Apoptosis, subcellular particles, and autoimmunity
Introduction
In an account of the seminal experiments that lead to the discovery of apoptosis as the genetically programmed pathway of cell death, Kerr [1] describes the initial observation of apoptotic bodies, subcellular particles (SCPs) resulting from cellular condensation and fragmentation. Microscopy of histologic preparations of ischemic liver, basal cell carcinoma, and adrenal glands in neonate animals consistently revealed small, round particles suggesting a mode of cell death that was distinct from necrosis [2]. The ultrastructural features of such SCPs allowed the investigators to conclude that SCPs are the final products of a process that begins with the condensation of nuclear chromatin and the aggregation of chromatin against the nuclear envelope. Subsequently, the nuclear envelope constricts in several locations to generate nuclear fragments that independently move to the cell surface and form surface protrusions, later called blebs [3]. The blebs separate from the remainder of the cell and cause membrane-bound SCPs containing nuclear fragments or remnants of the cytoplasm. These particles are taken up by surrounding cells and specialized phagocytes [2].
In light of the enormous impact that the initial description of apoptosis had on biology, it is important to recognize that several years earlier, apoptotic bodies were observed to play a unique role as protagonists in the disease process of systemic lupus erythematous (SLE). Microscopic examination of bone marrow biopsies from SLE patients consistently revealed polymorphonuclear leukocytes that had ingested fragments of apoptotic nuclei from other cells [4]. These unusual cells containing additional nuclei beside their own were called LE cells and were recognized as reliable diagnostic markers for SLE. Soon thereafter, it became clear that a factor from SLE sera was required to allow phagocytosis of SCPs containing apoptotic nuclear fragments. Kanai et al. [5] isolated an antibody to a conformational epitope composed of DNA and histones that could mediate the uptake of nuclear fragments by phagocytes. Other researchers identified LE cells in aspirates taken from synovial fluids, cerebrospinal fluids, and pleural effusions of SLE patients [6]. However, despite the conceptual advance that the discovery of the LE cell provided for our understanding of SLE, relatively few studies explored the possible connection between the release of nuclear fragments in apoptosis and the induction of autoantibodies to nucleoprotein antigens.
Section snippets
Molecular mechanisms of apoptotic cell clearance
Apoptotic cell clearance depends on specific phagocyte receptors and serum proteins that facilitate apoptotic cell recognition. Separate, yet complementary pathways contribute toward the recognition of cells in early versus late stages of apoptosis [7], [8], [9].
Among the earliest signs of apoptosis is the cell surface exposure of phosphatidylserine, a phospholipid that remains confined to the inner plasma membrane in most viable cells [10]. The identification of phosphatidylserine as one of
Tissue-specific clearance mechanisms
Depending on the location where cell death occurs, clearance of apoptotic cells may be accomplished in different ways. Important variables include the rate of cell turnover, the type of cell that undergoes apoptosis, the type of phagocyte that ingests the dying cell, the receptor(s) used for apoptotic cell recognition, and the stage of apoptosis at which the apoptotic cell is recognized and engulfed. For example, Kupffer cells of the liver [45] and macrophages of the splenic red pulp [46]
Defective clearance and autoimmunity
Efficient and complete clearance of apoptotic remnants is crucial for the avoidance of autoimmunity. This was demonstrated by the increased prevalence of autoimmune responses in individuals with decreased function of C1q or C4 complement components [39]. In fact, homozygous deficiency of C1q represents the greatest known single risk factor for SLE [54]. The production of autoantibodies and incidence of glomerulonephritis that characterize human complement deficiencies have been reproduced in
Late stages of apoptosis and the induction of autoimmunity
How can the idea that apoptotic cells induce autoimmunity be reconciled with the fact that apoptosis is a necessary and ubiquitous feature of tissue homeostasis in multicellular organisms? One important consideration is that apoptosis is a progressive chain of events in which an initiating signal is transmitted through a network of specialized enzymes [75] until, over time, nearly all cellular contents have been modified in unique ways. Many cellular components are cleaved by caspases and as a
Synopsis of research from the authors' laboratory
Our work has explored the circumstances that lead to the induction of systemic autoimmune responses to nuclear antigens [82], [83]. Nuclear antigens are packaged within large apoptotic blebs that cause SCPs containing tightly packed DNA and are bound by remnants of the nuclear envelope. We have considered the possibility that nuclear antigens derived from apoptotic cells can initiate and sustain an autoimmune response [74], [82]. Antibodies from mouse models of SLE and APS may be particularly
Prospects for the future
Research exploring the relationship between apoptosis and the induction of autoimmunity is rapidly gaining momentum. Within the near future, conclusive proof for the role of apoptosis in providing autoantigenic stimuli will be provided. Soon, even greater efforts will be marshaled to explore the precise molecular connections between the effects of apoptotic modifications in different tissues and the induction of disease-specific autoantibodies. In addition, we anticipate that defects in
Acknowledgements
We thank Dr. Marc Monestier for the kind gift of the purified FC3 antibody and Mr. Tim Higgins, senior illustrator, for graphical arts. The research in the authors' laboratory was supported by the NIAID (AI054938), an institutional grant from the University of Tennessee Health Sciences Center, the Center of Excellence in Structural Biology, the Center of Excellence for Diseases of Connective Tissue, and the UT Rheumatic Disease Research Core Center of the National Institutes of Health.
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