Pathogenic impact of immune-related cells in Batten disease

The neuronal ceroid lipofuscinoses (NCLs or Batten disease) are inherited neurodegenerative diseases of children. In all types of NCL glial activation, the innate immune response of the brain, precedes neurodegeneration. However, it is unclear whether adaptive immune responses are also involved in these diseases, or if they directly contribute to disease pathogenesis. Therefore, we examined the role of adaptive immune cells in mouse models of Infantile NCL (Ppt1-/- mice) and Juvenile NCL (Cln3-/- mice) by identifying, localising, and subsequently genetically removing immune components. Characterising the adaptive immune response within Ppt1-/- and Cln3-/- mice, we revealed evidence for progressive CNS infiltration by different classes of T-cells in both forms of NCL. To analyse the pathogenic impact of these lymphocytes, we crossbred PptP/- mutants with mice deficient in Rag-1, which lack T- and B-lymphocytes. Disease progression was significantly delayed in immune deficient PptP/ /Rag-1-/- mice, which displayed ameliorated neuroinflammation and neuron loss. We also crossed our Infantile and Juvenile NCL mouse models with mice deficient in sialoadhesin (Sn), a binding protein found on macrophages and microglia, and is involved in pro-inflammatory T-cell regulation. Disease progression was also slowed down, with significantly increased neuron survival in both Sn deficient NCL mice. However, contrasting effects on glial activation were observed between Ppt1~/-/ ’ Sn~/-and Cln3-/-/Sn-/- mice. Whereas glial activation was only marginally attenuated in Cln3-/-/Sir/- mice, significantly decreased microglial activation and enhanced astrocytosis were observed in Ppt1-/-/Str/- mice. These latter findings suggest an unexpected link between macrophage-expressed Sn and astrocytosis in Taken together, our findings prove that adaptive immune cells and sialoadhesin each appear to contribute to disease progression in Infantile and Juvenile NCL mice.<br/>Therefore, both immune components could prove to be suitable therapeutic targets for these fatal disorders.

Name dc:type.qualificationname

Doctor of Philosophy

Level dc:type.qualificationlevel

Doctoral Thesis

Grantor dc:publisher.institution

King's College London

Year dc:date.issued

2012

Author dc:creator

• Kühl, Thomas

Advisors dc:contributor.advisor

• Cooper, Jonathan
• Williams, Brenda Patricia

Language dc:language

eng

Identifier

oai:kclpure.kcl.ac.uk:studenttheses/ff86b71b-e859-4d91-a378-421eab71ae97

OAI identifier oai:identifier

oai:kclpure.kcl.ac.uk:studenttheses/ff86b71b-e859-4d91-a378-421eab71ae97