Apoptotic Cells as a Source of Autoantigens

The autoantibody response in patients and animals with autoimmune disease exhibits clonal expansion, affinity maturation, and class switching, and provides evidence that the immune responses in these processes are antigen driven and T-cell dependent. Experimental evidence indicates that most autoantigens are indeed unified by their susceptibility to structural modification during cell death. Although autoantigens have been demonstrated to undergo several types of modification during cell death, this chapter focuses only on the proteolytic cleavage of autoantigens, and the mechanisms whereby such changes might lead to initiation of an autoimmune response. Proteases play a critical role in the apoptotic process through targeted cleavage of a limited group of downstream substrates that are functionally important in the maintenance of life. The caspases, a family of cysteine proteases with an absolute requirement for cleavage after aspartic acid, constitute the most prominent apoptotic protease family. Furthermore, it is possible that cleavage of autoantigens influences immunogenicity, it is equally likely that the presence and structural features of the cleavage site itself influence antigen processing and epitope selection, and that different mechanisms apply to different autoantigens.