A researcher in neuroimmunology &
systems biology

science

Toxic protein congests inflamed neurons

Image: Benjamin Schattling

Background

In multiple sclerosis, neurons are confronted with inflammation. However, how neurons react to this challenge and whether their reaction primarily helps or hurts remains unknown.

findings

Inflammation in the nervous system triggers toxic deposition the protein Bassoon in neuronal cell bodies. Pharmacological intervention can dissolve Bassoon aggregates.

contribution

Disease model, computational analysis, data analysis, experimental design, figure design, writing, shared first authorship.

Year

2019

Species

Mouse, Human, Fly

Abstract

Multiple sclerosis (MS) is characterized by inflammatory insults that drive neuroaxonal injury. However, knowledge about neuron-intrinsic responses to inflammation is limited. By leveraging neuron-specific messenger RNA profiling, we found that neuroinflammation leads to induction and toxic accumulation of the synaptic protein bassoon (Bsn) in the neuronal somata of mice and patients with MS. Neuronal overexpression of Bsn in flies resulted in reduction of lifespan, while genetic disruption of Bsn protected mice from inflammation-induced neuroaxonal injury. Notably, pharmacological proteasome activation boosted the clearance of accumulated Bsn and enhanced neuronal survival. Our study demonstrates that neuroinflammation initiates toxic protein accumulation in neuronal somata and advocates proteasome activation as a potential remedy.

Publication

Reference

B. Schattling, J. B. Engler, C. Volkmann, N. Rothammer, M. S. Woo, M. Petersen, I. Winkler, M. Kaufmann, S. C. Rosenkranz, A. Fejtova, U. Thomas, A. Bose, S. Bauer, S. Träger, K. K. Miller, W. Brück, K. E. Duncan, G. Salinas, P. Soba, E. D. Gundelfinger, D. Merkler, M. A. Friese, Bassoon proteinopathy drives neurodegeneration in multiple sclerosis. Nat. Neurosci. 22, 887–896 (2019).

science

Pregnancy fosters disease-specific regulatory T cells

Image: Jan Broder Engler

background

Pregnancy suppresses the disease activity of multiple sclerosis. However, whether pregnancy directly modulates the repertoire of T cell receptors is unclear.

findings

The multiple sclerosis mouse model triggers the usage of disease-specific T cell receptors. Pregnancy boosts disease-specific regulatory T cells, which might support the suppression of disease.

contribution

Computational analysis, experimental planning, data analysis, figure design, writing, shared first authorship.

Year

2019

Species

Mouse

Abstract

Disease activity of autoimmune disorders such as multiple sclerosis and its mouse model experimental autoimmune encephalomyelitis (EAE) is temporarily suppressed by pregnancy. However, whether disease amelioration is due to nonspecific immunomodulation or mediated by Ag-specific regulation of disease-causing conventional T cells (Tcon) and immunosuppressive regulatory T cells (Tregs) remains elusive. In the current study, we systematically analyzed changes of the TCRβ repertoire driven by EAE and pregnancy using TCR sequencing. We demonstrate that EAE, but not pregnancy, robustly increased TCR repertoire clonality in both peripheral Tcon and Treg. Notably, pregnancy was required for the expansion of Treg harboring the dominant EAE-associated TRBV13-2 chain and increased the frequency of EAE-associated clonotypes within the Treg compartment. Our findings indicate that pregnancy supports the expansion of Treg clonotypes that are equipped to recognize EAE-associated Ags. These Treg are thereby particularly suited to control corresponding encephalitogenic Tcon responses and likely contribute to pregnancy-associated protection in autoimmunity.

