Immunology
Our immunological studies focus on what provokes autoimmunity. We aim to decipher the deregulated cell types in multiple sclerosis and other neuroimmunological diseases and here in particular T cells and dendritic cells. We want to understand the molecules that serve as regulators of immune cell function and the effector molecules that invigorate an autoimmune response. In addition, learning from evolution, e.g. by understanding how pregnancy and sex differences shape immune responses, will help the quest for novel immunomodulatory treatments for neuroimmunological diseases.
Dendritic cells coordinate the innate and adaptive immune response. Therefore, they are involved in the initiation of an
autoimmune response. However, many fundamental questions are still unanswered and the mechanisms how they induce an autoimmune
response are ill defined. By using specific transgenically modified mouse lines and models we study how different molecular
regulators coordinate the activation, migration and function of DCs. This understanding will help us to devise approaches to treat or
prevent autoimmune diseases, such as multiple sclerosis.
Friese Group
T lymphocytes can be divided into CD4+ and CD8+ T cells, of which CD8+ T cells predominate in multiple sclerosis lesions.
However, the precise role of CD8+ T cells in the disease aetiology and pathogenesis is still not understood. Especially it is
unknown which antigens CD8+ T cells infiltrating the brain recognise with their diverse T cell receptors (TCR). Furthermore,
mechanisms leading to their dysregulation and brain infiltration remain to be defined. Besides conventional CD8+ T cells
carrying diverse TCRs, we and others recently discovered the presence of T cells with an invariant, very restricted TCR
repertoire in multiple sclerosis lesions. These cells are evolutionarily conserved, abundant in humans and are named due to their first discovery at sites of mucosal tissue, mucosa-associated invariant T (MAIT)
cells. We aim to define the role of conventional CD8+ T cells and MAIT cells in multiple sclerosis and to unravel, how
they are regulated and what they recognise. reAnother T cell subset likely involved in MS pathogenesis are regulatory CD4+ T cells. Their dysfunction
in multiple sclerosis leads to an insufficient inhibition of auto-aggressive T cell responses. Therefore, we aim to understand the mechanisms of their dysfunctional state. We ask, which functional pathways of suppression can be exploited as therapeutic strategy to regain tolerance in multiple sclerosis.
Friese Group
Females are two to three times more often affected by multiple sclerosis than males. Moreover, pregnancy in female multiple sclerosis patients is associated with a substantial decrease in relapse rate. However, post-partum the relapse rate increases in a rebounding fashion above the rate seen before pregnancy. Currently we do not understand the
biological mechanisms underlying the sexual dimorphism and pregnancy-related effects in multiple sclerosis. We aim at deciphering these powerful,
evolutionary-driven regulatory pathways of immunomodulation and at exploiting them to inform novel therapeutic approaches in multiple sclerosis patients. We currently focus on the role of hormones and genetic factors in T cell regulation, and in shaping the immune repertoire using animal models and cohort studies with multiple sclerosis patients and healthy individuals.
Friese Group Heesen Group
Neurobiology
Inflammatory insults lead to progressive degeneration of axons and neurons that is key for the development of permanent neurological disability in chronic inflammatory diseases such as multiple sclerosis. Our neurobiological studies focus on the molecular mechanisms of this inflammation-induced neuronal degeneration. Stress response pathways can determine neuronal injury, but hormetic stress also stimulates signalling pathways that enhance the abilities of neurons to resist inflammatory stressors. Thus, we aim at discovering conserved molecular pathways that enhance neuronal resilience. Inhibiting damaging pathways or reinforcing protective pathways may lead to the development of novel interventions for neurodegenerative disorders. We aim at identifying, understanding and modulating these key pathways in neurons to ameliorate neurodegeneration in multiple sclerosis and other neurodegenerative diseases.
