Chemical-induced allergy and autoimmunity

Abstract

This thesis aims towards a better understanding of the mechanisms that lead to chemical-induced adverse immune effects. We focussed thereby on the initial induction stage of the immune reaction that consists of three major steps: (i) formation of neoantigen, (ii) processing and presentation of the neoantigen, and (iii) recognition of peptide-MHC-complex by the T cell. Chemical induced allergy or autoimmunity is often observed after administration of certain drugs or after contact with industrial or environmental chemicals. T cells play a central role in the development of drug-induced adverse immune reactions. A major difficulty in studying T-cell reactions to sensitizing chemicals is the fact that in most cases the ultimate neoantigen recognized by "drug-specific" T cells is unknown. As most T cells can only recognize peptides on MHC molecules, chemicals have to bind to a protein carrier in order to be recognized by T cells. Parts of this neoantigen are presented on MHC molecules on the surface of the APC and can be engaged by T cells. In order to bind to proteins, most chemicals have to be metabolized into protein-reactive intermediates, called haptens. Although the liver is the main organ for metabolic transformation, it does not play a major role in the induction of chemical induced adverse immune effects. In contrast, cells from the immune system itself, like neutrophils and monocytes have been shown to be involved in drug-metabolism prior to drug-induced adverse immune effects. In this thesis we have tried to elucidate some of the mechanisms involved in chemical induced adverse immune effects. Some of the steps possibly involved in the formation of neoantigens and subsequent T cell recognition are discussed. The hypothesis that extrahepatic metabolism plays an important role in the formation of neoantigen with the prohaptens procainamide and aniline could be substantiated, and the processing of protein adducts, presentation of neoantigens and subsequent recognition of either haptenated peptides or cryptic peptides by T cells was shown. Furthermore, this thesis elucidates some of the mechanisms involved in cross-sensitization and discusses the possible implications of T-cell cross-reactivity in chemical induced allergy and autoimmunity.