Publication

Reference

J. B. Engler, N. F. Heckmann, J. Jäger, S. M. Gold, M. A. Friese, Pregnancy Enables Expansion of Disease-Specific Regulatory T Cells in an Animal Model of Multiple Sclerosis. J. Immunol. 203, 1743–1752 (2019).

science

T cell repertoire dynamics during pregnancy in multiple sclerosis

Artwork: dianelavoie.com

background

Pregnancy suppresses the disease activity of multiple sclerosis. However, the impact of pregnancy on the clonal T cells composition in multiple sclerosis patients remains unclear.

findings

Longitudinal assessment of the T cell repertoire in multiple sclerosis patients reveals clonal dynamics compatible with contraction of autoreactive T cells during pregnancy.

contribution

Data analysis, figure design, writing, second authorship.

Year

2019

Species

Human

Abstract

Identifying T cell clones associated with human autoimmunity has remained challenging. Intriguingly, many autoimmune diseases, including multiple sclerosis (MS), show strongly diminished activity during pregnancy, providing a unique research paradigm to explore dynamics of immune repertoire changes during active and inactive disease. Here, we characterize immunomodulation at the single-clone level by sequencing the T cell repertoire in healthy women and female MS patients over the course of pregnancy. Clonality is significantly reduced from the first to third trimester in MS patients, indicating that the T cell repertoire becomes less dominated by expanded clones. However, only a few T cell clones are substantially modulated during pregnancy in each patient. Moreover, relapse-associated T cell clones identified in an individual patient contract during pregnancy and expand during a postpartum relapse. Our data provide evidence that profiling the T cell repertoire during pregnancy could serve as a tool to discover and track “private” T cell clones associated with disease activity in autoimmunity.

Publication

Reference

C. Ramien, E. C. Yusko, J. B. Engler, S. Gamradt, K. Patas, N. Schweingruber, A. Willing, S. C. Rosenkranz, A. Diemert, A. Harrison, M. Vignali, C. Sanders, H. S. Robins, E. Tolosa, C. Heesen, P. C. Arck, A. Scheffold, K. Chan, R. O. Emerson, M. A. Friese, S. M. Gold, T Cell Repertoire Dynamics during Pregnancy in Multiple Sclerosis. Cell Rep. 29, 810–815.e4 (2019).

science

Single nuclei sequencing of multiple sclerosis brains

Image: Jan Broder Engler

Background

Multiple sclerosis leads to neuronal loss and functional impairment. However, insights into human pathology at single cell resolution are hard to obtain.

findings

Single nuclei sequencing of human post mortem brains uncovers cellular stress signatures and differential vulnerability of neuronal subtypes.

contribution

Consultation on data analysis, co-authorship.

Year

2019

Species

Human

Abstract

Multiple sclerosis (MS) is a neuroinflammatory disease with a relapsing-remitting disease course at early stages, distinct lesion characteristics in cortical grey versus subcortical white matter and neurodegeneration at chronic stages. Here we used single-nucleus RNA sequencing to assess changes in expression in multiple cell lineages in MS lesions and validated the results using multiplex in situ hybridization. We found selective vulnerability and loss of excitatory CUX2-expressing projection neurons in upper-cortical layers underlying meningeal inflammation; such MS neuron populations exhibited upregulation of stress pathway genes and long non-coding RNAs. Signatures of stressed oligodendrocytes, reactive astrocytes and activated microglia mapped most strongly to the rim of MS plaques. Notably, single-nucleus RNA sequencing identified phagocytosing microglia and/or macrophages by their ingestion and perinuclear import of myelin transcripts, confirmed by functional mouse and human culture assays. Our findings indicate lineage- and region-specific transcriptomic changes associated with selective cortical neuron damage and glial activation contributing to progression of MS lesions.

Publication

Reference

L. Schirmer, D. Velmeshev, S. Holmqvist, M. Kaufmann, S. Werneburg, D. Jung, S. Vistnes, J. H. Stockley, A. Young, M. Steindel, B. Tung, N. Goyal, A. Bhaduri, S. Mayer, J. B. Engler, O. A. Bayraktar, R. J. M. Franklin, M. Haeussler, R. Reynolds, D. P. Schafer, M. A. Friese, L. R. Shiow, A. R. Kriegstein, D. H. Rowitch, Neuronal vulnerability and multilineage diversity in multiple sclerosis. Nature. 573, 75–82 (2019).

science

Arc amplifies migratory speed across dendritic cell subsets

Image: Friederike Ufer

Background

Arc expression enables fast inflammatory migration in migratory dendritic cells. However, the phylogenetic origin of Arc positive cells remains unclear.

findings

Arc expression is restricted to a small specialized fraction within each migratory dendritic cell subset. These cells are required for fast infectious migration.

contribution

Data discussion, figure design, writing, second authorship.

