Clearance Deficiency and Cell Death Pathways: A Model for the Pathogenesis of SLE

Abstract

Alterations of cell death pathways, including apoptosis and the neutrophil specific kind of death called NETosis, can represent a potential source of autoantigens. Defects in the clearance of apoptotic cells may be responsible for the initiation of systemic autoimmunity in several chronic inflammatory diseases, including systemic lupus erythematosus (SLE). Autoantigens are released mainly from secondary necrotic cells because of a defective clearance of apoptotic cells or an inefficient degradation of DNA-containing neutrophil extracellular traps (NETs). These modified autoantigens are presented by follicular dendritic cells to autoreactive B cells in germinal centers of secondary lymphoid organs. This results in the loss of self-tolerance and production of autoantibodies, a unifying feature of SLE. Immune complexes (IC) are formed from autoantibodies bound to uncleared cellular debris in blood or tissues. Clearance of IC by blood phagocytes, macrophages, and dendritic cells leads to proinflammatory cytokine secretion. In particular, plasmacytoid dendritic cells produce high amounts of interferon-α upon IC uptake, thereby contributing to the interferon signature of patients with SLE. The clearance of antinuclear IC via Fc-gamma receptors is considered a central event in amplifying inflammatory immune responses in SLE. Along with this, the accumulation of cell remnants represents an initiating event of the etiology, while the subsequent generation of autoantibodies against nuclear antigens (including NETs) results in the perpetuation of inflammation and tissue damage in patients with SLE. Here, we discuss the implications of defective clearance of apoptotic cells and NETs in the development of clinical manifestations in SLE.

Confirmation of five novel susceptibility loci for Systemic Lupus Erythematosus (SLE) and integrated network analysis of 82 SLE susceptibility loci

“…In fact, pathways identified in this study, which contain multiple known SLE loci, could be used as follow-up targets for further studies. Perhaps most interesting is apoptosis, which has been previously reported as a model for SLE pathogenesis (46).…”

Self-dsDNA in the pathogenesis of systemic lupus erythematosus

“…Self-dsDNA is restricted strictly to the nucleus and mitochondria, but could be released from these organelles in the process of cell death [9]. Cell death, including apoptosis, necrosis and NETosis (special cell death of neutrophil through NETs), is the major potential resource of self-dsDNA which activates the immune system and leads finally to autoimmune disease [10].…”

Elimination of Nucleoproteins in Systemic Lupus Erythematosus and Antinuclear Autoantibodies Production

“…This concept deines that in SLE the most likely source of autoantigens and also leading autoimmunity inductor could be apoptotic bodies on the surface of apoptotic cells, containing almost all characteristic SLE antigens, or, as an alternative, necrotic cell debris. Another obligate condition for autoimmunity induction is postulated to be impaired clearance of the cellular "waste" and, as a consequence, antigen uptake by immature dendritic cells and their activation [121]. Several diferent impairments of the clearance pathway are proposed to induce SLE.…”