The SFB/CRC 128 Symposium, themed “Multiple sclerosis and related disorders – past, present, and future,” unfolded on April 29th and 30th, 2024, within the historic Castle of Münster University and thus at the center of the city. This symposium garnered significant attendance and served as an exemplary forum to discuss advances in the field, present novel research avenues and treatment strategies, and address central scientific questions and unmet clinical needs in Multiple Sclerosis (MS) and neuroimmunology.

Commencing early on Monday morning, the event attracted an audience of over 100 basic and translational scientists, many of whom have worked as members of the DFG-funded collaborative research center 128, “Multiple Sclerosis.” The symposium showcased the translation of medical research from bench to bedside, providing a comprehensive overview of the current state and future directions of research in MS and neuroimmunology through inspirational talks, engaging discussions, and poster presentations.

Frauke Zipp (Mainz) and Heinz Wiendl (Münster), the co-spokespersons of the SFB/CRC, inaugurated the symposium by examining the evolution in the MS field and its needed development in the next decade. They focused on trends such as biomarkers of disease and therapy response, enabling individualized treatment of MS in the (near) future. Then, the audience delved into neuroimmunology with Jonathan Kipnis (St. Louis), who provided new insights into brain-immune interactions at the brain’s borders. Roland Liblau (Toulouse) presented his latest work on tissue-resident T cells and the chronicity of CNS inflammatory diseases. Britta Engelhardt (Bern) outlined her novel research that is devoted to understanding the function of the different brain barriers in regulating CNS immune surveillance and how their impaired function contributes to neuroinflammatory diseases such as MS. With his talk on neuroprotection through inflammatory cytokines, Burkhard Becher (Zurich) provided insights into the latest developments in this exciting field of research.

The subsequent session on myelin, chaired by Ludia Sorokin (Münster), focused on the role of oligodendrocytes. While Martin Kerschensteiner (Munich) questioned if (and how) surviving oligodendrocytes contribute to remyelination, Tanja Kuhlmann (Münster) discussed the consequences of oligodendrocytes in MS lesions. Peter Calabresi (Baltimore) elaborated on how complement C3 defines disease-associated glial subtypes mediating neuroinflammation and neuronal pathology. Neuroinflammation leads to neuronal stress responses that contribute to neuronal dysfunction and loss. Manuel Friese (Hamburg) provided a closer look at the neuronal inflammatory stress response in MS and ways to therapeutically address it.

Vinzenz Fleischer (Mainz) opened the session on imaging in MS by examining structural brain networks and his talks was complemented by Albrecht Stroh (Mainz). Benedetta Bodini (Toulouse) shared thoughts and data about the past, current, and future role of Positron Emission Tomography (PET) imaging in MS. Alexander Flügel (Göttingen) highlighted the impact of live cell imaging on our understanding of T cell function under homeostatic and autoimmune conditions in the brain.

In the past 12 years, the CRC 128 has contributed to the careers of many young scientists. In the young investigator talk, six of them gave a concise glimpse into their specialty. Beatrice Wasser (Mainz) spoke about how interference with AMPA receptor signaling ameliorates neuroinflammation, while Lisa Richter (Munich) explained the role of IL-6 in shaping local immune milieus in the CNS. Louisa Müller-Miny (Münster) outlined how CSF flow cytometry can help diagnose and understand neuroimmunology by showing use case examples and perspectives; and Timo Uphaus (Mainz) thought outside the box by illustrating the function of the blood-brain barrier not only in neuroinflammation but also in ischemic stroke. Clara de la Rosa del Val (Munich) provided insights into essential cytokines driving macrophage phenotypes in neuroinflammation. The final talk in this session was given by Andreas Schulte-Mecklenbeck (Münster), who presented a study on immune profiling revealing that discrete cellular immune fingerprints indicate distinct disease trajectories in early MS, recently published in Science Translation Medicine.

The session on “Novel directions and technologies” was opened by chair Martin Kerschensteiner (Munich), who introduced Alexandre Prat (Montreal) who exceptionally highlighted the benefit of single-cell RNA sequencing for understanding human MS and ALS brain endothelial cells. Tobias Bopp (Mainz) elaborated on the role of metabolic communication in the development and manifestation of autoimmunity, while Gerd Meyer zu Hörste (Münster) gave an overview of his latest work studying brain borders in neuroinflammation. The integration of large data from high-throughput technologies into complex models is one of the biggest challenges for future high-tech medicine. Sergio Baranzini (San Francisco) presented solutions to this in his lecture on integrating “omics” with AI for precision medicine. With her insights into the mechanisms of action of B cell depletion therapies in MS, Jen Gommerman (Toronto) built a bridge to the sixth session of the symposium that asked, “Is there still a role for T cell immunology, or should we prioritize B cells in understanding MS?” Chair Sven Meuth (Düsseldorf) opened this second day of the symposium where the focus shifted from MS to other neuroimmunologic diseases.

