Altered Structure of Autoantigens During Apoptosis 455 John C. Hall, Livia Casciola-Rosen, and Antony Rosen

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1 APOPTOSIS IN THE RHEUMATIC DISEASES Preface David S. Pisetsky xiii Mechanisms of Apoptosis 441 David A. Martin and Keith B. Elkon The understanding of the apoptotic program has grown exponentially over the past decade. Numerous human diseases have been directly linked to genetic defects in the apoptotic pathways, including cancer, neurodegenerative disorders, and autoimmune diseases. Caspases initiate and amplify various death signals, allowing for selective and ordered cellular demolition. The fine balance between pro- and antiapoptotic Bcl-2 family members regulates the cell fate in response to many (but not all) stress or signaling pathways. Recent discoveries highlight the complex integration of signals from various organelles that determine cell fate and the multiple functions of central players in the apoptotic process. It is likely that the knowledge obtained in a relatively time will translate into better diagnostics and therapies to enhance or retard cell death in the appropriate clinical circumstances. Altered Structure of Autoantigens During Apoptosis 455 John C. Hall, Livia Casciola-Rosen, and Antony Rosen The clustering and concentration of autoantigens at the surface of apoptotic cells, in combination with the striking tolerance-inducing function of apoptotic cells, have focused attention on abnormalities in apoptotic cell execution and clearance as potential susceptibility and initiating factors in systemic autoimmunity. Structural changes that occur during cell death may influence the immunogenicity of self antigens. This article discusses the modifications that autoantigens undergo during cell death, identifies certain proimmune forms of apoptotic death in which autoantigen structure is frequently modified, and reviews the mechanisms through which such structural changes might lead to initiation of an autoimmune response. VOLUME 30 NUMBER 3 AUGUST 2004 vii

2 Genetic Models for the Clearance of Apoptotic Cells 473 Philip L. Cohen and Roberto Caricchio The immunogenic potential of nuclear antigens exposed during apoptosis, together with considerable animal data suggesting that impaired apoptotic clearance can result in systemic lupus erythematosus (SLE) like autoimmunity, has lent support to the idea that self-immunization with apoptotic debris is a key driving mechanism in lupus. The multiple roles of complement receptors, diverse scavenger receptors, and intermediate proteins that bind to and opsonize apoptotic cells indicate a complex web of interactions leading to the clearance of apoptotic debris. Disturbances in parts of this system may lead to lupus or to lupus exacerbations. Therapy directed toward augmenting clearance and decreasing concomitant inflammation may lead to improved management of SLE. The Role of Death-Associated Molecular Patterns in the Pathogenesis of Systemic Lupus Erythematosus 487 Dror Mevorach This article describes apoptotic cell clearance mechanisms and discusses altered mechanisms for clearance of dying material, which represents a central pathogenic process in the development and acceleration of systemic lupus erythematosus. The article also explores ways to use this perspective for a potential direction for future treatments. Apoptosis and Systemic Lupus Erythematosus 505 Ahmed Sheriff, Udo S. Gaipl, Reinhard E. Voll, Joachim R. Kalden, and Martin Herrmann Reduced clearance of dying cells by macrophages or increased apoptosis provokes accumulation of cellular fragments in various tissues. This process seems to induce the uptake of autoantigens from apoptotic nuclei or chromatin by dendritic cells (DCs). Then, the DCs present altered self-epitopes to naive T cells. Thus, autoreactive T cells are activated accidentally and may now provide T-cell help for B cells that present peptides processed from secondary necrotic/late apoptotic prey. Impaired phagocytic removal of early apoptotic cells may cause accumulation of secondary necrotic cells and debris in the germinal centers of secondary lymph organs. The latter bind complement and can, therefore, be trapped on the surfaces of follicular DCs (FDCs). B cells may get in contact with intracellular autoantigens that had been released during late stages of apoptotic cell death and are immobilized by FDCs. Consecutively, B cells that had, for example, gained specificity for nuclear auto-antigens during random somatic mutations can receive a short-term survival signal. After migration into the mantle zone, these autoreactive B cells may finally be activated by autoreactive viii

3 CD4 + T helper cells. B cells then differentiate into memory or plasma cells. The plasma cells produce those pathogenic nuclear autoantibodies. Many defects are known with respect to the clearance of apoptotic cells and cell material, especially that of nuclear origin. Reflecting on the plethora of defects of clearance of apoptotic material already demonstrated in systemic lupus erythematosus, it is reasonable to argue that, for many patients, failure of clearance is at the heart of their disease. Nucleosomes in the Pathogenesis of Systemic Lupus Erythematosus 529 Sophie Koutouzov, Antonio L. Jeronimo, Henri Campos, and Zahir Amoura Systemic lupus erythematosus (SLE) is characterized by the development of a large array of autoantibodies that primarily are directed against the whole chromatin (antinucleosome) and its individual components, dsdna and histones. Apoptotic defects and impaired removal of apoptotic cells could contribute to an overload of autoantigens (and in particular of nucleosomes) in circulation or in target tissues that could become available to initiate an autoimmune response. In susceptible individuals, this can lead to autoantibodymediated tissue damage. In addition to intrinsic or secondary apoptosis/apoptotic cell removal defects, certain apoptotic stimuli (eg, UV, viruses) could lead to posttranscriptional modifications that generate autoantigen cryptic fragments for which cells of the immune system have not been tolerized. Besides their role as a major immunogen in lupus, nucleosomes participate in antibody-mediated renal pathogenicity and act as a bridging molecule that recognizes heparin sulfate/collagen V components of the glomerular basement membrane. New tools that were developed to detect antinucleosome antibodies in the serum of patients (by ELISA) have shown the specificity and the high sensitivity of antinucleosome antibody reactivity in SLE. In particular, antinucleosome could be a useful marker of patients who have SLE and lack anti-dsdna antibodies, a prognosis marker for imminent relapse, and a diagnosis marker of lupus nephritis. The Stimulation of Toll-Like Receptors by Nuclear Antigens: A Link Between Apoptosis and Autoimmunity 559 Ann Marshak-Rothstein, Liliana Busconi, Ian R. Rifkin, and Gregory A. Viglianti As immunologists have long understood, effective responses to foreign antigens require adjuvants. It is now apparent that the initiation of autoimmune disease is comparably facilitated by adjuvant activity. In the case of antinuclear antibodies, it seems that DNA itself can serve as an endogenous adjuvant. Similar to many of the microbial adjuvants, mammalian DNA mediates its effect through a Toll-like receptor in this case, TLR9. ix

