Immunotherapy

Identification of class I MHC-associated phosphopeptides as targets for cancer immunotherapy. Zarling, A. L. et al. Proc. Natl Acad. Sci. USA 103, 14889–14894 (2006)

Infection or cellular transformation can be accompanied by changes in protein expression and/or metabolism that alter the peptides displayed on MHC class I molecules and recognized by CD8+ T cells. Indeed, one of the hallmarks of malignant transformation is alterations in the phosphorylation of cellular proteins. Zarling et al. proposed that, when these phosphoproteins are degraded by the proteasome, cancer-specific phosphopeptides could be generated, and these could be presented by MHC class I molecules on malignant cells. A comparative analysis of phosphopeptides presented at the surface of various cancer cells showed that these endogenously expressed MHC-class-I-associated phosphopeptides were recognized by specific CD8+ T cells. This recognition is a result of both the level of expression and the phosphorylation of the underlying source proteins. These phosphopeptides are therefore potential targets for cancer immunotherapy.

Viral immunity

Virus-induced type I IFN stimulates generation of immunoproteasomes at the site of infection. Shin, E.-C. et al. J. Clin. Invest. 12 Oct 2006 (doi: 10.1172/JCI29832)

Type II interferon (IFN) is known to be the initial and main inducer of the 26S proteasome (also known as the immunoproteasome; an important cytosolic antigen-processing complex) during viral infections. A type I IFN response, however, is induced by many viruses much earlier than a type II IFN response, so in this study the role of type I IFNs in the induction of immunoproteasomes was investigated. In vitro, type I IFNs triggered the induction, assembly and proteolytic activity of immunoproteasomes in human liver cells. In vivo, in contrast to the currently held view, the intrahepatic induction of functional immunoproteasomes in response to infection of chimpanzees with hepatitis C virus occurred earlier than the intrahepatic expression of type II IFN. The authors propose that this might be one explanation for the effectiveness of type-I-IFN-based therapies when administered early during infection with hepatitis C virus.

Autoimmunity

Persistent expression of autoantibodies in SLE patients in remission. Yurasov, S. et al. J. Exp. Med. 203, 2255–2261 (2006)

Untreated systemic lupus erythematosus (SLE) is characterized by defective early B-cell-tolerance checkpoints, so autoreactive and polyreactive antibodies accumulate in the circulating mature naive (resting) B-cell compartment. Current treatment protocols can induce long-term remission but frequently fail to prevent relapses. This report investigated the status of early B-cell tolerance in patients with SLE who are in clinical remission. Increased amounts of autoreactive and polyreactive antibodies continued to be produced in these patients, although they had fewer B cells that express these antibodies than did patients with active disease. The persistence of autoreactive mature naive B cells in patients with SLE who are in clinical remission indicates that abnormalities in early B-cell-tolerance checkpoints are an integral feature of SLE.