Radway-Bright, Emma-Louise; (2002) The pathogenic potential of the anti-phospholipid antibodies associated with the antiphospholid syndrome and systemic lupus erythematosus. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The Antiphospholipid antibody Syndrome (APS) is characterised by recurrent thromboembolic phenomena, recurrent foetal loss and thrombocytopenia, in association with anticardiolipin antibodies (aCL) and / or lupus anticoagulant (LA). The causal role of aCL in APS, and the mechanisms by which aCL may induce disease are not clear. Part of this work explores the pathogenic role of antibodies to anionic phospholipids. In the first instance, a high prevalence of antiphospholipid (aPL) antibodies has been observed in patients with APS secondary to Systemic Lupus Erythematosus and their first degree relatives, but not in their spouses or in normal controls. The absence of clinical disease in the relatives illustrates that multiple factors contribute to the development of disease, including genetic, hormonal and environmental factors. The present study also shows that the presence of aPL antibodies is not a function of the infertile state, but rather a consequence of the IVF procedure. Infertile women who had received one to three cycles of IVF treatment had a higher prevalence of aPL antibodies than infertile women who had had no treatment and fertile women used as controls (p<0.0001). There was no difference between infertile women who were yet to receive IVF and the fertile controls. In order to determine other factors that may be required to induce APS, an attempt has been made to establish an animal model of APS, in mice with severe combined immune deficiency (SCID mice). The model has been used to evaluate the pathogenic potential of monoclonal aCL antibodies in the direct precipitation of tissue damage. Oxidised low-density lipoprotein (ox- LDL) has been used as an additional stimulus, to increase the oxidative state of the mice. This attempt was unsuccessful in precipitating tissue damage, on this occasion, as discussed. Molecular biology techniques have been used to determine if transference of binding specificity (from IgG anti-dsDNA antibody to aCL) or enhancement of an antibody's ability to bind antigen is possible by sequence manipulation. The results show that even small changes in a sequence can effect an antibody's antigen binding ability. This knowledge of antibody structure can be used to study the structure of aPL antibodies, and their antigen binding capabilities.

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