The putative role of apoptosis-modified histones for the induction of autoimmunity in Systemic Lupus Erythematosus

In recent years, it has become evident that Systemic Lupus Erythematosus (SLE) is a disease characterized by an array of autoantibodies directed against the native nucleosome, its DNA component and/or its histone component. Nuclear antigens are generated and released in vivo during apoptosis. A hallmark of apoptosis is the cleavage of chromatin by caspase-activated DNase. This fragmentation occurs at the internucleosomal level and leads to DNA ladder formation classically associated with apoptosis. Thus, dysregulation of DNA fragmentation might be directly linked to the induction of autoimmunity in SLE. In our studies, activated human lymphoblasts contain high amounts of core histones in their cell lysates after apoptosis induction. This accumulation correlated highly with markers of early apoptosis (Annexin V positive, propidium iodide negative), but not with markers of late apoptosis or necrosis. Interestingly, accumulation of core histones or nucleosomes in cell lysates was detected as early as 30 or 60 min after UV irradiation, whereas phosphatidylserine externalization occurred 2 hr after apoptosis induction. Our results suggest that extranuclear accumulation of core histones is a very early event in apoptosis, preceding the externalization of phagocytosis signals on the outer membrane surface of apoptotically dying lymphoblasts. The following review will discuss these results in a broader perspective which includes our hypothesis of how apoptosis dysregulation during early phases may contribute to the induction of autoimmunity against nuclear autoantigens as seen in SLE. (C) 2003 Elsevier Inc. All rights reserved.