- Complement in neuroinflammation
- Studies in leprosy and Amyotrophic Lateral Sclerosis
- Award date
- 24 January 2017
- Number of pages
- Document type
- PhD thesis
- Faculty of Medicine (AMC-UvA)
The complement system is a part of the innate immunity, and plays an important role in host immunity and inflammation. We previously identified the terminal membrane attack complex (MAC) of the complement system as a key determinant of neurodegeneration and demonstrated that its inhibition is neuroprotective. Besides being part of a mechanism of defence to invading pathogens, MAC has the capacity to cause damage to self-cells and is consequently implicated in many diseases.
I describe studies on two diseases, Amyotrophic lateral sclerosis (ALS) and leprosy, both with severe impact on the nervous system. ALS is a progressive neurodegenerative disease, leading to muscle atrophy and eventually death. Leprosy is a chronic debilitating disease caused by Mycobacterium leprae (M. leprae), resulting in peripheral nerve impairment.
The mechanisms of neurodegeneration in ALS and the molecular events of nerve injury due to M. leprae are unclear. However, in both diseases complement activation has been detected.
I propose that complement activation, consequently MAC deposition on tissue, contributes to neurodegeneration and disease severity in Amyotrophic lateral sclerosis and leprosy.
In this thesis I show that MAC targets the axons in nerve biopsies of leprosy patients and is deposited on at the neuromuscular-junction in muscle biopsies of ALS patients. In animal models I show that preventing MAC formation has an effect on demyelination in a model for M. leprae induced nerve damage, and also on the disease severity in a SODG93A mouse model of ALS. Overall, these experiments show that complement components are putative targets for future therapies.
- Author's full name: Nawal Bahia El Idrissi
Thesis (complete) (Embargo until 24 January 2019)
Chapter 3: Complement activation in leprosy: A retrospective study shows elevated circulating terminal complement complex in reactional leprosy (Embargo until 24 January 2018)
Chapter 4: In situ complement activation and T-cell immunity in leprosy spectrum: An immunohistological study on leprosy skin (Embargo until 24 January 2019)
Chapter 5: Complement upregulation and activation on motor neurons and neuromuscular junctions in the SOD1(G93A) mouse model of familial amyotrophic lateral sclerosis (Embargo until 24 January 2019)
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