While great progress has been made in understanding and controlling the inflammatory component of the disease, the pathophysiological mechanisms of neuroaxonal injury are still not understood and only poorly affected by immunomodulatory drugs. Pathological mechanisms of inflammation-induced neuroaxonal injury include oxidative stress, mitochondrial dysfunction and ion channel activity. We study how energy shortage can be counteracted by improving neuronal energy production or optimising energy consumption. Moreover, we identified several different neuronal ion channels, such as acid-sensing ion channel 1 (ASIC1), transient receptor potential melastatin 4 (TRPM4) cation channel and voltage-gated sodium channels that show an enhanced activity during CNS inflammation. More recently, we focussed on inflammatory-induced disturbances of neuronal protein turnover with toxic protein accumulations. As MS shows a predictable temporo-spatial pathological evolution of clinical progression we investigate whether protein accumulation and aggregation and its propagation could explain the progression of neuronal degeneration in MS, as has been postulated in primary neurodegenerative diseases, such as Alzheimer’s, Parkinson’s or Huntington’s disease. We study additional ion channels and G-protein coupled receptors and their involvement in this process as well as their disturbed downstream signalling pathways that drive both neuronal resistance and injury.
Friese Group
We study the mechanisms that drive endothelial and neuronal dysfunction in infectious diseases associated with neurological complications, such as cerebral malaria and viral encephalitis. Malaria is the most prevalent febrile illness worldwide and is caused by a parasite that is transmitted by mosquitos. Cerebral malaria refers to brain dysfunction in parasitaemic patients and is associated with high rates of morbidity and mortality. Similarly, encephalitis, an acute inflammation of the brain that is predominantly caused by viral infections results in widespread neuronal damage. We focus on understanding the molecular mechanisms that drive neuronal injury in cerebral malaria and viral encephalitis, with the ultimate goal to decipher the mechanisms that govern permissiveness or resistance of the central nervous system that can be translated into novel strategies of prevention, diagnosis and/or treatment. These studies are jointly run in collaboration with the group of Prof. Thomas Jacobs at the Bernhard Nocht-Institute for Tropical Medicine (BNITM) in Hamburg.
Friese Group Heesen Group
Evolutionary drive of physical abilities has resulted in optimized brain function by exercise and dietary energy restriction. Such energetic challenges result in an adaptation of neuronal stress-response pathways with mitochondrial biogenesis and increased neuronal resistance to stressors. Since chronic inflammation during multiple sclerosis results in an overload of neuronal stressors and dysfunction of mitochondria, we explore how behavioural interventions like exercise, diet and exposure to hypoxia can ameliorate neurodegeneration during multiple sclerosis and possibly other neurodegenerative diseases. Besides studying these processes on a molecular level, we analyse the impact of exercise and hypoxia on clinical outcomes in multiple sclerosis patients in clinical trials.
Friese Group Heesen Group
Target identification is a critical step in the drug discovery and development process, however even more critical is the development of lead compounds inhibiting the target molecule. In order to expedite development of new drugs with neuroprotective potentials by targeting newly identified neuronal pathways leading to inflammation-induced neurodegeneration, we teamed up as a partner of the consortium NEU2 with pharmaceutical (MerckSerono) and biotech companies (Evotec, Fraunhofer IME SP) and aim at identifying compounds, which we can test in pre-clinical models. This has led to promising compounds with preclinical neuroprotective activity in in vivo models of inflammation-induced neurodegeneration that will be further developed within additional consortia efforts.
Friese Group
Systems Biology
Understanding the mechanisms by which neurons alter and maintain their molecular signatures during inflammation is fundamental in understanding their injury. Similarly, autoimmunity changes cellular states by altering gene and protein expression in certain immune cell subtypes. High dimensional readouts such as next-generation sequencing and single cell sequencing, as well as proteomics enable us not only to analyse the complete molecular signatures of cells but also the cascade of events that defines cellular dysfunction or injury. Therefore, we use systems biology to get a comprehensive description of molecular and cellular components and their interactions in neurons and immune cells to predict disease processes (biomarker development) but also to identify novel master regulators of disease, which could be interesting targets for future drug development.
