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Macrophages and Neutrophils in ANCA Associated Vasculitis

Ohlsson, Susanne LU (2014) In Lund University, Faculty of Medicine, Doctoral Dissertation Series 2014:43.
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... (More)
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. (Less)
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author
supervisor
opponent
  • Witko-Sarsat, Veronique, Département Immunologie-Infection-Inflammation, INSERM U1016 Institut Cochin, Paris, France
organization
publishing date
type
Thesis
publication status
published
subject
in
Lund University, Faculty of Medicine, Doctoral Dissertation Series
volume
2014:43
pages
72 pages
publisher
Department of Nephrology, Lund University
defense location
Segerfalksalen, BMC A10, Lund
defense date
2014-04-24 09:15
ISSN
1652-8220
ISBN
978-91-87651-68-7
language
English
LU publication?
yes
id
7fefe45f-696f-4a22-b42d-a29e0a12a365 (old id 4378615)
date added to LUP
2014-04-08 11:50:30
date last changed
2016-09-19 08:44:48
@phdthesis{7fefe45f-696f-4a22-b42d-a29e0a12a365,
  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. <br/><br>
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.<br/><br>
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.<br/><br>
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.<br/><br>
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.},
  author       = {Ohlsson, Susanne},
  isbn         = {978-91-87651-68-7},
  issn         = {1652-8220},
  language     = {eng},
  pages        = {72},
  publisher    = {Department of Nephrology, Lund University},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine, Doctoral Dissertation Series},
  title        = {Macrophages and Neutrophils in ANCA Associated Vasculitis},
  volume       = {2014:43},
  year         = {2014},
}