Systemic autoantigens have diverse functions and subcellular distributions. However, they cluster in surface structures during apoptosis. Cysteine proteases, called caspases, are involved in the initiation (eg caspase-8) and the effector (eg caspases-3, -6, and -7) phases of the apoptotic cascade. Caspases cleave many autoantigens, generating identical fragments in all forms of apoptotic death described. It is therefore unlikely that these fragments would initiate autoimmunity. Granzyme B is a serine protease located in the cytoplasmic granules of cytotoxic T lymphocytes (CTL) and natural killer (NK) cells. While both CTL and NK cells can trigger Fas/FasL-mediated apoptosis (where L is ligand), they can also effect cell death by granule-exocytosis-induced cytotoxicity. This may be accompanied by distinct patterns of cleavage of autoantigens, a process which could release cryptic epitopes and initiate systemic autoimmunity. To investigate whether granzyme B cleaves systemic autoantigens, to generate fragments which are distinct from those liberated by caspases during apoptosis.