4 DNA as a Marker of Cell Death in Systemic Lupus Erythematosus 575 David S. Pisetsky DNA circulates in the blood in systemic lupus erythematosus, among other conditions, and plays a role in immunopathogenesis in the form of immune complexes. As shown in experiments in mice, blood DNA levels rise following treatments to induce apoptosis and the administration of cells made apoptotic or necrotic in vitro. In mice lacking macrophage function, however, blood levels do not rise following administration of dead cells. These results indicate that circulating DNA may be a marker of cell death, although its levels likely reflect a complex process involving the interactions of macrophages with dead and dying cells. More to Death than Dying: Apoptosis in the Pathogenesis of SSA/Ro-SSB/La-Associated Congenital Heart Block 589 Robert M. Clancy and Jill P. Buyon The mechanism by which maternal anti-ssa/ro-ssb/la antibodies initiate and perpetuate inflammation and eventuate in scarring of the atrioventricular node (the signature lesion of congenital heart block) is not yet defined. In vitro and in vivo studies suggest that one pathologic cascade that leads to scarring may be initiated by way of apoptosis which results in translocation of SSA/Ro-SSB/La antigens and subsequent surface binding by maternal autoantibodies. These opsonized cardiocytes are phagocytosed by macrophages, which secrete factors that modulate fibroblasts into myofibroblasts, a scarring phenotype. The exaggerated apoptosis (amplified physiologic apoptosis or defective clearance) that is observed in autopsy slides from fetuses who had congenital heart block may provide the pivotal clue to understanding the pathogenicity of the maternal autoantibodies. Apoptosis in Rheumatoid Arthritis: Friend or Foe 603 Hongtao Liu and Richard M. Pope A better understanding of the mechanisms that contribute to the resistance of synovial macrophages and fibroblasts to apoptosis will not only provide better insights into the mechanisms contributing to the perpetuation of rheumatoid arthritis (RA) but will also help identify targets for the development of novel, more effective, and long-lasting therapies for the treatment of patients with RA. To avoid toxicity, such as the induction of apoptosis of critical organs, the mechanisms by which these molecules are targeted and therapy delivered must be carefully selected, using the insights obtained from studies characterizing the mechanisms that promote chronic inflammation. x

5 HMGB1 as a Mediator of Necrosis-Induced Inflammation and a Therapeutic Target in Arthritis 627 Ulf Andersson and Kevin J. Tracey For the second time in recent history, studies directed at the pathogenesis of infectious disease have led to the identification of an endogenous mediator of arthritis. HMGB1, a 30-kD nuclear and cytoplasmic protein widely studied as a DNA-binding protein, is a newly described cytokine and a necessary and sufficient mediator of lethal sepsis. HMGB1 is passively released during cell necrosis, but not apoptosis; it activates an inflammatory response to necrosis, but not apoptosis. Furthermore, HMGB1 can also be actively secreted by stimulated macrophages or monocytes in a process that requires acetylation of the molecule, enabling a translocation from the nucleus to secretory lysosomes. Recent evidence indicates that HMGB1 is a mediator of arthritis because of the following: (1) it is produced at the site of joint inflammation, (2) it causes the development of arthritis when applied to normal joints, and (3) therapies that inhibit HMGB1 prevent the progression of collagen-induced arthritis in rodents. Anti-HMGB1 may be studied in future clinical trials of diseases of excessive production of HMGB1, such as severe sepsis and arthritis. Apoptosis in Osteoarthritis 639 Thomas Aigner, Hyun A. Kim, and Helmtrud I. Roach Many studies have shown that apoptotic cell death occurs at an increased rate in osteoarthritic cartilage. Whichever type of cell death takes places in articular cartilage, it is important to prevent, because it is detrimental to articular cartilage maintenance. Thus, it is important to characterize events going on during cellular degeneration in more detail. Overall, physicians have reached a reasonable level of understanding of the extent of cell death occurring in the disease process, but they are still at an early stage in the understanding of the mechanisms underlying this process and the means of intervening in this facet of cartilage destruction. Apoptosis in Glomerulonephritis 655 Jeremy Hughes, Jean-Francois Cailhier, Simon Watson, and John S. Savill Apoptosis is of fundamental importance and plays a key role in determining the outcome of glomerulonephritis. Under ideal circumstances, apoptosis deletes infiltrating leukocytes and excess numbers of resident cells that are surplus to requirements, thereby facilitating tissue remodeling and the restoration of normal tissue architecture. Apoptosis also has a darker side, however, and may be responsible for the deletion of critically important resident glomerular cells, xi

6 resulting in hypocellular scarring and loss of renal function. Recent data indicate that glomerular cell apoptosis may be manipulated to improve outcome in experimental models of renal inflammation. It is hoped that further research will provide novel therapeutic strategies for patients with inflammatory glomerulonephritis. Index 677 xii