Various natural and industrial products can induce autoimmune-like abnormalities when ingested or inhaled. A lupus-like syndrome resulting from consumption of more than 40 different medications is the most fully characterized aseptic autoimmune disease caused by an environmental agent, and identifying the mechanism underlying this phenomenon is the overall objective of this investigation. IgG antibodies to the (H2A-H2B)-DNA subunit of chromatin are the serologic marker for this syndrome, and appearance of this antibody is presumably due to the activation of chromatin-specific T-helper cells. These T-cells are normally quiescent or deleted, and it is proposed that xenobiotics disrupt the process that establishes central T-cell tolerance to chromatin. This hypothesis will be tested using procainamide-hydroxylamine (PAHA) as the prototype drug. Well-established T-cell clones will be made non-responsive to their cognate antigen by engagement of the T-cell receptor in the absence of co-stimulation, and the capacity of PAHA to interfere in this process will be measured by lymphokine secretion and proliferation. Induction of T-cell anergy in vitro may reflect the events that occur during positive selection of T-cells on self-antigen in the thymus, and the capacity of PAHA to induce chromatin-reactive T-cells and B-cells will be tested by intrathymic injection of the drug in an in vivo mouse model. Drug-induced T-cells will be expanded in vitro, and their phenotype, antigen specificity and in vivo helper activity will be characterized. Parallel studies using short-term thymic organ culture will allow examination of critical variables in the disruption by PAHA of T-cell maturation in the thymus. Mice transgenic for a neo-self antigen and its cognate T-cell receptor will be used to rigorously test the underlying hypothesis that PAHA promotes autoreactivity by interfering with positive selection of T-cells in the thymus. Findings from these studies on how reactive small molecules can initiate autoimmunity may provide a general model for environmentally-induced immune system activation.
Showing the most recent 10 out of 21 publications