Year

2017

Species

Mouse

Abstract

The key function of migratory dendritic cells (migDCs) is to take up antigens in peripheral tissues and migrate to draining lymph nodes (dLN) to initiate immune responses. Recently, we discovered that in the mouse immune system activity-regulated cytoskeleton associated protein/activity-regulated gene 3.1 (Arc/Arg3.1) is exclusively expressed by migDCs and is a central driver of fast inflammatory migration. However, the frequency of Arc/Arg3.1-expressing cells in different migDC subsets and Langerhans cells (LCs), their phylogenetic origin, transcription factor dependency, and functional role remain unclear. Here, we found that Arc/Arg3.1+ migDCs derived from common DC precursors and radio-resistant LCs. We detected Arc/Arg3.1+ migDCs in varying frequencies within each migDC subset and LCs. Consistently, they showed superiority in inflammatory migration. Arc/Arg3.1 expression was independent of the transcription factors Irf4 or Batf3 in vivo. In intradermal Staphylococcus aureus infection that relies on inflammatory antigen transport, Arc/Arg3.1 deletion reduced T-cell responses. By contrast, Arc/Arg3.1 deficiency did not hamper the immune response to systemic Listeria monocytogenes infection, which does not require antigen transport. Thus, Arc/Arg3.1 expression is independent of ontogeny and phenotype and although it is restricted to a small fraction within each migDC subset and LCs, Arc/Arg3.1+ migDCs are important to facilitate infectious migration.

Publication

Reference

J. Tintelnot, F. Ufer, J. B. Engler, H. Winkler, K. Lücke, H. W. Mittrücker, M. A. Friese, Arc/Arg3.1 defines dendritic cells and Langerhans cells with superior migratory ability independent of phenotype and ontogeny in mice. Eur. J. Immunol. 49, 724–736 (2019).

science

Progesterone boosts regulatory T cells in pregnancy

Artwork: Jan Broder Engler

Background

Pregnancy conveys temporary protection from multiple sclerosis disease activity. However, the underlying mechanisms are still incompletely understood.

findings

Differential steroid resistence favors regulatory over conventional T cells in the presence of high levels of progesterone.

contribution

Execution of experiments, experimental planning, data analysis, figure design, writing, first authorship.

Year

2017

Species

Mouse

Abstract

Pregnancy is one of the strongest inducers of immunological tolerance. Disease activity of many autoimmune diseases including multiple sclerosis (MS) is temporarily suppressed by pregnancy, but little is known about the underlying molecular mechanisms. Here, we investigated the endocrine regulation of conventional and regulatory T cells (Tregs) during reproduction. In vitro, we found the pregnancy hormone progesterone to robustly increase Treg frequencies via promiscuous binding to the glucocorticoid receptor (GR) in T cells. In vivo, T-cell–specific GR deletion in pregnant animals undergoing experimental autoimmune encephalomyelitis (EAE), the animal model of MS, resulted in a reduced Treg increase and a selective loss of pregnancy-induced protection, whereas reproductive success was unaffected. Our data imply that steroid hormones can shift the immunological balance in favor of Tregs via differential engagement of the GR in T cells. This newly defined mechanism confers protection from autoimmunity during pregnancy and represents a potential target for future therapy.

