O'Neil, Deborah Antoinette; (1997) The enzymology of antigen processing. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Little is known of the exact sequence of events that occur in the processing of exogenously derived antigen for presentation via major histocompatability class II (MHCII) antigens. Proteolytic enzymes, namely cathepsin proteinases, are responsible for degrading endocytosed antigen in specific intracellular compartments of antigen presenting cells (APC). It is still unclear how such a wide variety of peptides can be generated from a single antigen and in such a way that a hierarchy of immunogenicity exists amongst these peptides. The gastrointestinal epithelium is among the non-lymphoid tissues implicated as having the potential to process and present antigen. How the processing of exogenous antigen by 'non-professional' APC such as these relates to that of the professional APC population of the immune system remains largely undefined. A feature common to both professional APC and the epithelial cells of the gastrointestinal tract is their interaction with the regulatory mediators of the immune system; cytokines. These compounds have powerful immunmodulatory effects on many aspects of the immune response, but little is known of their effects on antigen processing in such cells. The following studies investigate the enzymology of antigen processing in a number of contexts. The degradation of a model antigen, hen egg lysozyme, by different cathepsin proteinases, and the interaction of the products of such digestions with the MHC were investigated. The effects of various pro-inflammatory and anti-inflammatory immune mediators on processing function and proteinase levels in such cells were then determined. Finally, the ability of gastrointestinal epithelial cells to process antigen, and the regulation of this function by a panel of cytokines was investigated. The data obtained from these studies suggest that by regulating the enzymes responsible for the degradation of exogenously acquired antigen, the conditions under which such processing occurs determine the repertoire of immunogenic determinants that are generated.

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