Friedemann Paul group

Paul Lab

Clinical Neuroimmunology

Profile

Multiple sclerosis (MS) is the most frequent chronic inflammatory disease of the central nervous system and primarily affects young adults.

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.

Team

Group Leader

Prof. Dr. med. Friedemann Paul, Facharzt für Neurologie
friedemann.paul@charite.de

 

Coordination Team

PD Dr. Tanja Schmitz-Hübsch,  Leader Research Outpatient Clinic
tanja.schmitz-huebsch@charite.de
studienambulanz-ag-paul@charite.de

Dr. med. Judith Bellmann-Strobl, Leader Neuroimmunological Outpatient Clinic
judith.bellmann-strobl@charite.de
hochschulambulanz-buch@charite.de

PD Dr. rer. nat. Chotima Böttcher, Leader Laboratory Research
Chotima.boettcher@charite.de / ORCID

Jana Bigall, Studynurse Team Lead
jana.bigall@charite.de

Vanessa Tatum, Project Management Lead
vanessa.tatum@charite.de

 

Research Teams

Clinical Research Endpoints/Motor outcome

Team Leader: PD Dr. Tanja Schmitz-Hübsch

PD Dr. Tanja Schmitz-Hübsch,  Scientific Lead Motor Function/Supervision of Clinical Data
tanja.schmitz-huebsch@charite.de

Dr. Eva Dorsch, Physician

Dr. Rohat Geran, Physician

Dr. Patrick Schindler, Physician

Dr. Philipp Klyscz, Physician

Dr. Pia Sperber, Physician

Dr. Rebekka Rust, Neurologist

Single-cell and spatial profiling 

Team Leader: PD Dr. rer. nat. Chotima Böttcher

PD Dr. rer. nat. Chotima Böttcher, Team Leader: Single-cell and Spatial Profiling in Neuroimmunology
Chotima.boettcher@charite.de / ORCID

 

Adeline Jeanne Dehlinger, M.Sc., PhD student
adeline.dehlinger@charite.de

 

 

Dr. Camila Fernández Zapata, Postdoctoral fellow
maria.fernandez@charite.de / ORCID

 

 

Christian Böttcher, Biological Technician, Biomaterials and protein analysis
Christian2.boettcher@charite.de

 

 

Gerardina Gallaccio, M.Sc., PhD student
gerardina.gallaccio@charite.de

 

 

GueHo Jang, M.Sc., PhD student
gueho.jang@charite.de

 

 

Meng Wang, MD., PhD student
meng.wang@charite.de

 

 

Praveen Nath, M.Sc., Data Manager
praveen-jagan.nath@charite.de

 

 

Wenbo Sun, MD, PhD student

 

 

Visual Team

Team Leader: Juniorprof. Dr. Hanna Gwendolyn Zimmermann

Juniorprof. Dr. Hanna Gwendolyn Zimmermann, Team Leader: Visual System Research
hanna.zimmermann@charite.de

Lukas Reeß, Optometrist

Carla Leutloff, Optometrist

Gilberto Solorza Buenrostro, Physician

MRI Team

Team Leader: Prof. Dr. med. Friedemann Paul

Prof. Dr. med. Friedemann Paul, Team Leader: MRI Team
friedemann.paul@charite.de

Dr. Claudia Paarmann-Chien, Senior Postdoc
claudia.paarmann-chien@charite.de

Dr. Lina Anderhalten, Postdoctoral fellow

Darius Mewes, MD/PhD Student

Henri Trang, PhD Student

Qianlan Chen, PhD Student

Michael Sheel, Neuroradiologist

Susan Pikol, Medical Technical Assistant

Cynthia Kraut, Medical Technical Assistant for Radiology

Adaptive Immunity and Novel Therapies

Team Lead: Dr. Maria Hastermann

Dr. Maria Hastermann, Physician - Team Leader: Adaptive Immunity and Novel Therapies
maria.hastermann@charite.de

Sara Cestari, PhD Student

Melina Quast, MD/PhD Student

Study Assistance Team

Team Lead: Jana Bigall

Jana Bigall, Studynurse Team Lead
jana.bigall@charite.de
studienambulanz-ag-paul@charite.de

Mirjana Mitrovic, Office - Research Outpatient Clinic

Katharina Stößlein, Studynurse - Research Outpatient Clinic

Claudia Messelhäußer, Studynurse - Research Outpatient Clinic

Luisa Kegel, Studynurse - Research Outpatient Clinic

Bibiane Seeger-Schwinge, Medical Technical Assistant - Laboratory

Nora Seelig, Medical Technical Assistant - Laboratory

 

