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Chamberlain-Banoub, Jayne L.
Languages: English
Types: Doctoral thesis
Subjects: R1
This thesis describes the evaluation of the role of Complement (C) and C regulators (CRegs) in experimental models of peripheral neuropathy and neuromuscular disease. Although a role for C in mediating peripheral neuropathy has previously been demonstrated in Guillain-Barre Syndrome (GBS) and its well characterised animal model Experimnetal Autoimmune Neuritis (EAN), evaluation of the role of individual components is lacking. C activation has also been widely implicated in the pathology seen in myasthenia gravis (MG) and its associated animal model Experimental Autoimmune Myasthenia Gravis (EAMG), although the precise effectors are uncertain. Evaluation of the extent of protection conferred by CRegs in the peripheral nervous system (PNS), and the ability of the myelin-producing Schwann cell to synthesize C components was a vital first step in determining the susceptibility of the system to C attack, and for providing a method of targeting key C-related molecules for further study in vivo. This work demonstrated that the PNS is well protected from membrane attack complex (MAC) attack, with high expression of the terminal pathway regulator, CD59. Crry was also highly expressed, while CD55 had a limited expression, suggesting a possible alternative role for this protein. CD46 was not expressed in the PNS. Testing the susceptibility of C and CReg deficient and knockout animals to induction of EAN and EAMG would enable further clarification of the role of individual C components to disease pathogenesis. For EAN, various antigens derived from myelin protein zero (PO) were generated to induce disease in rodents. Using this panel of antigens, specific, reproducible EAN was not achieved, and the possible reasons for this are discussed. C activation at the neuromuscular junction (NMJ) contributes to pathology in MG, although the precise role of the MAC is undear. EAMG was used to test the susceptibility of wikHype rats versus rats deficient in the terminal pathway component C6, to disease induction. Wildtype rats demonstrated severe weakness following induction of passively transferred EAMG, while C6 deficient rats were completely protected, demonstrated by protection against clinical disease, reduction in acetylcholine receptor (nAChR) loss, absence of inflammatory infiltrates and lack of C9 deposition. Reconstitution of human C6 to the C6 deficient rats resulted in increased disease. Soluble and fusion protein forms of CRegs, and a novel C5 inhibitor were also tested for their ability to abrogate disease in this model. Preliminary studies of EAMG induction in CReg knockout mice revealed that a lack of CD55 and CD59 markedly enhanced disease, although this remains to be confirmed. In conclusion, this work demonstrates: 1 The potential susceptibility of the PNS to C-mediated pathology 2 The difficulties in inducing EAN in rodents using published protocols 3 That MAC is the major drive to NMJ destruction in EAMG CRegs tested in EAMG hold promise for treatment of inflammatory disease, and analysis of the role of CRegs in EAMG in the mouse may shed new light on the precise effectors mediating disease pathogenesis.
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