Paul Lab

MS is causally based upon autoimmune processes; this means that the body's own immune system mistakes the nervous system as "foreign" and initiates an inflammation reaction, as a result of which nerve cells and axons, with their sheathing protective coating, are damaged. Many different neurological symptoms can occur. People suffering from MS can for example feel tingling sensations or numbness, receive paralyses or balance disorders, stumble more frequently or develop problems with their sight.

The course taken by MS varies greatly between individuals, and its course cannot be predicted well in individual patients. One of our fields of activity is the development and establishing of new progress and prognosis markers. These include, for example, the improvement of possibilities in the field of magnetic resonance imaging (MRI), e.g. ultra-high-field MRI and also the establishing of new imaging procedures such as optical coherence tomography (OCT).

It is not yet possible to cure MS. Progression and symptoms can, however, be positively influenced by various drug therapies and non-drug measures. Another fields of activity is the development and conducting of clinical studies with the aim of improving the therapeutic possibilities of MS. These include on the one hand clinical studies of phases I to IV, which we partly carry out in cooperation with the industry, and on the other hand new non-drug treatment approaches such as repetitive transcranial magnetic stimulation for the treatment of depressiveness and fatigue and visual restitution therapy for the improvement of persisting sight impairments after inflammation of the optic nerve.

Other diseases on which we have a research focus are Susac syndrome and neuromyelitis optica.

The Clinical Neuroimmunology group works in close cooperation with the interdisciplinary outpatient clinics of the Experimental and Clinical Research Center (ECRC). In addition to the Neuroimmunology outpatient clinic, other additional disciplines ensure state-of-the-art patient care based on the current state of knowledge.

For more information, explore MDC’s latest findings in the MS field.

Single-cell and spatial profiling in neuroinflammation

Chotima Böttcher, M. Camila Fernández Zapata, Gerardina Gallaccio, Adeline Dehlinger, Meng Wang, Christian Böttcher, Praveen Nath, Wenbo Sun, GueHo Jang

Research Line

Neuroinflammation is a common feature of autoimmune diseases of the central nervous system (CNS) such as multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), in which the pathologies are associated with various immune responses in different body compartments e.g. local inflammation, microglial activation, and CNS or gut infiltration of circulating immune cells. Characterization of more diverse immune cell types residing in different body compartments including gut, peripheral blood, cerebrospinal fluid (CSF), brain interface and brain parenchyma is required for better understanding dynamic compartmentalization of these cells in early as well as in the progressive stages of diseases.

In our team, we characterize the metabolomic and proteomic profiles of body fluid (i.e. plasma and CSF) that associate with functional and phenotypic changes of immune cells in gut, peripheral blood, CSF and the CNS of MS, NMOSD and MOGAD patients/donors, using mass cytometry and imaging mass cytometry. We aim to assess dynamic cell signalling of immune cells from different compartments using a combination of deep protein and metabolomics profiling with phenotypic profiling, in order to unravel neuroinflammation-associated phenotypic transmission of immune cells and how these cells are involved in CNS homeostasis.

 Selected Publications

1. Fernández Zapata C, Giacomello G, Spruth EJ, Middeldorp J, Gallaccio G, Dehlinger A, ..., Böttcher C. Differential compartmentalization of myeloid cell phenotypes and responses towards the CNS in Alzheimer`s disease.Nat Commun. 13(1):7210. doi: 10.1038/s41467-022-34719-2 (2022).
2. Böttcher C*, van der Poel M*, Fernández-Zapata C*, Schlickeiser S, Leman JKH, Hsiao CC et al. Single-cell mass cytometry reveals complex myeloid cell composition in active lesions of progressive multiple sclerosis. Acta Neuropathol Commun 8, 136 (2020). 
3. Böttcher C*, Fernández-Zapata C*, Snijders GJL, Schlickeiser S, Sneeboer MAM, Kunkel D et al. Single-cell mass cytometry of microglia in major depressive disorder reveals a non-inflammatory phenotype with increased homeostatic marker expression. Transl Psychiatry 10, 310 (2020).
4. Fernández-Zapata C, Leman JKH, Priller J, Böttcher C. The use and limitations of single.cell mass cytometry for studying human microglia function. Brain Pathol. 30(6):1178-1191. doi: 10.1111/bpa.12909 (2020).
5. Böttcher C*, Schlickeiser S*, Sneeboer MAM*, Kunkel D, Knop A, Paza E et al. Human microglia regional heterogeneity and phenotypes determined by multiplexed single-cell mass cytometry. Nat Neurosci 22, 78–90 (2019).
6. Böttcher C*, Fernández-Zapata C*, Schlickeiser S*, Kunkel D, Schulz AR, Mei HE et al. Multi-parameter immune profiling of peripheral blood mononuclear cells by multiplexed single-cell mass cytometry in patients with early multiple sclerosis. Sci Rep 9, 19471 (2019).
7. Sankowski R*, Böttcher C*, Masuda T, Geirsdottir L, Sagar, Sindram E, Seredenina T et al. Mapping microglia states in the human brain through the integration of high-dimensional techniques. Nat Neurosci 22, 2098–2110 (2019).