Identification of reliable diagnostic and prognostic biomarkers would enable treatment to be personalized so that patients destined to experience aggressive disease could receive appropriately potent therapies directly from diagnosis, while those who will experience more benign disease are not exposed to the risks and side effects of unnecessary immunomodulation. Using bulk, as well as single cell transcriptional and microRNA profiling of circulating immune cells isolated from multiple sclerosis patients with clearly defined disease courses, we aim at identifying distinguishable biomarkers. Furthermore, we expect to identify currently unknown mechanistic pathways contributing to the dysregulation of different immune cell subsets in multiple sclerosis. Certain aspects are jointly analysed with the Fraunhofer IME SP.
Friese Group
After neuronal sensing of inflammation downstream signalling pathways will be activated that drive both neuronal resilience and injury. Thus, accessing the dynamics of gene expression programs during the course of inflammation is a promising approach to identify potentially protective or injurious signalling networks. Here we analyse the neuronal epigenome, transcriptome, miRNome and proteome to decipher novel target structures for neuroprotective treatment strategies.
Friese Group
Clinical Research
Based on the concept of health as an ability to adapt to changing personal and environmental settings, clinical research at the INIMS aims to develop treatments with a comprehensive approach. Therefore, clinical care and research includes assessment and consideration of psychological and psychosocial aspects of multiple sclerosis as well as educational (i.e. evidence-based patient information), behavioural (i.e. psychological) and lifestyle (i.e. exercise) interventions. Moreover, we pursue phase I and phase II treatment trials combined with mechanistic laboratory studies in the area of unmet clinical needs such as safe treatments in early MS (i.e. boswellic acids, immunological tolerance induction), highly immunosuppressive approaches for aggressive MS (i.e. autologous hematopoietic stem cell transplantation) but also neuroprotective concepts (i.e. erythropoietin). Complementing this approach, we conduct research to improve assessment tools, develop novel outcome parameters with clinical relevance, and optimize study designs.
Autonomy preferences, risk perception, risk knowledge and factors relevant for medical decision making differ between different patient groups. We study approaches of decision support in a European network to enhance patient autonomy. Online tools are increasingly used; upcoming projects focus on education about the relevance of MRI, motherhood choice and pregnancy management. Moreover, we pursue adherence determining factors and interventions as well as illness narratives as decision support factors.
Heesen Group
Patients with multiple sclerosis are at high risk for depression and cognitive impairment including difficulties with memory and information processing. We study the role of inflammatory and neurodegenerative processes for the pathogenesis of these impairments by combining clinical assessments with neuroimaging of relevant brain circuits and laboratory studies using techniques from molecular biology, immunology and endocrinology. We focus on how the brain communicates with the immune system (brain-immune-endocrine networks) and how disturbances in these networks can give rise to difficulties in higher-order brain functions such as cognition and mood regulation. Neuropsychiatric symptoms might be the most disabling factors and have a considerable impact on activity and participation. As only few therapeutic options are available, there is an unmet need to develop novel approaches including highly standardised psychological interventions that can be implemented at a larger scale in MS. We develop interventions that are accompanied with mechanistic investigations.
Heesen Group
Behavioural interventions that target aspects of well-being and lifestyle can be effective in increasing quality of life, reducing neuropsychiatric symptoms and may also have some effects on pathobiological processes in MS. However, they often require highly trained specialists and are thus strongly limited in their scalability and are not available to most patients with MS. We are developing novel, internet-based eHealth applications that can be tailored to the individual patient’s needs and preferences and test their efficacy on psychological as well as biological outcomes in randomised controlled trials.
Heesen Group
Adherence to any kind of long-term treatment in chronic disease is a major health issue while on the other hand adherence to a protective lifestyle presumably has substantial impact on the brain. We explore factors being relevant for behaviour change and maintenance of behaviour change.
Heesen Group
Currently exercise is the most effective neuroprotective treatment but disease-stage adapted format and dosing as well as mechanisms and long-term effectiveness are ill defined. We study exercise with clinical, imaging, neurophysiologic and molecular approaches.
