The Clinical Neuroimmunology Lab (Prof Derfuss) studies the biology of multiple sclerosis and related diseases from two approaches. The top-down approach depends on observational studies of immunologic parameters in patients, both in response to treatment and in the natural history of the disease. The bottom-up approach involves in vitro and in vivo experimental modeling of plausible hypothetical mechanisms to explain the observations. The group is funded by SNF project grants, a Sinergia grant, as well as by the Swiss Personalized Health Initiative and grants from industry and private foundations.
First results of the top-down approach obtained in the SNF-Sinergia-funded collaboration with immunologists and computational biologists in Zürich (Nr. 10.000.065/ CRSII—222718) were published in January 2024 (Ulutekin C, Galli E, Schreiner B. Cell Rep Med. 2024). This paper analyzes the effect of B cell depletion on the immune landscape using high-dimensional single-cell immuno-phenotyping.
We will continue this approach to characterize the particular peripheral immune cell populations that are involved in the pathogenesis of MS. In one project, we will analyze the combined effects of sequential immunotherapies. Moving forward, we will focus more on the role of EBV, with one approach continuing to use the high dimensional, high throughput techniques that have been central to the collaboration thus far, and the “bottom up” approach using humanized mice to study the interaction between EBV infected B cells and the CNS in vivo.
In 2024, the group completed its flagship study of the mechanistic connection between Epstein- Barr virus (EBV) and lesion formation in MS (paper under review). A clear association between previous EBV infection and MS incidence has been well established by several groups over many years, but a mechanistic explanation for this dependency is still lacking.
By combining data from our autoreactive B cell screening pipeline with results from experiments with transgenic mouse models, and patient biopsy data obtained in collaboration with the department of Neuropathology in Freiburg/Br, we assembled a model that posits an initial CNS infection as a driver of immune cell infiltration, combined with the EBV-driven expansion of an auto reactive B cell clone. Results from animal modeling have revealed that autoreactive B cells that enter the CNS during localized inflammation are - in the absence of cognate T cell help - normally efficiently eliminated by activation- induced cell death.
The EBV protein LMP1 provides a surrogate for this T cell signaling, and leads to the survival of autoreactive, CNS-infiltrating B cells, the secretion of autoantibody, and localized demyelination. Figure 9 is a graphical abstract summarizing methods and findings.
The experimental Neuroimmunology Group's (Prof Pröbstel Anne-Katrin) current research focuses on three main topics: (I) deciphering microbial-immune cell crosstalk in MS, (II) decoding pathogenic B cell and antibody profiles in MOGAD, (III) identifying microbial and immune signatures associated with treatment (non-) response.
Achievements in 2024 include: (1) In a joint effort with the groups of Prof Gommermann (Toronto) and Prof Zipp (Mainz) and contributions from Jens Kuhle (Workstream 2), we demonstrated that elevation of BAFF following B cell depletion therapy offers neuroprotection in MS and EAE (Wang*, Lüssi*, Neziraj*, Pössnecker* et al. Science Translational Medicine, 2024) pointing towards a potential novel mode of action of anti-CD20 depleting therapies through immune regulatory responses.
(2) In experimental models Lena Siewert and Elisabeth Pössnecker identified antigen-specific activation of gut originating immune cells as a driver of autoimmune neuroinflammation with implications for the role of the microbiome in triggering autoreactive immune response in MS patients (Siewert et al., under revision).
(3) In a mutlicenter effort led by Anne-Katrin Pröbstel in collaboration with Jens Kuhle, we investigated the role of NfL and GFAP as a monitoring biomarker in MOGAD and AQP4-NMOSD (Kim SH, Gomes ABAGR, et al. JAMA Neurol. 2024).
Unraveling the Role of Immunosenescence in Multiple Sclerosis.
In the past year the research group of Prof M. Mehling (Translational Neuroimmunology) at DBM has focused on understanding the interplay between immune aging and the disease course of multiple sclerosis (MS), particularly in relation to cytomegalovirus (CMV) infection and disease-modifying treatments (DMTs). As part of the Swiss Multiple Sclerosis Cohort (SMSC) study at the University Hospital Basel, the group investigated T cell senescence profiles and their functional characteristics across various treatment groups. In a cohort of 229 persons with MS (pwMS), they characterized T cell subsets using multiparameter flow cytometry and analyzed biomarkers such as neurofilament light chain (NfL) and senescence-associated secretory phenotype (SASP) factors. These findings highlight CMV as a significant driver of T cell senescence, independent of DMT. Notably, we observed that CMV reactivity is linked to a less severe disease course, while CMV-antibody negative individuals exhibit stronger correlations between T cell senescence and disease activity. Additionally, the data obtained reveal distinct age-related T cell profiles across individuals treated with different DMTs, with DMF-treated patients showing differential associations between markers of T cell senescence and disease activity depending on CMV status. These findings underscore the importance of personalized therapeutic strategies that consider both immunosenescence and anti-viral reactivity. Ongoing research aims to further elucidate these complex interactions to allow for personalized MS treatment strategies improving patient outcomes.