Funding

1. Dynamic compartmentalization of myeloid cell responses in neuroinflammation (SFB-TRR167-Neuromac: https://www.sfb-trr167.uni-freiburg.de/)
2. Proteo-metabolomic dissection of AhR-mediated inflammation in multiple sclerosis (TAhRget, BMBF)
3. The continuum of microglial subpopulations to functional changes in multiple sclerosis (SPP2395, DFG)
4. Imminent disease prediction and prevention at the environment host interface (IMMEDIATE, Horizon-RIA-EU)

Magnetic Resonance Imaging

Friedemann Paul, Claudia Chien, Darius Mewes, Lina Anderhalten, Henri Trang, Qianlan Chen, Michael Sheel, Susan Pikol, Cynthia Kraut

Diagnosis, differential diagnosis, monitoring of disease course and treatment effects in patients with autoimmune inflammatory CNS diseases such as multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), or the newly emerging disease entity myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) still pose significant challenges for neurologists and evoke anxiety in affected patients. Our work focuses on the contribution of conventional and advanced structural and functional MRI techniques (as well as visual system research, immune cell profiling and serum derived biomarkers (for example, aquaporin-4 (AQP4) antibodies, myelin oligodendrocyte glycoprotein (MOG) antibodies) to diagnosis and differential diagnosis of autoimmune CNS diseases. Moreover, we use these methods to deepen our understanding of the association of structural and functional CNS changes with clinical symptoms (using state of the art and innovative measures of neurological disability, cognitive dysfunction, visual function), as well as with disease course and treatment response. Imaging (and biomarker) studies are embedded into ongoing longitudinal observational (i.e. BERLimmun (including CIS, MS, NMOSD and MOGAD patients), acute optic neuritis (ACON)) studies with >500 recruited patients, yielding clinically and paraclinically extremely well phenotyped cohorts, and are applied in interventional trials (neuroprotective, symptomatic) with the aim of broadening treatment options.

Using quantitative multi-parameter mapping (MPM), MRI studies can investigate clinically relevant microstructural changes with high reliability over time and across subjects and sites. We have established a fast MPM protocol with 3D multi-echo fast low angle shot (FLASH) acquisitions including post-processing optimized for longitudinal clinical studies to obtain after reconstruction the following whole-brain MPM maps with 1.6 mm isotropic resolution: proton density (PD), magnetization transfer saturation (MT), longitudinal relaxation rate (R1), and transverse relaxation rate (R2*). The intra-subject stability of the 1.6-mm MPM protocol is 2-3 times higher than for the standard 1-mm sequence and can be achieved in less than half the scan duration. By combining Gibb’s ringing correction and bias field correction using acquired B1+ maps we achieved excellent stability of a 7-minute MPM sequence. The MPM sequence and a corresponding multi-shell diffusion-weighted imaging (DWI) sequence derived from the human connectome project and suitable to calculate Neurite Orientation Dispersion and Density Imaging (NODDI) are part of the core imaging protocol of the ongoing Berlimmun study.

Adaptive Immunity and Novel Therapies

Maria Hastermann, Sara Cestari, Melina Quast

Research Line

•Neuromyelitis optica (NMO) is a devastating inflammatory disease of the central nervous system (CNS) with yet unknown pathogenesis. Major hallmarks of NMO include lesions located especially in the optic nerve as well as extensive longitudinal spinal cord lesions and the production of anti-AQP4-antibodies in the majority of NMO patients. We and others could demonstrate in animal models, that effector T cells are relevant for NMO pathogenesis. Furthermore generalized upregulation of T cell activity in NMO patients and presence of AQP4 specific T cells in the blood of NMO patients that can be activated by AQP4-peptides has been demonstrated. In a physiological state humoral and cellular immune components are important players in host defence against non-self-antigens that can turn against self through mechanisms of cross reactivity when dysregulation occurs in the immune system. Therefore powerful counter-mechanisms that should prevent autoimmunity are present in the immune system. The main mediators of peripheral tolerance are regulatory T cells (Treg cells). A growing body of evidence suggests a role for Treg cells in the suppression of autoimmune diseases. Unfortunately no studies concerning Treg cell impairment and their involvement in possible treatment options in NMO exist to date.

 

•Therefore the main focus of this Team is to a) analyze Treg cell status in NMOSD patients with special attention to Treg cell numbers and their functionality b) to establish rodent and in-vitro models of NMOSD c) test in these models to what extent (AQP4 specific) Treg cells and other novel therapeutic strategies influence the development of astrocytopathic and subsequently demyelinating lesions and d) to observe the interaction of pro- and anti-inflammatory humoral and cellular immune components and their impact on neuronal and supportive cells in the CNS.  Ultimately the results of these studies will provide knowledge whether e.g. (AQP4 specific Treg)-cell therapy is a feasible approach for specific and effective treatment of NMOSD with the benefit of low side effects and adverse events.

 

We are working on this with a translational approach; this means that we try to transfer new developments and findings from basic research directly into clinical work.

The Clinical Neuroimmunology Group is a part of the Experimental and Clinical Research Center (ECRC), a cooperation between the MDC and the Charité - Universitätsmedizin Berlin. For patients interested in our group, please refer to our Neuroimmunology outpatient clinic.