Our major interest is in the causes and mechanisms underlying the human autoimmune diseases. The immune response to self-antigens is an ongoing one in many autoimmune diseases, and appears to be driven by continued exposure to antigen. However, the mechanisms underlying this ongoing release of autoantigens, the sites from which this might occur, and the reasons for the extraordinary correlation of particular autoantigens with unique disease phenotypes, remain unclear. We have recently observed that autoantigens in systemic autoimmune diseases are clustered and concentrated in the surface blebs of apoptotic cells, indicating that this programmed cell death process may have important roles in providing toleragens in normal individuals. We have also recently observed that the majority of autoantigens are further unified by their susceptibility to cleavage by granzyme B during cytotoxic lymphocyte granule-induced cell death, which is not a feature of non-autoantigens. These studies have focused attention on this unique cell death process as the potential immunizing stimulus in this group of disorders. We are currently studying the cell biology and biochemistry of autoantigens during cell death induced by different stimuli, and are defining the roles of structurally modified autoantigens in initiation and propagation of the human diseases.

Rosen A and Casciola-Rosen L. (2001) Clearing the way to mechanisms of autoimmunity. Nature Med. News & Views 280: 55-159 [PubMed]

Andrade F, Bull HG, Thornberry NA, Ketner GW, Casciola-Rosen LA, and Rosen A.. (2001) Adenovirus L4-100K assembly protein is a granzyme B substrate that potently inhibits granzyme B-mediated cell death. Immunity 194:173-179 [PubMed]

Casciola-Rosen L, Andrade F, Ulanet D, Wong WB, and Rosen A.. (1999) Cleavage by granzyme B is strongly predictive of autoantigen status: Implications for initiation of autoimmunity. J. Exp. Med. 175:1383-7 [PubMed]

Andrade, F., Roy, S., Nicholson, D.M., Thornberry, N. Rosen, A., and Casciola-Rosen, L. (1998) Granzyme B directly and efficiently cleaves several of the downstream substrates of caspases: Implications for CTL-induced apoptosis. Immunity 115:302-12 [PubMed]

Casciola-Rosen,L.A. , Anhalt,G., and Rosen, A. (1994) Autoantigens targeted in systemic lupus erythematosus are clustered in two populations of surface structures on apoptotic keratinocytes. J. Exp. Med. 172:6828-6837 [PubMed]