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Title: Human lysosomal associated membrane protein-2 (LAMP-2) : a molecular bridge between infection and autoimmunity in an animal model of focal necrotising and crescentic glomerulonephritis (FNCGN)
Author: Cunningham, Dawn Anne
ISNI:       0000 0001 3400 3232
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2007
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Pauci-immune focal necrotising and crescentic glomerulonephritis (FNCGN) is a severe form of kidney disease often associated with anti-neutrophil cytoplasmic antibodies (ANCA). Well pocumented . ANCA target proteins . include myeloperoxidase (MPO) and proteinase 3 (PR3), both contained in the Iysosomes of neutrophils. A study by Kain et al (1995) identified a novel ANCA target; lysosomal associated membrane protein 2 (LAMP-2) (Kain et aI., 1995) recognised by FNCGN patient sera. An immunodominant epitope shares sequence homology with a peptide found on bacterial adhesion protein fimH (Kain et aI., Manuscript in Preparation). The aim of this work has been to evaluate the pathogenic potential of cross reactive antibodies that bind to both LAMP-2 and fimH to provide an explanation of how persistent infection can drive chonic inflammatory responses that underpin autoimmune disease. A WKY rat model of FNCGN was used to examine this concept of molecular mimicry by using both passive and active immunisation schedules. Recombinant fragments of human and rat LAMP-2 and bacterial fimH were generated and purified ·following expression in plasmid vectors. The WKY rat model was first passively immunised with rabbit antibodies specific for human LAMP-2 (hLAMP-2) to confirm that they had the ability to cross-react with sequence homologous rat LAMP-2 (rLAMP-2). Indirect immunofluorescence (IIF) and ELISA confirmed cross reactivity and further indicated that antihLAMP- 2 resulted in tissue damage similar to that observed in human FNCGN. Further, active immunisation with hLAMP-2 in the presence of adjuvant was sufficient to break tolerance, generating a pathogenic antibody response specific for both human and rat LAMP-2.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available