The role of complement and granulocyte colony stimulating factor in ANCA associated vasculitis

Hieutrophil cytoplasmic antibody (ANCA) associated vasculitis is a systemic disease i affects the kidneys, lungs, and other tissues. ANCA were first described in patients i focal necrotising glomerulonephritis in 1982, with myeloperoxidase )) and proteinase 3 (PR3) subsequently shown to be the antigenic targets responsible rthe perinuclear and cytoplasmic staining patterns, respectively. Infection is thought to erbate disease partially through the production of the proinflammatory cytokine TNFot i primes neutrophils for respiratory burst. In this thesis, the role of another cytokine, Milocyte-colony stimulation factor (GCSF) is examined both in vitro and in vivo. Previous i have implicated the complement system in ANCA vasculitis. Furthermore, TNFot •d neutrophils which have been activated with ANCA in vitro are known to release a >r into the supernatant which causes complement activation in normal serum. This w has yet to be identified, although many candidates such as the alternative pathway aonent properdin have been suggested. In this work it is shown that GCSF antrations are elevated in patients with acute ANCA vasculitis and that GCSF can prime ted neutrophils for anti-MPO induced respiratory burst. A passive antibody transfer i model of anti-MPO vasculitis was established and GCSF administration was shown to te disease. Experiments also explored other models of anti-MPO vasculitis based •PO-deficient mice. The mouse model was also used to investigate the effect of icy of either properdin or MASP2 in disease. Using the passive anti-MPO passive Sr model, properdin deficiency was shown to have no effect on the extent of disease ! MASP2-deficiency exacerbated disease by a mechanism which has yet to be identified. iwork has established GCSF as a key cytokine and possible therapeutic target, and I novel observations on complement in ANCA vasculitis.

Name dc:type.qualificationname

Doctor of Philosophy

Level dc:type.qualificationlevel

Doctoral Thesis

Grantor dc:publisher.institution

King's College London

Year dc:date.issued

2013

Author dc:creator

• Freeley, Simon

Advisors dc:contributor.advisor

• Kemper, Claudia
• Robson, Michael

Language dc:language

eng

Identifier

oai:kclpure.kcl.ac.uk:studenttheses/997a1669-beac-4225-8a9a-51afc5004276

OAI identifier oai:identifier

oai:kclpure.kcl.ac.uk:studenttheses/997a1669-beac-4225-8a9a-51afc5004276