Publication

Reference

J. B. Engler, N. Kursawe, M. E. Solano, K. Patas, S. Wehrmann, N. Heckmann, F. Lühder, H. M. Reichardt, P. C. Arck, S. M. Gold, M. A. Friese, Glucocorticoid receptor in T cells mediates protection from autoimmunity in pregnancy. Proc. Natl. Acad. Sci. U.S.A. 114, E181–E190 (2017).

science

Dendritic cell mobility depends on Arc

Image: Joseph Tintelnot

background

Migratory dendritic cells continuously surveil their surrounding and deliver antigens to the draining lymph nodes. However, specific markers for this cell type are still missing.

findings

Migratory dendritic cells express high levels of Arc, which boosts their mobility and enables fast inflammatory migration.

contribution

Data analysis, figure design, writing, shared second authorship.

Year

2016

Species

Mouse

Abstract

Skin-migratory dendritic cells (migDCs) are pivotal antigen-presenting cells that continuously transport antigens to draining lymph nodes and regulate immune responses. However, identification of migDCs is complicated by the lack of distinguishing markers, and it remains unclear which molecules determine their migratory capacity during inflammation. We show that, in the skin, the neuronal plasticity molecule activity-regulated cytoskeleton-associated protein/activity-regulated gene 3.1 (Arc/Arg3.1) was strictly confined to migDCs. Mechanistically, Arc/Arg3.1 was required for accelerated DC migration during inflammation because it regulated actin dynamics through nonmuscle myosin II. Accordingly, Arc/Arg3.1-dependent DC migration was critical for mounting T cell responses in experimental autoimmune encephalomyelitis and allergic contact dermatitis. Thus, Arc/Arg3.1 was restricted to migDCs in the skin and drove fast DC migration by exclusively coordinating cytoskeletal changes in response to inflammatory challenges. These findings commend Arc/Arg3.1 as a universal switch in migDCs that may be exploited to selectively modify immune responses.

Publication

Reference

F. Ufer, P. Vargas, J. B. Engler, J. Tintelnot, B. Schattling, H. Winkler, S. Bauer, N. Kursawe, A. Willing, O. Keminer, O. Ohana, G. Salinas-Riester, O. Pless, D. Kuhl, M. A. Friese, Arc/Arg3.1 governs inflammatory dendritic cell migration from the skin and thereby controls T cell activation. Sci Immunol. 1, eaaf8665 (2016).

science

Genetic risk variant of CD226 impairs regulatory T cells

Image: INIMS, Hamburg

background

A genetic variant of the CD226 gene is associated with increased risk of developing multiple sclerosis. However, the mechanism by which this accurs is still unclear.

findings

The risk variant of CD226 leads to reduced CD226 surface espression and impaired regulatory T cell function.

contribution

Animal model, Treg transfer, data analysis, second authorship.

Year

2015

Species

Human, Mouse

Abstract

Recent association studies have linked numerous genetic variants with an increased risk for multiple sclerosis, although their functional relevance remains largely unknown. Here we investigated phenotypical and functional consequences of a genetic variant in the CD226 gene that, among other autoimmune diseases, predisposes to multiple sclerosis. Phenotypically, effector and regulatory CD4(+) memory T cells of healthy individuals carrying the predisposing CD226 genetic variant showed, in comparison to carriers of the protective variant, reduced surface expression of CD226 and an impaired induction of CD226 after stimulation. This haplotype-dependent reduction in CD226 expression on memory T cells was abrogated in patients with multiple sclerosis, as CD226 expression was comparable to healthy risk haplotype carriers irrespective of genetic variant. Functionally, FOXP3-positive regulatory T cells from healthy carriers of the genetic protective variant showed superior suppressive capacity, which was again abrogated in multiple sclerosis patients. Mimicking the phenotype of human CD226 genetic risk variant carriers, regulatory T cells derived from Cd226-deficient mice showed similarly reduced inhibitory activity, eventually resulting in an exacerbated disease course of experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis. Therefore, by combining human and mouse analyses we show that CD226 exhibits an important role in the activation of regulatory T cells, with its genetically imposed dysregulation impairing regulatory T cell function.

