The Balance between Pro- and Antiinflammatory Molecules in ANCA-Associated Vasculitis

Research output: ThesisDoctoral Thesis (compilation)

Abstract

ANCA-associated systemic vasculitis (AASV) is a group of inflammatory disorders, characterized by inflammation and necrosis of blood vessels and frequently granuloma formation. Patients with AASV make autoantibodies, so called ANCA, against proteins present in the granules of neutrophils and monocytes, mainly proteinase 3 (PR3) and myeloperoxidase (MPO). Clinically, disease progression is characterized by a relapsing-remitting course. Although remitting in nature, disease flares can lead to permanent organ damage or even death. Moreover, the standard therapy of today, high-dose corticosteroids and cyclophospahamide, is associated with severe side effects like bladder cancer and severe infections and although effective in inducing remission, the relapse rates are high.

The pathogenesis is still unknown and the importance of ANCA debated. In this thesis some fundamental aspects, like gene expression of the ANCA antigens and status of immune activation have been addressed. The main findings are those of a PR3-expression in circulating monocytes, 9-fold higher in our patients than in the controls, together with deranged circulating cytokine pattern. Most interestingly, these findings are present in patients who are in complete clinical remission, indicating some kind of basic defect in the immune system. A disability to resolve inflammatory processes would eventually lead to self-perpetuating grumbling activity, held back by local protease inhibitors like SLPI and inhibitory cytokines like IL-10. This would create a borderline environment, making it easy for some sort of unknown trigger, such as a virus or another environmental factor, to elicit a full blown inflammatory response. ANCA could, if present, probably fuel this process by interacting with antigens expressed on the surface of neutrophils and monocytes.

Besides the pathogenic aspects, some of the results might have clinical implications. IL-6 seems to be a potential marker of imminent relapse and should be thoroughly evaluated as such in a larger patient study over a longer time period. IL-8, on the other hand, might be a prognostic marker, considering the strong association with impending organ damage. The finding of low IL-10 levels being associated with relapse tendency of course evokes interest in exploring its therapeutic potential.
Original languageEnglish
QualificationDoctor
Awarding Institution
  • Nephrology
Supervisors/Advisors
  • [unknown], [unknown], Supervisor, External person
Award date2003 Dec 5
Publisher
ISBN (Print)91-628-5897-1
Publication statusPublished - 2003

Bibliographical note

Defence details

Date: 2003-12-05
Time: 09:15
Place: Segerfalksalen, Wallenberg neurocentrum, Sölvegatan 17, Lund

External reviewer(s)

Name: Savage, Caroline
Title: Professor
Affiliation: Birmingham University, UK

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Article: I. Ohlsson S, Ljungkrantz I, Ohlsson K, Segelmark M, Wieslander J (2001) Novel distribution of the secretory leukocyte proteinase inhibitor in kidney. Mediat Inflamm 10, 347-350.

Article: II. Ohlsson S, Falk R, Yang JJ, Ohlsson K, Segelmark M, Wieslander J (2003) Increased expression of the secretory leukocyte proteinase inhibitor in Wegener’s granulomatosis. Clin Exp Immunol 131, 190-196.

Article: III. Ohlsson S, Wieslander J, Segelmark M (2003) Increased circulating levels of proteinase 3 in patients with anti-neutrophilic cytoplasmic autoantibodies-associated systemic vasculitis in remission. Clin Exp Immunol 131, 528-535.

Article: IV. Ohlsson S, Hellmark T, Pieters K, Sturfelt G, Wieslander J, Segelmark M. Increased monocyte transcription of the proteinase 3 gene – cause or consequence of ANCA-associated systemic vasculitis? (Submitted)

Article: V. Ohlsson S, Wieslander J, Segelmark M. Circulating cytokine profile in ANCA-associated vasculitis – prediction of outcome? (Submitted)

Subject classification (UKÄ)

  • Urology and Nephrology

Free keywords

  • nephrology
  • Urologi
  • nefrologi
  • Urology
  • monocyte
  • SLPI
  • proteinase 3
  • ANCA
  • vasculitis
  • inflammation

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