The cellular redox environment alters antigen presentation

Cysteine-containing peptides represent an important class of T cell epitopes, yet their prevalence remains underestimated. We have established and interrogated a database of around 70,000 naturally processed MHC-bound peptides and demonstrate that cysteine-containing peptides are presented on the surface of cells in an MHC allomorph-dependent manner and comprise on average 5-10% of the immunopeptidome. A significant proportion of these peptides are oxidatively modified, most commonly through covalent linkage with the antioxidant glutathione. Unlike some of the previously reported cysteine-based modifications, this represents a true physiological alteration of cysteine residues. Furthermore, our results suggest that alterations in the cellular redox state induced by viral infection are communicated to the immune system through the presentation of S-glutathionylated viral peptides, resulting in altered T cell recognition. Our data provide a structural basis for how the glutathione modification alters recognition by virus-specific T cells. Collectively, these results suggest that oxidative stress represents a mechanism for modulating the virus-specific T cell response.This work was supported, in whole or in part, by National Institutes of Health Grant R01 NS036592. This work was also supported by an infrastructure grant (Grant LE100100036) from the Australian Research Council (ARC) and a project grant from the Juvenile Diabetes Research Foundation (17-2012-134)

Customers and patrons of the mad-trade: the management of lunacy in eighteenth-century London: with the complete text of John Monro's 1766 case book

This book is a lively commentary on the eighteenth-century mad-business, its practitioners, its patients (or "customers"), and its patrons, viewed through the unique lens of the private case book kept by the most famous mad-doctor in Augustan England, Dr. John Monro (1715-1791). Monro's case book, comprising the doctor's jottings on patients he saw in the course of his private practice--patients drawn from a great variety of social strata--offers an extraordinary window into the subterranean world of the mad-trade in eighteenth-century London. The volume concludes with a complete edition of the case book itself, transcribed in full with editorial annotations by the authors. In the fragmented stories Monro's case book provides, Andrews and Scull find a poignant underworld of human psychological distress, some of it strange and some quite familiar. They place these "cases" in a real world where John Monro and othersuccessful doctors were practicing, not to say inventing, the diagnosis and treatment of madness