Publication

Reference

M. Piédavent-Salomon, A. Willing, J. B. Engler, K. Steinbach, S. Bauer, B. Eggert, F. Ufer, N. Kursawe, S. Wehrmann, J. Jäger, S. Reinhardt, M. A. Friese, Multiple sclerosis associated genetic variants of CD226 impair regulatory T cell function. Brain. 138, 3263–74 (2015).

science

Regulatory T cells control SmD1-reactive T cells in lupus

Image: Pomeranz et al, Nature 2009

background

Autoreactive T cells play an important role in systemic lupus erythematosus. However, their reliable detection remains a technical challenge.

findings

Intracellular CD154 expression can identify autoreactive T cells in the peripheral blood of systemic lupus erythematosus patients after depletion of regulatory T cells.

contribution

Execution of experiments, data analysis, figure design, writing, first authorship.

Year

2011

Species

Human

Abstract

Objective. Autoreactive CD4 T cells specific for nuclear peptide antigens play an important role in tolerance breakdown during the course of systemic lupus erythematosus (SLE). However, reliable detection of these cells is limited due to their low frequency in peripheral blood. The authors assess autoreactive CD4 T cells in a representative SLE collective (n=38) by flow cytometry and study the influence of regulatory T cells (Treg) on their antigenic challenge.

Methods. CD4 T-cell responses were determined according to intracellular CD154 expression induced after 6-h short-term in-vitro stimulation with the SLE-associated autoantigen SmD1(83-119). To clarify the influence of Treg on the activation of autoreactive CD4 T cells, CD25 Treg were depleted by magnetic activated cell sorting before antigen-specific stimulation in selected experiments.

Results. In the presence of Treg, autoreactive CD4 T-cell responses to SmD1(83-119) were hardly observable. However, Treg removal significantly increased the frequency of detectable SmD1(83-119)-specific CD4 T cells in SLE patients but not in healthy individuals. Consequently, by depleting Treg the percentage of SmD1(83-119)-reactive SLE patients increased from 18.2% to 63.6%. This unmasked autoreactivity of CD4 T cells correlated with the disease activity as determined by the SLE disease activity index (p=0.005*, r=0.779).

Conclusions. These data highlight the pivotal role of the balance between autoreactive CD4 T cells and CD25 Treg in the dynamic course of human SLE. Analysing CD154 expression in combination with a depletion of CD25 Treg, as shown here, may be of further use in approaching autoantigen-specific CD4 T cells in SLE and other autoimmune diseases.

Publication

Reference

J. B. Engler, R. Undeutsch, L. Kloke, S. Rosenberger, M. Backhaus, U. Schneider, K. Egerer, D. Dragun, J. Hofmann, D. Huscher, G. R. Burmester, J. Y. Humrich, P. Enghard, G. Riemekasten, Unmasking of autoreactive CD4 T cells by depletion of CD25 regulatory T cells in systemic lupus erythematosus. Ann. Rheum. Dis. 70, 2176–83 (2011).

blog

Hertie Neuroscience Network

Year

2020

I am excited to be part of the Hertie Network of Excellence in Clinical Neuroscience, which just started in June 2020 with its first symposium in Heidelberg. Thanks to the organizers for an inspiring meeting and the chance to participate remotely via video calling.

Within the network, six selected excellent research sites are initially supported for three years. The five million euros provided in the first funding period mainly support the Hertie Academy of Clinical Neuroscience, which will promote four scientific fellows per location.

In my project I will focus on viral delivery of neuroprotection against inflammation. Make sure to also checkout the other fellows from the Hertie Network Hamburg and the other sites in the Hertie Network of Excellence in Clinical Neuroscience.

blog

Corona Dashboard

Image: The Biodiversity Heritage Library

Year

2020

The Coronavirus disease (COVID-19) outbreak in winter 2019/2020 had an immediate impact on the lives of millions of people around the globe. At the same time many data scientist, including me, started to analyze publicly available data in an attempt to get a feeling for the extent of the crisis.

The most easily accessible data are undoubtedly epidemiological measures that are collected and published by academic and governmental institutions. For me, these data were the starting point to look into the dynamics of the disease with a focus on Germany, Europe and the World.

