Clustering and Proteolytic Cleavage of Autoantigens in Surface Blebs of Apoptotic Cells

Abstract

There is now a persuasive body of evidence demonstrating that the highly specific humoral immune response to autoantigens in systemic lupus erythematosis (SLE) is T-cell—dependent, and that flares in SLE result when this primed immune system is rechallenged with self antigen (reviewed in refs. 1–3). However, the mechanisms responsible for the initiation of the primary immune response to these molecules, and for subsequently stimulating the secondary response to targeted antigens, remain unclear (4,5). Several recent studies demonstrate that a potential for T-cell autoreactivity resides in the immunologic nonequivalency of different areas of self molecules, since tolerance is only induced to dominant determinants, which are generated and presented at suprathreshold concentrations during the natural processing of whole protein antigens (reviewed in refs. 6 and 7). Those determinants that are not generated at all, or are generated at subthreshold levels during antigen processing (termed “cryptic”), do not tolerize T cells, allowing potentially autoreactive T cells recognizing this cryptic self to persist. The hypothesis that autoimmunity arises when normally cryptic determinants become visible to the immune system has received increased attention in the past several years, and several experimental systems have now provided clear evidence that the balance of dominant vs cryptic epitopes in a self molecule can be profoundly influenced by forces that alter the “immunologic” structure of molecules (7). Examples include the revelation of cryptic epitopes through novel cleavage (8,9), or through altered conformation induced by high-affinity ligand binding (e.g., to an antibody or receptor molecule [10–12]). The unique, high-titer autoantibody responses that characterize different autoimmune diseases can therefore be viewed as the immunologic impression of the initiating events that revealed suprathreshold concentrations of nontolerized structure in a proimmune context, thus satisfying the stringent criteria for the initiation of a primary immune response (13). We have proposed that high-titer autoantibodies to the very specific group of cellular molecules targeted in SLE might therefore reflect this common feature (14). The corollary of this proposal is that if the perturbed state can be re-created in vitro, autoantigens will be unified by alterations of concentration, distribution, and structure. We have therefore used high-titer autoantibodies as probes of the cell biology and biochemistry of autoantigens during different clinically relevant perturbed states, to search for those circumstances in which autoantigens become clustered, concentrated, and structurally modified (14–19). This chapter highlights apoptosis as the perturbed state underlying the initiation and propagation of SLE, and focuses attention on the alterations in the cell biology and biochemistry that unify lupus autoantigens during this form of cell death. These studies raise numerous questions about the normal immune consequences of apoptosis in tissues during different forms of apoptosis. In addition, the likely focus of future studies is also outlined.