Systemic lupus erythematosus: a matter of life and death.

Like most serious diseases, systemic lupus erythematosus (SLE) is a matter of life and death. This reality is evident at the levels of clinical outcome as well as immunopathogenesis. Despite improvements in therapy, lupus is often fatal, with infection, renal failure, and severe nervous system manifestations contributing to mortality. Furthermore, accelerated atherosclerosis can lead to fatal myocardial infarction and stroke, extending the impact of lupus beyond the organs usually considered affected by this disease (1). The nexus of life and death in SLE is also key to current models on the etiology of disease. Indeed, a substantial body of literature posits that lupus is an aberrant response to cell death. Thus, as shown in studies of patients as well as animal models, an increase in the extent of cell death or a failure to clear away the remnants of dead and dying cells may trigger an immunologic cascade that culminates in autoimmunity and organ-specific injury and damage. The effector elements in this scenario are immune complexes comprised of antinuclear antibodies and nuclear debris derived from dead and dying cells (2). Although the death of a cell (as well as a person) represents a simple, albeit stark, event, the paths to this outcome are both diverse and complicated. This complexity defies clear nomenclature, although, in the simplest possible conceptualization, cells die by 2 pathways: apoptosis and necrosis. Apoptosis is programmed cell death. This death pathway, which can occur in both physiologic and pathologic settings, involves the systematic disassembly of cells mediated by enzymes, called caspases, which promote the degradation of cellular macromolecules and their topologic rearrangement. In contrast, necrosis is a form of sudden cell death that is almost always pathologic and results from physical or chemical trauma. While a necrotic cell may burst open or disintegrate, the contents are not subject to degradation by the induction of cellular enzymes (3,4). The difference between apoptotic and necrotic cells may also pertain to their immunologic function, with apoptotic cells being antiinflammatory and necrotic cells being proinflammatory. This difference may reflect the release or expression of a unique class of molecules called alarmins. Alarmins are nuclear and cytoplasmic molecules that become potent immune stimulators upon a change in their location or context. When exposed by cells during death, alarmins can trigger innate immunity and promote antigen-specific immune responses (5). Among the alarmins whose expression may differ with apoptosis and necrosis, high mobility group box chromosomal protein 1 (HMGB-1) is a nonhistone nuclear protein that is a prototype of this class of immune stimulator. HMGB-1 is released by dead and dying cells, with posttranslational modifications during the death forms determining activity (6–9). The process of apoptosis is not static, however, and, if allowed to proceed, can transform to a state that has been termed late apoptosis or, more pertinently, secondary necrosis. Although the processes of primary and secondary necrosis are characterized by distinct kinetics and biochemical events, many investigators have postulated that both types of necrosis have similar proinflammatory properties. Because the body generates an enormous number of apoptotic cells each day, Dr. Pisetsky’s work was supported by a VA Merit Review grant and a Lupus Foundation of America grant. Dr. Rönnblom’s work was supported by the Swedish Research Council, the Dana Foundation, and the Swedish Rheumatism Association. David S. Pisetsky, MD, PhD: Durham VA Medical Center, and Duke University Medical Center, Durham, North Carolina; Lars Rönnblom, MD, PhD: Uppsala University, Uppsala, Sweden. Address correspondence and reprint requests to David S. Pisetsky, MD, PhD, Durham VA Medical Center, Room 151G, 508 Fulton Street, Durham, NC 27705. E-mail: dpiset@acpub.duke. edu. Submitted for publication January 27, 2009; accepted in revised form February 20, 2009. Arthritis & Rheumatism