Thanks to the great open-source tools in the R ecosystem, conducting and publishing such an analysis has become incredibly straightforward. I chose the great bookdown package by Yihui Xie as a framework and compiled the status quo, outbreak kinetics, case mortality and containment of disease in a concise and regularly updated Corona report.

Of course my report is far from being exhaustive and in the meantime data science teams around the world have been busy to create an unmanageable variety of corona data visualizations. Two of them I would like to highlight here. 1) Our world in data is always a good starting point, both as a resource for raw data as well as for carefully conducted data analysis. 2) The Financial times had a very informative look at local excess deaths relative to previous years, representing a very solid measure that is widely independent of diagnostic testing and reporting practices.

blog

Heatmaps from tidy data

Image: The Biodiversity Heritage Library

Year

2019

The clarity and ease of use of the tidyverse ecosystem spearheaded by Hadley Wickham made it an essential tool for a whole generation of data scientists working with R. The concept of tidy data and its manipulation has proven to be so intuitive and powerful that many people, including me, would not like to miss it.

In case you have not come across the tidyverse yet, I highly recommend the free online book R for Data Science. I guess, it is save to say that this book permanently changed the way I do analysis every day.

However, if you adopted the tidyverse philosophy, you really feel the pain when you are forced to go back to data types like matrices and lists, for example when constructing gene expression heatmaps. As this is a task I am frequently confronted with, I developed my first R package called tidyheatmap that allows you to easily plot complex heatmaps from tidy data. It includes straightforward formatting, annotation, clustering and scaling with just a few additional key strokes.

Finally, I want to give a really big shout-out to Raivo Kolde who developed the great pheatmap package, which is doing all the heavy lifting behind the scenes of tidyheatmap.

blog

Dr. Martini Prize

Year

2018

I am very honored to receive the Dr. Martini Prize, handed over by Hamburg Senator for Science, Research and Equality, Katharina Fegebank, for my work on immune regulation during pregnancy.

The Dr. Martini Prize is the oldest medical prize in Germany. Since 1883 it has been awarded annually on February 12, the anniversary of Erich Martini’s death. The prize is dedicated to the “promotion of young scientists” and is awarded by the Dr. Martini Foundation to scientists who work in Hamburg hospitals and are engaged in basic clinical research and new therapeutic approaches.

About

Jan Broder Engler is a postdoctoral fellow at the Institute of Neuroimmunology and Multiple Sclerosis at the Universitätsklinikum Hamburg-Eppendorf.

During his medical studies at the Charité – Universitätsmedizin Berlin he joined the group of Gabriela Riemekasten for T cell autoimmunity at the German Rheumatism Research Centre Berlin. He received his MD in 2010 for investigating T cell responses to a nuclear autoantigen in systemic lupus erythematosus1.

After completing his studies in Berlin he joined the group of Manuel Friese at the Institute of Neuroimmunology and Multiple Sclerosis in Hamburg and focussed on mechanisms of pregnancy-induced immune tolerance in multiple sclerosis2. While working on this topic he was involved in several immunological projects3–5 and received his PhD in human biology in 2015.

Sparked by a workshop at the The European Bioinformatics Institute in 2014, he got fascinated by systems biology. He began to establish laboratory and computational workflows for transcriptomics, single-cell transcriptomics and epigenetics in the lab. Using these techniques, he investigated neuronal responses to inflammation and their consequence for neuronal survival6,7. Moreover, he applied T cell receptor sequencing to characterize the suppression of multiple sclerosis by pregnancy8,9.

Currently, Broder works on neuronal injury and develops strategies to equip neurons with countermeasures against stress and inflammation. Since 2020 he is a fellow of the Hertie Academy of Clinical Neuroscience.

For his data analyses and visualizations he strongly relies on the ecosystem around the programming language R, for which he develops open source software tools.

