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Title: Modulation of voltage-gated potassium channels: a pathophysiological mechanism of potassium channel antibodies in limbic encephalitis?
Author: Alexander, Sian
ISNI:       0000 0001 3411 2308
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2007
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Limbic encephalitis (LE) is a central nervous system disorder that is characterised by memory impairments, confusion, agitation and seizures, and associated with hyperintense lesions of the medial temporal lobe, seen with MRI. Anti-voltage-gated potassium channel (VOKC) antibodies have been been detected in the plasma of a subset of LE patients using a 125I-a-dendrotoxin (a-DTX) radioimmunoprecipitation assay, suggesting that the likely antigens are VOKC Kv1.l, 1.2 and 1.6 subunits. Symptoms of the disease improve markedly with immunosuppression, correlating with similarly dramatic falls in the titre of anti-VOKC antibodies, thus implicating anti-VOKC antibodies in the pathogenesis of LE. Circumstantial evidence from studies of inherited channelopathies and animal models of reduced VOKC activity suggests that VOKC dysfunction may contribute to the pathogenesis of LE. This thesis addresses whether anti-VOKC antibodies (i) bind to a-DTX-sensitive subunits and (ii) affect VOKC function. Immunofluorescence data show that binding of LE patient IgO to the surface of primary neurons and Kvl-expressing HEK-293/HEKTSA cells could not be detected with indirect immunofluorescence. Comparison of intracellular labelling with patient and control IgO showed that no additional labelling could be detected with LE patient IgO. Electrophysiological data show first, that a-DTXsensitive currents could not be reliably isolated from primary cultured hippocampal neurons; second, that NMT or LE samples did not affect VOKCs expressed by neuroblastoma-l cells; third, that none of the LE samples affected potassium currents in Kvl-transfected HEK-293 cells. These data suggest that 'anti-VOKC' antibodies may not bind directly to Kv1.111.2/1.6 homomers, or to a range of Kv1.I/1.2/1.6 subunit-containing heteromers in transfected cells. The findings instead suggest that 'anti-VOKC' antibodies in LE patient plasma may bind to a Kvl-associated protein that contributes to a-DTX-sensitive complexes in the radioimmunoprecipitation assay, but is absent from Kv1.111.2/1.6-transfected cells. Future work to characterise whether another antigen is bound by LE patient anti-VOKC antibodies will be important in determining how these antibodies contribute to the pathogenesis of LE.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available