Paul Lab

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)

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.

Research Line