Dr. Lina Samira Bahr, Team Lead Metabolic Team
lina.bahr@charite.de

Dr. Pia Sperber, Team Lead Data Management
pia.sperber@charite.de

Martin Weygandt, Scientist

Susanna Asseyer, Physician

Lil Meyer-Arndt, Physician

 

Neuroimmunological Outpatient Clinic

Neuroimmunological Outpatient Clinic

Team Lead: Dr. med. Judith Bellmann-Strobl

Dr. med. Judith Bellmann-Strobl, Leader Neuroimmunological Outpatient Clinic
judith.bellmann-strobl@charite.de
hochschulambulanz-buch@charite.de

Dr. Uta Hoppmann, Neurologist

Dr. Janina Behrens, Neurologist

Philippe Manceau, Neurologist

Gritt Stoffels, Studynurse

Dr. Joseph Kuchling, Physician

Anja Mähler, Leader Nutritional Consultation

Dr. Nadja Siebert, Neurologist

Elena Steinle, Studynurse

Research

Multiple sclerosis (MS) is the most frequent chronic inflammatory disease of the central nervous system and primarily affects young adults.
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.
 

Publications

News

Patients

Our focus is upon the improvement of the therapeutic and diagnostic possibilities for neuroimmunological diseases, especially for multiple sclerosis.

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.

Clinical Studies

 

Research Outpatient Clinic

 

BERLimmun

Berlin Registry of Neuroimmunological Entities (BERLimmun) - a monocentric prospective observational study on the long-term course of neuroimmunological diseases.

Sponsor: IIT

Recruitment: yes

Local PI: PD Dr. Tanja Schmitz-Hübsch

Study Number: German Clinical Trial Register DRKS00026761

 

Akute ON

Acute Optic Neuritis Study (AON-S), a monocentric, prospective observational study on symptomatology, diagnosis, therapy and prognosis of acute optic neuritis.

Sponsor: IIT

Recruitment: yes

Local PI: Dr. Susanna Asseyer/Prof. Dr. Friedemann Paul

Study Number: NCT05605951

 

COGEMS II

Neural mechanisms of mental and emotional processes in multiple sclerosis and their relevance to disease severity.

Sponsor: IIT

Recruitment: yes

Local PI: PD Dr. Martin Weygandt

 

EFC16645 Hercules BTkI phase iii

A Phase 3, randomized, double-blind, efficacy and safety study comparing SAR442168 to placebo in participants with nonrelapsing secondary progressive multiple sclerosis (HERCULES).

Sponsor: Sanofi

Recruitment: Screening closure 29.11.2022

Local PI: Prof. Dr. Friedemann Paul

Study Number: EudraCT 2020-000647-30 

 

EFC16035 PERSEUS BTkI phase iii

A Phase 3, randomized, double-blind, efficacy and safety study comparing SAR442168 to placebo in participants with primary progressive multiple sclerosis (PERSEUS).

Sponsor: Sanofi

Recruitment: yes

Local PI: Prof. Dr. Friedemann Paul

Study Number: EudraCT 2020-000645-14 

 

GenSeMS Project

Sponsor: IIT

Recruitment: yes

Local PI: Prof. Dr. Stefan Gold

 

HOPE-MS

Clinical validity of confirmed disease progression defined by marker-less home-based assessment of motor function in multiple sclerosis (HOPE-MS).

Sponsor: IIT (Celgene)

Recruitment: yes

Local PI: PD. Dr. Tanja Schmitz-Hübsch

 

Kyrios phase IV

Tracking the immune response to SARS-CoV-2 modRNA vaccines in an open-label multicenter study in participants with relapsing multiple sclerosis treated with ofatumumab s.c. (KYRIOS).

Sponsor: Novartis

Recruitment: closed

Local PI: Prof. Dr. Friedemann Paul

 

WN43194 Satralizumab phase iii (Meteoroid)

A phase III, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of satralizumab as monotherapy or in addition to baseline therapy in patients with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD).

Sponsor: Roche

Recruitment: yes

Local PI: PD. Dr. Tanja Schmitz-Hübsch

Study Number: NCT05271409

 

Study MOG001 (Parexel 247511) phase iii (CosMOG)

A Randomized, double-blind, Placebo-controlled, multicenter Phase 3 pivotal study to evaluate the efficacy and safety of rozanolixizumab to treat adult patients with Myelin Oligodendrocyte Glycoprotein (MOG) Antibody-Associated Disease (MOG-AD).

