We are pleased to report that Aim 1 — the comprehensive interrogation of the immune compartment in monozygotic twin pairs discordant for multiple sclerosis — has been completed, and the results have been published in two high-impact journals with visibility in both the medical and basic biology fields (Ingelfinger, Gerdes et al. Nature, 2022; Ingelfinger et al. Med, 2024). Our approach eliminated the majority of bias attributed to variable genetic and early environmental influences in a heterogenous population and allowed for the distillation of clearly disease driven immune signatures in MS. Beyond the strong genetic predisposition endowed by a variant of the IL-2Ra, we found that the IL-2 pathway is also highly related to the environmental risk of developing MS. Additional dysregulations were observed in the myeloid compartment with an elevated GM-CSF sensing in a subset of monocytic cells of MS individuals.
Aim 2, the development of representation-learning methods to account for paired or longitudinal samples is ongoing. Several breakthroughs were accomplished by collaborations with our teams computational biologists and collaborating labs. Some of these accomplishments can be read in (Diebold et al., 2022; Ingelfinger et al., 2022a-c; Kreutmair et al., 2022a-b; Nuñez et al. 2023, Driessen, Unger et al. 2024; Ingelfinger et al., 2024; Ulutekin, Galli et al., 2024).
Aim 3, using patient samples of MS-like disorders (MS-Mimics) and longitudinal samples of patients undergoing disease-modifying therapy is ongoing. The identification of a biomarkers for monitoring the disease response upon Dimethyl fumarate is published (Diebold et al., 2022). The investigation of MS patients undergoing B cell depletion therapy identified key mechanistic underpinnings of this clinically highly successful treatment. Upregulated CD27 expression on T cells suggested that disruption of T–B cell interactions contribute to the therapeutic effect. After confirming this finding in a second independent cohort, the work was published (Ulutekin, Galli et al. Cell Rep Med, 2024).
For the investigation of MS-Mimics, we transitioned from CyTOF to single-cell spectral flow cytometry due to the latter's superior dynamic range, sensitivity, and acquisition speed. We developed the expertise and tools in our lab to push that technology to the limit by creating panels with 40-45 parameters. MOG-IgG antibody disease (MOG-AD) is a typical MS-mimic since it can share symptoms with MS, but differs in the clinical course and treatment. We found that MOG-AD patients show expanded activated B cell subsets with a phenotype similar to lupus patients. Additionally circulating CXCR3⁺ CD4⁺ memory T cells are reduced - likely due to their retention in the inflamed central nervous system, as seen in a transgenic mouse model. A manuscript summarizing the findings is under revision.
