Immunopathogenesis of cortical demyelination in Multiple Sclerosis
Nielsen Lagumersindez Denis
Doctoral thesis
Date of Examination:
2015-11-09
Date of issue:
2015-11-20
Advisor:
Nessler, Stefan Dr.
Referee:
Brück, Wolfgang Prof. Dr.
Referee:
Reichardt, Holger Prof. Dr.
Persistent Address: http://hdl.handle.net/11858/00-1735-0000-0028-8638-F
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Abstract
English
Cortical demyelination is a key pathological feature of multiple sclerosis (MS) and clinically linked to cognitive deficits and disability progression. Extensive band-like subpial demyelination is even a specific feature of the disease. However, the immunological mechanisms driving cortical demyelination have not yet been defined due to a lack of cortical pathology in the classical experimental models of MS. To elucidate the immunopathogenesis of cortical demyelination, we developed a novel mouse model with subpial and perivascular cortical MS-like lesions. We demonstrate that in addition to a pathogenic anti-myelin antibody response, perivascular cortical demyelination is primarily dependent on activated encephalitogenic T cells, natural killer (NK) cells and CCR2+ inflammatory monocytes. In contrast, subpial cortical demyelination occurs independently of activated T cells, but requires specific antibodies and a fully functional complement cascade. To translate the results obtained into a treatment option for MS, we evaluated the therapeutic efficacy of a humanized mouse anti-human CCR2 antibody, which efficiently depletes CCR2+ monocytes in marmosets with experimental autoimmune encephalomyelitis (EAE). Depleting inflammatory monocytes was well tolerated and significantly reduced cortical demyelination in marmoset monkeys with EAE. Our findings thus delineate a differential involvement of immunological effector mechanisms in perivascular and subpial cortical lesion formation, shed light on the exquisite vulnerability of subpial cortical tissue in multiple sclerosis and translate into a preclinical treatment approach for cortical demyelination.
Keywords: cortical demyelination; multiple sclerosis; EAE; stereotactic injection; transgenic mouse model; marmoset
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Molekulare Medizin [169]