Sponsor: UCB

Recruitment: yes

Local PI: Prof. Dr. Friedemann Paul

Study number: NCT05063162

 

Motosense

Sensitivity of quantitative motor performance measures in multiple sclerosis – a prospective cohort study over two years using Microsoft Kinect.

Sponsor: IIT

Recruitment: closed

Local PI: Prof. Dr. Friedemann Paul

 

MSIM 7T

7 Tesla MRI in patients with multiple sclerosis and other neuroimmunological disorders.

Sponsor: IIT

Local PI: Prof. Dr. Friedemann Paul

 

PREPARE phase II

Prevention of paclitaxel-related neurologic adverse events with lithium - a randomized, double-blind, placebo-controlled, exploratory proof-of-concept phase II clinical trial for the prevention of chemotherapy-induced neurotoxicity.

Sponsor: IIT

Recruitment: yes

Local PI: Prof. Dr. Matthias Endres

 

QMS (MR Elastographie BCAN)

MR elastography in patients with multiple sclerosis.

Sponsor: IIT

Local PI: Prof. Dr. Ingolf Sack

 

RDoC

Sponsor: IIT

Recruitment: yes

Local PI: Prof. Dr. Stefan Gold/Prof. Dr. Isabel Dziobek

 

PRECOMS Schwangersch. und MS

Database on family planning and pregnancies in multiple sclerosis and Neuromyelitis optica spectrum disease (PreCoMS).

Sponsor: IIT

Local PI: Prof. Dr. Friedemann Paul

 

TempiMS

Specified laboratory investigations in Portugal.

Sponsor: IIT

Recruitment: yes

Local PI: Prof. Dr. Friedemann Paul

 

TregNMO

Regulatory T cells in Neuromyelitis optica.

Sponsor: IIT

Recruitment: yes

Local PI: Dr. Maria Hastermann

 

Valkinect (incl Ataxie)

Determining the accuracy, reliability, validity, and responsiveness of video-operceptive motion analysis with Microsoft Kinect - VALKINECT.

Sponsor: IIT

Recruitment: yes

Local PI: Prof. Dr. Friedemann Paul

 

 

Neuroimmunological Outpatient Clinic (Hochschulambulanz)

 

CFS-CARE

Care Model for Patients with Chronic Fatigue Syndrome (ME/CFS).

Sponsor: IIT

Recruitment: yes

Local PI: Prof. Dr. Carmen Scheibenbogen

 

DMSG MS-Register

Patient registry of the German Multiple Sclerosis Society, Federal Association (DMSG) within the MS Research and Project Development GmbH (MSFP), DMSG MS-Register.

Sponsor: DMSG

Recruitment: yes

Local PI: Prof. Dr. Friedemann Paul

 

PreCoMS

Family planning and pregnancies in multiple sclerosis (PreCoMS)

Sponsor: IIT

Recruitment: yes

Local PI: Dr. Nadja Siebert

Study Number: NCT05010902

 

POST COVID Beobachtungsstudie (PA-COVID-19)

Analysis of the Pathophysiology and Pathology of Corona Virus Disease 2019 (Pa-COVID-19).

Sponsor: IIT

Recruitment: yes

Local PI: Prof. Carmen Scheibenbogen / Dr. Judith Bellmann-Strobl

 

PA-COVID-19-Unterstudie

Dynamic vascular analysis of the retina in the Pa-COVID-19 study.

Sponsor: IIT

Recruitment: yes

Local PI: Prof. Dr. Friedemann Paul

 

VERI-LONG

A study to investigate improvement in physical function in SF-36 with Vericiguat compared with Placebo in participants aged 18 to 50 years with post-COVID-19 syndrome (PCS and PCS/CFS).

Sponsor: IIT (Bayer)

Recruitment: yes

Local PI: Dr. Judith Bellmann-Strobl

Study Number: EudraCT 2021-005494-11   NCT05697640

Friedemann Paul
Prof. Dr. Friedemann Paul
Group Leader
Contact

Neuroscience Clinical Research Center
Charité Campus Mitte

 

Tel:  +49 (0)30 450 539 705
Fax: +49 (0)30 450 539 915
friedemann.paul@charite.de

 

Experimental and Clinical Research Center
Lindenberger Weg 80
13125 Berlin