Autoantibodies as reporters identifying aberrant cellular mechanisms in tumorigenesis

A common, if not intrinsic, feature of autoimmunity is a humoral immune response manifested by the production of autoantibodies targeted against self-cellular proteins and nucleic acids (1). Although first studied comprehensively in rheumatic autoimmune disease, autoantibodies and autoimmunity have now become major areas of research in many other illnesses, including type 1 diabetes and other diseases discussed in this Perspective series (2–4); the paraneoplastic neurological disorder (PND) syndromes (5, 6); bullous skin diseases; liver disease; and many others (for review see ref. 7). Among the many known autoantigens are several ubiquitous cellular proteins involved in fundamental cellular functions such as DNA replication and transcription. The process by which these and other self-molecules become immunogenic is not yet understood (8). The study of tumor-associated autoimmunity may offer insights not only into the pathogenesis of autoimmune diseases in general, but perhaps also into the events that drive certain classes of cancer. Thus, changes in the structure or expression of certain self proteins, occurring during tumorigenesis, suggest mechanisms by which the immune system could be primed to perceive tumor-associated epitopes as foreign. One major route to cancer autoimmunity involves genetic mutations resulting in the production of defective p53 tumor suppressor protein. Another pathway, active in individuals with liver cancer, involves the aberrant expression of specific mRNA-binding proteins that may induce cell proliferation by preventing the turnover of mRNAs for growth factors. Other classes of mRNA-binding protein are normally restricted to the immunologically privileged domain of the brain but can become expressed ectopically and represent autoantigens in the PND syndromes. Together, these findings highlight the importance of altered post-transcriptional control at different stages of tumorigenesis.