Chronic inflammation of the central nervous system (CNS) is caused by sustained activation of CNS cells such as microglial and astrocytes, and recruitment and activation of other peripheral and tissue-resident immune cells within the brain. This persistent inflammation can lead to progressive brain damage, impaired neuronal function and eventually to severe disability and cognitive weakening.
The Infante-Duarte lab focuses on the pathophysiology of chronic CNS damage, in particular in multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD). We want to understand how components of the immune system contribute to CNS inflammation and neurodegeneration. Moreover, we investigate how brain inflammation affects structures of the brain extracellular matrix and develop matrix-related non-invasive imaging tools (principally MR-based approaches) for monitoring progression and therapy response in neuroinflammation.
Prof. Dr. Carmen Infante Duarte
Alba Del Rio Serrato
Maria E. Schröder
Rafaela Vieira da Silva
MD/ MD-PhD Students
Innate lymphoid cells (LCs) constitute a new family of innate immune cells that act as important modulators of the immune response. The ILC compartment comprises a highly heterogeneous group of cells that have been divided into five subsets based on their developmental pathways and their phenotypical and functional profiles: cytotoxic NK cells, helper-like ILC1, ILC2 and ILC3s and LTi cells.
We have shown evidence for deficient NK cell activity in patients with MS, suggesting that NK cells may have a protective, disease-limiting role in neuroinflammation. However, both beneficial as well as detrimental roles for NK cells have been found in studies using EAE. Since former studies made no distinction between the heterogeneous group 1 ILC compartment that includes NK and also ILC1, we further hypothesized that the apparent conflicting results may also originate from the lack of proper discrimination between the different ILC subtypes. Although ILCs have been reported to be present predominantly in barrier and mucosal tissues, we and others have reported that in steady-state conditions, the adult CNS also contains infiltrating and resident ILCs (predominantly ILC2s and group 1 ILCs). These ILCs are located in both, parenchymal and non-parenchymal structures, and display a strict tissue compartmentalization (parenchyma, perivascular spaces, subdural meninges and choroid plexus). Furthermore, these ILCs seem to start infiltrating the brain during early stages of development and do not re-circulate.
Thus, our line of research focuses on the study of the formation and heterogeneity of the CNS-ILC compartment, and its role in the development and maintenance of tissue homeostasis of the CNS. Furthermore, we study the immunomodulatory roles of ILCs in the context of neuroinflammation as the one observed during MS and its experimental autoimmune mouse model, the EAE.
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Neuromyelitis optica spectrum disorders (NMOSD) are a group of severe antibody-mediated autoimmune diseases of the CNS, long believed to be rare variants of MS. Serum autoantibodies against aquaporin-4 (AQP4-IgG) are found in ≥ 80 % of NMOSD patients. Around 10-40% of AQP4-IgG seronegative NMOSD patients are seropositive for autoantibodies against myelin oligodendrocyte glycoprotein (MOG-IgG) and suffer from the newly described (MOG)-associated disease (MOGAD). Increasing evidence suggests a contribution of both innate and adaptive immune components to the inflammatory cascade inside the CNS. In this line, we previously showed that NMOSD neutrophils display deficient functionalities such as reduced fMLP-induced neutrophil migration and oxidative burst.
Currently, we are investigating immune alterations, in particular affecting B cell and neutrophil functionality, that may contribute to the pathophysiology of NMOSD and MOGAD. We hypothesized that neutrophils from patients may have a deficient response to death stimuli and, therefore, accumulate within the brain tissue and contribute to the inflammation. In our more recent project, cell death of neutrophils from patients and healthy controls are being investigated in an in-vitro set-up.
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The extracellular matrix (ECM) is a complex and specialized compartment composed of a network of glycosaminoglycans (GAGs), proteoglycans and glycoproteins that mediates diverse cellular and molecular processes. In multiple sclerosis, the brain matrix has emerged as an important player in disease pathogenesis. Thus, we hypothesize that inflammation-related ECM alterations are excellent targets to in-vivo image tissue pathology in the course of autoimmune neuroinflammatory disorders, such as MS and its animal model of experimental autoimmune encephalomyelitis (EAE).
In our previous work, we showed that, during brain inflammation, very small superparamagnetic iron oxide nanoparticles (VSOP) bind to modified GAGs on activated brain endothelial cells and ECM. Using the VSOP we also demonstrated that VSOP reveals pathological alterations in the choroid plexus. Furthermore, we showed that non-invasive multifrequency magnetic resonance elastography (MRE) detect and quantify in vivo neuropathological changes based on the biomechanical properties of brain tissue. Moreover, our more recent data indicated that MRE senses sex-specific features of the brain tissue as well as specific alterations of the CNS matrix during brain inflammation, which are also visualized by VSOP but not by gadolinium-based contrast agents.
Currently, we are investigating the nature and reversibility of ECM modifications occurring during neuroinflamation and the possibility to image those change in vivo by MRE and/or nanoparticle- or contrast agent-based MRI.
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Free radicals generated in the context of neuroinflammatory processes are known to cause mitochondrial damage and impair mitochondrial transport in axons. We therefore hypothesize that under inflammatory conditions and subsequent oxidative stress, defective transport and function of mitochondria may contribute to neuronal damage.
As part of this project, we investigate the influence of oxidative stress on the motility, morphology and functionality of axonal mitochondria in a model of ex vivo explanted spinal nerve roots and in acute brain sections.
We were able to show that oxidative stress leads to reduced axonal transport as well as to changes in mitochondrial morphology and functionality, both in the spinal root and the brain section models. Our investigations are now aimed at elucidating the mechanism of mitochondrial impairments as well as evaluating new treatment strategies for neuroprotection in our ex vivo models.
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