Network. 2021. Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity. Proc Natl Acad Sci U S A. 118(1):e2018457118.

The Collaborative Research Center 128 “Multiple Sclerosis” is entering its third round. As the German Research Association announced, the major project with locations in Münster, Mainz and Munich will be supported for a further four years (until mid-2024). Speaker Prof. Heinz Wiendl, Co-Spokesperson Prof. Frauke Zipp (Mainz) and other scientists are researching multiple sclerosis – a chronic inflammatory and neurodegenerative disease of the central nervous system. Their focus is on the interaction between the immune and nervous systems on a molecular, cellular and systems biological level. The 35 principal investigators and their teams analyse the changes in the immune system underlying the disease, effects the attack of the immune system has on the central nervous system and how these consequences can be modulated with the latest therapies. The 22 individual projects are tackling a wide range of topics, including the role of the intestinal microbiome in inflammation and nerve destruction in MS, the patterns of nerve damage that MS patients e.g. in MRI images show and the effect of various MS drugs on the immune system. In the next four years, the focus of her work will be on coping with illnesses. This means both better control and monitoring of the now widespread drugs for treating MS and translation – i.e. the transfer of research results into patient care and – the other way around – the use of knowledge from clinical practice for work in the laboratory.

Beatrice WasserEach year, the German Society for Immunology (DGfI) recognizes young scientists who have made an outstanding contribution in the field of immunology. This year, Dr. Beatrice Wasser, a Postdoc in the group of Prof. Frauke Zipp and Prof. Stefan Bittner in the Department of Neurology, was award the Herbert Fischer Prize for Neuroimmunology for her investigation of the mechanism by which cells of the central nervous system (CNS) can control autoreactive T lymphocytes. Dr. Wasser was able to show, for the first time, that myeloid cells in the CNS can trap and kill invading pathogenic T cells. This novel defense pathway could potentially be exploited, leading to a new therapy for T cell-induced autoimmune diseases such as multiple sclerosis.

This work was recently published in the Journal of Experimental Medicine:
Wasser B, Luchtman D, Löffel J, Robohm K, Birkner K, Stroh A, Vogelaar CF, Zipp F, Bittner S. CNS-localized myeloid cells capture living invading T cells during neuroinflammation. J Exp Med 2020; 217(6): e20190812.
The official press release of the DGfI is available here.

Happy about the new findings from the MS-TWIN study: PhD student Claudia Janoschka (right) and group leader Prof. Luise Klotz (Photo: Deiters-Keul)

The tremendous heterogeneity of the human population presents a major obstacle in understanding how autoimmune diseases like multiple sclerosis (MS) contribute to variations in human peripheral immune signatures. To minimize heterogeneity, SFB researchers from Munich and Muenster made use of a unique cohort of 43 monozygotic twin pairs clinically discordant for MS and searched for disease-related peripheral immune signatures in a systems biology approach covering a broad range of adaptive and innate immune populations on the protein level. Results of their work were published in the latest issue of the prestigious journal PNAS.
Despite disease discordance, the immune signatures of MS-affected and unaffected cotwins were remarkably similar. Twinship alone contributed 56% of the immune variation, whereas MS explained 1 to 2% of the immune variance. Notably, distinct traits in CD4+ effector T cell subsets emerged when Lisa Ann Gerdes, Claudia Janoschka and colleagues focused on a subgroup of twins with signs of subclinical, prodromal MS in the clinically healthy cotwin. Some of these early-disease immune traits were confirmed in a second independent cohort of untreated early relapsing-remitting MS patients. Early involvement of effector T cell subsets thus points to a key role of T cells in MS disease initiation.

Adapted from.
Gerdes LA° Janoschka C°, Eveslage M, Mannig B, Wirth T, Schulte-Mecklenbeck A, Lauks S, Glau L, Gross CC, Tolosa E, Flierl-Hecht A, Ertl-Wagner B, Barkhof F, Meuth SG, Kümpfel T, Wiendl H°, Hohlfeld R*, Klotz L*. Immune signatures of prodromal multiple sclerosis in monozygotic twins. Proc Natl Acad Sci U S A 117(35):21546-21556. (°,*= equal contribution)

News

Mon, 09/05/2022
Scientific Retreat including public Webinar
Muenster. For the first time after a longer pandemic-related break, the SFB 128 will host an onsite retreat. On Thursday and Friday, 23 and 24 June, the participating scientists will meet in Muenster to present the current status and developments of their projects. The event is also an opportunity for the exchange and the discussion […]...more
Wed, 19/01/2022
One drug – different effects: Metabolism of immune cells influences mode of action and could be an indicator for side effects
Muenster – One person can eat large amounts of pasta and still be a small dress size while another looks at a piece of chocolate and puts on weight: metabolism varies between individuals – and this goes beyond a subjective feeling. What is apparent in the overall organism also applies to each cell: the metabolism […]...more
Tue, 14/12/2021
Save the date: 2nd Inflammation & Imaging Symposium
Münster. Save the date: 12-14 September 2022! We cordially invite you to join this international symposium, jointly organized by the research networks CRC 1450, CRC 1009, CRC 1348, CRU 342, CRC/TR 128 and the Cells in Motion Interfaculty Centre at the University of Münster. At the same time, we will officially open the new research […]...more