Heesen Group Friese Group
We evaluate molecular approaches by conducting investigator-initiated trials for presumably safe but also for aggressive therapies. Immune tolerance induction is a focus in early disease, while autologous stem cell transplantation is investigated in early highly aggressive multiple sclerosis. Development of clinical trial designs (baseline-to-treatment and adaptive study designs) addresses the problem of recruitment to studies while licensed treatment already exists. Outcome research aims at improving the sensitivity and clinical meaningfulness of study endpoints by following triangulation of measurements: objective (e.g. MRI, optical coherence tomography, OCT), rate-based (e.g. walking test) and patient-reported (e.g. quality of life). We have also started to establish driving simulation as an ecological valid monitoring tool of cognitive functioning. Every clinical study is accompanied by elaborated mechanistic cellular and/or molecular studies to identify mechanisms of effectiveness or failure.
Heesen Group
Clinical research has a strong commitment to engage in early trials for neuroprotective treatments especially from
investigator-initiated trials. We work on improvement of outcomes and designs for these approaches with a focus on structural
MRI, OCT and elaborated clinical outcome such as accelerometry and computer-based contrast sensitivity but also new cognitive
measures such as social cognition.
Heesen Group
Imaging Research
Magnetic resonance imaging is the most promising approach to monitor subclinical disease activity in several neurological diseases including multiple sclerosis. At the INIMS, we aim to improve the understanding of integrity, structural and functional organisation of the brain and its adaptive or regenerative mechanisms by developing and validating new imaging techniques. Natural history cohorts and randomised controlled trials provide an ideal and translational framework to establish such techniques as a methodical link between disability progression and the underlying pathology. Moreover, multiple sclerosis can be seen as model disease that instructs our understanding of the structure and functional organisation of the healthy brain. Further research activities include the development of new post-processing algorithms, as well as the investigation of Optical Coherence Tomography (OCT) as an additional imaging method of neurodegeneration.
In general, standard MRI techniques only provide information on gross pathology in multiple sclerosis and allow us to visualize e.g. multiple sclerosis lesions within the brain and spine. Nevertheless, it is known that there are also more subtle changes within the brain parenchyma that cannot be detected with these standard techniques. We therefore aim to develop and test new MRI techniques that might increase the sensitivity to detect and visualize changes beyond the tip of the iceberg. In the future, this might enable us to better estimate and monitor disease progression and treatment effects.
Heesen Group
One aim of our research is to better detect, understand and classify pathologic changes within the brain in vivo and determine its topological association with disability. In natural history cohorts, we investigate the impact of neurodegeneration, inflammatory disease activity and functional adaption on long-term disease courses. Here, we combine new MRI techniques with high-end clinical outcomes such as mobile accelerometry or extensive neuropsychology. The overarching aim is to develop a toolbox of outcomes that is sensitive and specific for real-life functioning in multiple sclerosis patients, is suitable for personalised risk profiling and improves the explanatory power of clinical studies. Our special interest is the interaction between functional and structural networks and how connectivity changes mirror physiological processes, e.g. associated with healthy aging, or represent a multiple sclerosis specific pathology
Heesen Group
Due to the heterogeneity of multiple sclerosis, monitoring of disease activity and neurodegeneration needs to take a global perspective. For example, visual impairment is a common symptom of neuroimmunological diseases such as multiple sclerosis or neuromyelitis optica spectrum disorders (NMOSD). Combining diagnostic methods allows studying the integrity of the whole visual system from different perspectives: Visual functioning questionnaires address the patients daily functioning, advanced vision testing provides objective estimates of the vision impairment and retinal nerve layers in the OCT give detailed information of neurodegenerative processes. Visual evoked potentials and MRI can detect structural and functional alterations in the primary visual system. Using fMRI tasks and neuropsychology extend the basic visual functions towards higher cognitive abilities. Investigating the complex interactions in healthy individuals and patients provides new insights at the intersection between fundamental neuroscience, neuroimmunology and clinical care.
Heesen Group
