Macrophages and Neutrophils in ANCA Associated Vasculitis

Research output: ThesisDoctoral Thesis (compilation)

Abstract

Autoimmune diseases are diseases where the immune system attacks the body itself. They are commonly complex diseases with no clear aetiology, a fact that complicates treatment and the study of these diseases.
This thesis focuses on the rare group of autoimmune diseases ANCA associated vasculitides (AAV) that are characterized by the presence of anti-neutrophil cytoplasmic antibodies (ANCA) directed against the neutrophil granule proteins myeloperoxidase (MPO) or proteinase 3 (PR3). In AAV, small vessels, mainly capillaries are affected, making organs like the kidneys and respiratory tract particularly susceptible for damage. Despite treatment with immunosuppressive drugs, 12 % of patients die within the first year after diagnosis. Thus, there is an unmet need for better and more specific treatment options.
ANCA have for long been attributed at least some of the damage by binding to its antigen on neutrophils and stimulate their activation by reactive oxygen species (ROS) production and degranulation. The properties of ANCA have been extensively studied ever since their discovery in the early 1980’s. However, how ANCA develops in the first place is not known.
A common hypothesis how autoimmune diseases arise is that the clearance of apoptotic cells is impaired, leading to an increased exposure of certain antigens to the immune system and a subsequent autoimmune response. This theory was tested in the first and second paper of this thesis. Our results show that phagocytosis of apoptotic cells by macrophages (MØs) from AAV patients was not impaired compared to healthy MØs. The polarization of different MØ subtypes in the presence of AAV sera was also tested. Surprisingly, AAV serum polarized MØs were similar to a subtype connected to anti-inflammatory properties and increased phagocytosis ability, opposite to our hypothesis.
In the third and fourth paper, the stimulatory capacity of different IgG purified from PR3-ANCA patients were investigated. The ability of AAV IgG to stimulate neutrophils to produce ROS, degranulate and produce NETs was compared to affinity, ANCA levels, epitope specificity and clinical parameters. Our results show that affinity better predicts the ANCA activation potential compared to ANCA levels and that epitope specificity can change over time in the same patient. However, no particular epitope specificity was connected to increased activation of neutrophils.

Details

Authors
  • Susanne Ohlsson
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Urology and Nephrology
Original languageEnglish
QualificationDoctor
Awarding Institution
Supervisors/Assistant supervisor
Award date2014 Apr 24
Publisher
  • Department of Nephrology, Lund University
Print ISBNs978-91-87651-68-7
Publication statusPublished - 2014
Publication categoryResearch

Bibliographic note

Defence details Date: 2014-04-24 Time: 09:15 Place: Segerfalksalen, BMC A10, Lund External reviewer(s) Name: Witko-Sarsat, Veronique Title: [unknown] Affiliation: Département Immunologie-Infection-Inflammation, INSERM U1016 Institut Cochin, Paris, France ---

Related research output

Ohlsson, S., Sophie Ohlsson, Söderberg, D., Gunnarsson, L., Pettersson, Å., Mårten Segelmark & Thomas Hellmark, 2014, In : Clinical and Experimental Immunology. 176, 3, p. 363-372

Research output: Contribution to journalArticle

Ohlsson, S., Petrus Linge, Birgitta Gullstrand, Lood, C., Johansson, Å., Sophie Ohlsson, Lundqvist, A., Anders Bengtsson, Carlsson, F. & Thomas Hellmark, 2014, In : Clinical Immunology. 152, 1-2, p. 10-19

Research output: Contribution to journalArticle

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