In this first session of the second day, Jan Lünemann (Münster) provided an overview of his highly topical research on functional signatures of encephalitogenic antibodies in CNS autoimmune diseases. Fabienne Brilot (Sydney) examined biomarkers of a relapsing course in MOG antibody-associated disease; and Daniela Latorre (Zurich) used the example of Guillain-Barré-Syndrome to exemplify the role of autoreactive T cell immunity in human neurological autoimmune disorders. Edgar Meinl (Munich) closed the session by providing an overview of B cells and their mechanisms in neuro-immunology.

The final session, chaired by Aiden Haghikia (Magdeburg), was dedicated to learning pathogenesis via therapeutic intervention. Thomas Korn (Munich) emphasized the need for a fresh look at B cells in autoimmunity and – among other studies – presented his work on B cells in models of neuromyelitis optica spectrum disorders (NMOSD). Ari Waisman (Mainz) shared his insights on inflammatory mediators affecting blood barrier function in autoimmunity. Will cellular fingerprints help to evaluate clinical prognosis and decide on the treatment of MS? Luisa Klotz (Münster) and her team have conducted several studies on this topical question, and she discussed the main results in her talk. Naoto Kawakami (Munich) shared learnings acquired on the molecular mechanisms of T cell infiltration into the CNS with the audience. As the last speaker of this dense symposium, Nicholas Schwab (Münster) focused on reverse-translation and asked what next-generation sequencing of treatment cohorts can teach us about pathology.

Overall, all presentations reflected the enormous range of recent and ongoing MS research across the involved centers and worldwide. The principal investigators of the SFB/CRC 128 also summarized important findings from twelve years of research in this large-scale transregional DFG-funded project. Together with the distinguished guest speakers, they also gave ideas on where MS research should and will develop within the next decade.

Muenster. From September 12th to 14th scientists from Muenster University and their international guests discussed the latest developments in research on inflammation and the imaging of the immune system at the 2nd Inflammation & Imaging Symposium. The annual event is jointly organised by several research networks from Münster, among them the CRC/TRR 128 “Multiple Sclerosis”. A photo gallery with impressions from the conference can be found here.

Muenster. After a long pause, more than 90 participants of the CRC joined in Muenster Factory Hotel to update on the latest developments. We heard the most recent on a selection of the CRC projects and there was also plenty of time for fruitful discussion and socializing in the evening.

Münster – The biochemist and Principal investigator of the CRC 128 Prof. Dr. Lydia Sorokin has received the coveted “Advanced Grant” awarded by the European Research Council (ERC). The funding of ca. 2.3 million euros enables the realisation of outstanding research projects.
Lydia Sorokin heads the Institute for Physiological Chemistry and Pathobiochemistry at Muenster University. She investigates the extracellular matrix (ECM) of blood vessels, especially those of the brain. These vessels are impermeable to cells, toxins, and pathogens and are part of the blood-brain barrier (BBB). One of Lydia Sorokin’s most important projects deals with multiple sclerosis and the question of how leukocytes penetrate the brain via the BBB in this disease, thereby causing disease symptoms. The focus is on a particular space discovered by the Sorokin team that surrounds the cerebral blood vessels and is formed by structures of the ECM. This is a favourite residence of leukocytes before they enter the brain in inflammatory brain diseases. The aim of the ERC grant-funded project is to investigate the molecular processes that are required to maintain the BBB, but allow immune cells to penetrate this barrier. To this end, Lydia Sorokin and her team want to reproduce the essential components of the BBB in vitro in three dimensions. Combined with studies on genetically modified mice, the researchers want to find out how the leukocytes manage to penetrate the brain in inflammatory diseases. The replication of the BBB in the laboratory will allow for testing of different substances in order to develop novel drugs against inflammation or tumours in the brain.
The “Advanced Grants” funding line is aimed at established scientists, who have produced outstanding scientific work over the past ten years.

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.

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.