Thesis (Ph. D.)--University of Hong Kong, 2009. / Includes bibliographical references (leaves 188-245). Also available online.

Thesis (Ph. D.)--University of Hong Kong, 2009. / Includes bibliographical references (leaves 188-245). Also available in print.

published_or_final_version / Medicine / Doctoral / Doctor of Philosophy

published_or_final_version / Paediatrics and Adolescent Medicine / Master / Master of Research in Medicine

Systemic lupus erythematosus (SLE) is a chronic multiorgan autoimmune disorder characterized by abundant immune complex (IC) deposition, with nephritis being a major cause of morbidity and mortality. Yet, IC deposition alone is not sufficient for disease development suggesting that additional factors dictate the propensity for developing target organ injury. Genome-wide association studies have identified polymorphisms in the leukocyte integrin Mac-1 (CD11b/CD18, ITGAM) that associate with lupus nephritis. Although Mac-1 promotes inflammation by triggering leukocyte recruitment and cytotoxic functions, there is emerging evidence that it may also serve protective roles under certain conditions. We demonstrate that Mac-1 deficiency in the context of the uniquely human FcgRIIA a receptor that binds IgG-IC, promotes susceptibility to lupus nephritis in two independent animal models. Analysis of renal tissue and intravital microscopy revealed that Mac-1 modulates neutrophil recruitment by FcgRIIA. The SLE-associated variant of Mac-1 rs1143679 (R77H), results in reduced Mac-1 functions, but the underlying mechanism remains undefined. CD18 integrin mediated adhesion is a multistep process that begins with affinity changes for ligand via transmission of allosteric signals. Moreover, mechanical forces (e.g. shear flow) paradoxically increase the lifetime of integrin-ligand bonds, referred to as "catch-bonds". Here, we show that expression of Mac-1 R77H on neutrophils, and blocking antibodies to the extracellular b-propeller domain in which it resides, markedly impairs Mac-1 adhesion to ligand under shear flow. R77H expressing cells exhibit a shift in equilibrium towards a bent conformation, a lower affinity and on- and off- rate for ligand and an inability to form catch-bonds. Additional mutants and activating antibodies reveal that R77H prevents allosteric signal transmission to the aI-domain required for productive ligand binding.

published_or_final_version / abstract / Paediatrics and Adolescent Medicine / Master / Master of Philosophy

published_or_final_version / abstract / toc / Medicine / Master / Doctor of Medicine

The Best M.Phil Thesis in the Faculties of Dentistry, Engineering, Medicine and Science (University of Hong Kong), Li Ka Shing Prize, 2001-2003. / published_or_final_version / abstract / toc / Medicine / Master / Master of Philosophy

published_or_final_version / abstract / toc / Paediatrics and Adolescent Medicine / Master / Master of Philosophy

No description available.