Macrophages and Neutrophils in ANCA Associated Vasculitis
Author
Summary, in English
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.
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.
Department/s
Publishing year
2014
Language
English
Publication/Series
Lund University Faculty of Medicine Doctoral Dissertation Series
Volume
2014:43
Full text
Document type
Dissertation
Publisher
Department of Nephrology, Lund University
Topic
- Urology and Nephrology
Status
Published
ISBN/ISSN/Other
- ISSN: 1652-8220
- ISBN: 978-91-87651-68-7
Defence date
24 April 2014
Defence time
09:15
Defence place
Segerfalksalen, BMC A10, Lund
Opponent
- Veronique Witko-Sarsat