Selected publications

1. J. B. Engler, R. Undeutsch, L. Kloke, S. Rosenberger, M. Backhaus, U. Schneider, K. Egerer, D. Dragun, J. Hofmann, D. Huscher, G. R. Burmester, J. Y. Humrich, P. Enghard, G. Riemekasten, Unmasking of autoreactive CD4 T cells by depletion of CD25 regulatory T cells in systemic lupus erythematosus. Ann. Rheum. Dis. 70, 2176–83 (2011).

2. J. B. Engler, N. Kursawe, M. E. Solano, K. Patas, S. Wehrmann, N. Heckmann, F. Lühder, H. M. Reichardt, P. C. Arck, S. M. Gold, M. A. Friese, Glucocorticoid receptor in T cells mediates protection from autoimmunity in pregnancy. Proc. Natl. Acad. Sci. U.S.A. 114, E181–E190 (2017).

3. M. Piédavent-Salomon, A. Willing, J. B. Engler, K. Steinbach, S. Bauer, B. Eggert, F. Ufer, N. Kursawe, S. Wehrmann, J. Jäger, S. Reinhardt, M. A. Friese, Multiple sclerosis associated genetic variants of CD226 impair regulatory T cell function. Brain. 138, 3263–74 (2015).

4. F. Ufer, P. Vargas, J. B. Engler, J. Tintelnot, B. Schattling, H. Winkler, S. Bauer, N. Kursawe, A. Willing, O. Keminer, O. Ohana, G. Salinas-Riester, O. Pless, D. Kuhl, M. A. Friese, Arc/Arg3.1 governs inflammatory dendritic cell migration from the skin and thereby controls T cell activation. Sci Immunol. 1, eaaf8665 (2016).

5. J. Tintelnot, F. Ufer, J. B. Engler, H. Winkler, K. Lücke, H. W. Mittrücker, M. A. Friese, Arc/Arg3.1 defines dendritic cells and Langerhans cells with superior migratory ability independent of phenotype and ontogeny in mice. Eur. J. Immunol. 49, 724–736 (2019).

6. B. Schattling, J. B. Engler, C. Volkmann, N. Rothammer, M. S. Woo, M. Petersen, I. Winkler, M. Kaufmann, S. C. Rosenkranz, A. Fejtova, U. Thomas, A. Bose, S. Bauer, S. Träger, K. K. Miller, W. Brück, K. E. Duncan, G. Salinas, P. Soba, E. D. Gundelfinger, D. Merkler, M. A. Friese, Bassoon proteinopathy drives neurodegeneration in multiple sclerosis. Nat. Neurosci. 22, 887–896 (2019).

7. L. Schirmer, D. Velmeshev, S. Holmqvist, M. Kaufmann, S. Werneburg, D. Jung, S. Vistnes, J. H. Stockley, A. Young, M. Steindel, B. Tung, N. Goyal, A. Bhaduri, S. Mayer, J. B. Engler, O. A. Bayraktar, R. J. M. Franklin, M. Haeussler, R. Reynolds, D. P. Schafer, M. A. Friese, L. R. Shiow, A. R. Kriegstein, D. H. Rowitch, Neuronal vulnerability and multilineage diversity in multiple sclerosis. Nature. 573, 75–82 (2019).

8. J. B. Engler, N. F. Heckmann, J. Jäger, S. M. Gold, M. A. Friese, Pregnancy Enables Expansion of Disease-Specific Regulatory T Cells in an Animal Model of Multiple Sclerosis. J. Immunol. 203, 1743–1752 (2019).

9. C. Ramien, E. C. Yusko, J. B. Engler, S. Gamradt, K. Patas, N. Schweingruber, A. Willing, S. C. Rosenkranz, A. Diemert, A. Harrison, M. Vignali, C. Sanders, H. S. Robins, E. Tolosa, C. Heesen, P. C. Arck, A. Scheffold, K. Chan, R. O. Emerson, M. A. Friese, S. M. Gold, T Cell Repertoire Dynamics during Pregnancy in Multiple Sclerosis. Cell Rep. 29, 810–815.e4 (2019).