Characterization of the invasion of hematopoietic myeloid cells into the CNS during EAE

by Michael Haberl
Doctoral thesis
Date of Examination:2021-12-20
Date of issue:2022-12-01
Advisor:Prof. Dr. Alexander Flügel
Referee:Prof. Dr. Alexander Flügel
Referee:Prof. Dr. Dr. Hannelore Ehrenreich
Persistent Address: http://dx.doi.org/10.53846/goediss-9586

 

 

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Abstract

English

Experimental autoimmune encephalomyelitis (EAE), the classical animal model of multiple sclerosis, is caused by T cells directed against myelin antigens. Upon intravenous transfer, these cells appear in the vessels of the blood-brain-barrier (BBB) where they crawl extensively before entering the CNS. Once in the target tissue these cells are locally reactivated and start an inflammatory process leading to further recruitment of other inflammatory cells such as myeloid cells. Myeloid cells are known to play an important role in the effector phase of the disease, however, how they move in the vessels of the BBB, and which are the molecular cues that determine their motility is still not fully understood. Using intravital two-photon microscopy in Lewis rat EAE, we analyzed simultaneously the migratory behavior of encephalitogenic T cells and monocytes at the BBB. We show that these immune cell populations exhibit complex motility behavior that could not be depicted by standard motility analysis. Using a newly developed analysis based on unsupervised machine-learning, we found that monocytes and autoaggressive T cells employed heterogeneous motility patterns and these migratory patterns were distinct between the two immune cell populations. To identify the molecular cues shaping these motility patterns, we functionally interfered with integrins and chemokines. We found that not only the observed motility phenotypes responded differently to the interfering strategies but also this response was distinct between monocytes and T cells. Using our newly developed analysis system, we investigated how mechanical cues of the vasculature shape immune cell motility patterns and found that hemodynamic properties have a negligible effect on the motility of immune cells. In summary, our advanced motility analysis revealed that immune cell motility behavior at the BBB is guided by different rules. More importantly, immune cell subsets seem to be heterogeneous in themselves, reflected by their motility phenotype profiles, and in their usage of molecular cues. In-depth molecular characterization of these immune cell subsets is crucial for designing better therapeutic strategies in MS.
Keywords: EAE; experimental autoimmune encephalitis; neuroimmunology; T cell motility; MS; multiple sclerosis
 
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