Clearance of Apoptotic Bodies, NETs, and Biofilm DNA: Implications for Autoimmunity

Apoptosis and NETosis, two important pathways of programed cell death, differ in their morphologic features and their effects on the immune system. In apoptosis, nuclear chromatin compacts as it is packaged into nuclear fragments and apoptotic blebs (1), and uptake of apoptotic cells by phagocytes generally suppresses the immune response (2). In NETosis, named after neutrophil extracellular traps (NETs), nuclear chromatin relaxes and forms a fibrous meshwork upon release from the cell (3). In general, NETosis is induced by infection, inflammation, or trauma and represents a mechanism of innate immune activation (4). Neutrophils, the most abundant type of white blood cells, migrate toward a stimulus in coordinated fashion, and NETs may synchronize such neutrophil swarms (5). Despite the structural and functional differences between apoptosis and NETosis, significant aspects of their clearance pathways likely overlap, as specific serum proteins participate in the recognition and uptake of remnants from either cell death pathway. In vivo, it is likely that both cell death pathways are concurrently present and that apoptotic bodies and NETs entangle (6). Yet, a third type of DNA may intertwine with DNA from apoptotic and NETotic cells, as certain bacteria and fungi release extracellular DNA that is used to construct biofilms (7). How apoptotic bodies, NETs, and biofilm DNA (Figure ​(Figure1)1) are safely cleared is of great interest, because incomplete clearance leads to systemic inflammation and autoantibody production. Figure 1 Self and foreign antigens that may induce autoantibodies in autoimmunity. The potential contribution of apoptotic bodies, NETs, and bacterial biofilms to immune tolerance versus stimulation is indicated. The distribution and content of self (green) and . Systemic Autoimmune Diseases and Autoantibodies to Nuclear Antigens Molecular structures associated with dying cells are targets of autoantibodies in autoimmune diseases such as systemic lupus (SLE) (8), antiphospholipid syndrome (APS) (9), as well as other musculoskeletal/rheumatoid disorders (10). The resulting autoreactivities are idiosyncratic for each condition and thus are useful for clinical diagnosis. However, the antigens recognized by the autoantibodies are also involved in pathogenesis, as they accumulate at the sites of tissue damage and contribute to immune complex deposition (11). Tissue damage may worsen in the absence of serum nucleases such as DNAse I (12). Furthermore, the interactions between dying cells and the adaptive immune system strengthen over time, as somatic mutations and antigen selection optimize antibodies for improved binding (13). In SLE, antibodies to nuclear or plasma membrane antigens arise in the course of disease (14, 15). These antibodies avidly bind to apoptotic cells (16). Classical studies recognized that apoptotic cells are far better substrates for autoantibody binding than viable cells (17). However, monoclonal antibodies from mouse lupus models that bind to apoptotic blebs (16) also tightly bind to NETs released in response to bacterial pathogens (18). Our laboratory showed that NETotic cells provide suitable targets for autoantibodies from diverse human autoimmune disorders (19). Whether apoptotic or NETotic cell death, or both, provide antigens that induce autoantibody production is essential information for understanding the etiopathogenesis of autoimmune diseases (20).