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Apoptosis of Peripheral Blood Leukocytes in Systemic Lupus Erythematosus: Studies on Serum Induction and Complement-Dependent Clearance Mechanisms

Gullstrand, Birgitta LU (2010) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2010:22.
Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease involving many organ systems. The cause is not known, but a complex combination of environmental and genetic factors seems to be involved. In SLE upregulation of type I interferons, a hyperactive B-cell response, presence of autoantibodies against modified nuclear components, increased complement consumption, increased apoptosis and decreased clearance of apoptotic cells are seen. The purpose of this thesis was to investigate some of these mechanisms. The thesis is based on four papers (I-IV).

(Papers I and II) We found that the apoptosis inducing effect was specific for sera from SLE patients when comparing with sera from various control groups. However, the apoptosis... (More)
Systemic lupus erythematosus (SLE) is an autoimmune disease involving many organ systems. The cause is not known, but a complex combination of environmental and genetic factors seems to be involved. In SLE upregulation of type I interferons, a hyperactive B-cell response, presence of autoantibodies against modified nuclear components, increased complement consumption, increased apoptosis and decreased clearance of apoptotic cells are seen. The purpose of this thesis was to investigate some of these mechanisms. The thesis is based on four papers (I-IV).

(Papers I and II) We found that the apoptosis inducing effect was specific for sera from SLE patients when comparing with sera from various control groups. However, the apoptosis inducing effect was not related to SLE disease activity. Serum from SLE patients was demonstrated to induce classical caspase-dependent apoptosis in monocytes and lymphocytes. The apoptosis induction was not dependent on death receptors but involvement of the mitochondrial pathway was indicated.

(Paper III) Phagocytosis of apoptotic cells by macrophages and C3 deposition on apoptotic cells were investigated in the presence of sera lacking different complement proteins. We found that complement-mediated opsonisation and phagocytosis of apoptotic cells, particularly those undergoing secondary necrosis, are dependent mainly upon an intact classical pathway. C1q was not more important than other classical pathway components, suggesting a role in other pathogenetic processes than defect clearance of apoptotic cells.

(Paper IV) We evaluated the roles of serum complement and antibodies against histones in relation to phagocytosis of necrotic cell material by polymorphonuclear neutrophil granulocytes (PMNs). Phagocytosis of necrotic material by PMNs and high concentration of antibodies against a broad spectrum of histones correlated with active SLE disease. The specificities of these anti-histone antibodies appear to determine the complement-dependent phagocytosis.

In conclusion, sera from SLE patients have the capacity to contribute to an increased load of apoptotic cells. An efficient clearance of apoptotic and necrotic cell material is dependent on a functional classical pathway, and autoantibodies against histones reflect the presence of apoptotic or necrotic cells contributing to the autoimmune process in SLE. (Less)
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author
supervisor
opponent
  • Professor van Kooten, Cees, Department of Nephrology, C3p, Leiden University Medical Center, Leiden, The Netherlands.
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Complement, Apoptosis, SLE, Autoimmunity
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2010:22
pages
62 pages
publisher
Department of Laboratory Medicine, Lund University
defense location
Segerfalksalen, Wallenberg neurocenter BMC
defense date
2010-04-14 09:00
ISSN
1652-8220
ISBN
978-91-86443-36-8
language
English
LU publication?
yes
id
470593cf-0406-4bbb-8d3e-f865ab7a9c52 (old id 1566989)
date added to LUP
2010-03-17 09:45:23
date last changed
2018-05-29 11:51:26
@phdthesis{470593cf-0406-4bbb-8d3e-f865ab7a9c52,
  abstract     = {Systemic lupus erythematosus (SLE) is an autoimmune disease involving many organ systems. The cause is not known, but a complex combination of environmental and genetic factors seems to be involved. In SLE upregulation of type I interferons, a hyperactive B-cell response, presence of autoantibodies against modified nuclear components, increased complement consumption, increased apoptosis and decreased clearance of apoptotic cells are seen. The purpose of this thesis was to investigate some of these mechanisms. The thesis is based on four papers (I-IV).<br/><br>
(Papers I and II) We found that the apoptosis inducing effect was specific for sera from SLE patients when comparing with sera from various control groups. However, the apoptosis inducing effect was not related to SLE disease activity. Serum from SLE patients was demonstrated to induce classical caspase-dependent apoptosis in monocytes and lymphocytes. The apoptosis induction was not dependent on death receptors but involvement of the mitochondrial pathway was indicated. <br/><br>
(Paper III) Phagocytosis of apoptotic cells by macrophages and C3 deposition on apoptotic cells were investigated in the presence of sera lacking different complement proteins. We found that complement-mediated opsonisation and phagocytosis of apoptotic cells, particularly those undergoing secondary necrosis, are dependent mainly upon an intact classical pathway. C1q was not more important than other classical pathway components, suggesting a role in other pathogenetic processes than defect clearance of apoptotic cells. <br/><br>
(Paper IV) We evaluated the roles of serum complement and antibodies against histones in relation to phagocytosis of necrotic cell material by polymorphonuclear neutrophil granulocytes (PMNs). Phagocytosis of necrotic material by PMNs and high concentration of antibodies against a broad spectrum of histones correlated with active SLE disease. The specificities of these anti-histone antibodies appear to determine the complement-dependent phagocytosis.<br/><br>
In conclusion, sera from SLE patients have the capacity to contribute to an increased load of apoptotic cells. An efficient clearance of apoptotic and necrotic cell material is dependent on a functional classical pathway, and autoantibodies against histones reflect the presence of apoptotic or necrotic cells contributing to the autoimmune process in SLE.},
  author       = {Gullstrand, Birgitta},
  isbn         = {978-91-86443-36-8},
  issn         = {1652-8220},
  keyword      = {Complement,Apoptosis,SLE,Autoimmunity},
  language     = {eng},
  pages        = {62},
  publisher    = {Department of Laboratory Medicine, Lund University},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Apoptosis of Peripheral Blood Leukocytes in Systemic Lupus Erythematosus: Studies on Serum Induction and Complement-Dependent Clearance Mechanisms},
  volume       = {2010:22},
  year         = {2010},
}