The objective of this research proposal is to investigate in animal models the immunopathogenic mechanism(s) accounting for autoimmune gastrointestinal (G.I.) dysmotility. Autoimmunity targeting neurons in ganglia of the enteric nervous system (ENS), and extrinsic autonomic ganglia, is well-documented clinically in association with lung cancer, and may be a cause of several idiopathic forms of G.I. dysmotility, including congenital cases that are not explained by recognized gene defects. The rationale for the research plan is based on the inflammatory pathology found in ganglia, and IgG markers found in serum, of patients with the paraneoplastic entity. Recognized IgG markers are specific for ganglionic nicotinic acetylcholine receptor (AChR) and neuronal nuclear and cytoplasmic antigens. IgG specific for the ganglionic AChR is also found in some patients with idiopathic G.I. dysmotility. This IgG accompanies G.I. dysmotility in rabbits immunized with recombinant fragments or synthetic peptides of the ganglionic AChR a3 subunit, and causes G.I. dysmotility when injected into healthy mice.
The Specific Aims are: 1)to elucidate mechanisms responsible for the pathogenicity of AChR-IgG in adult animals, 2) investigate the potential of AChR-IgG to transfer G.I. dysmotility transplacentally, 3) define antigenic determinants of IgG and T cell responses contributing to G.I. dysmotility, and determine if inflammatory ENS ganglionitis will result from immunization strategies designed to activate cytotoxjc (CD8+) T cells specific for peptides derived from neuronal nuclear, cytoplasmic or AChR antigens. Methods include functional tests of G.I. motility, intracellular microelectrode studies of ganglionic synaptic transmission, analyses of cellular and humoral immune responses, production and characterization of monoclonal ganglionic AChR-lgGs, use of cobra venom factor to deplete complement, use of knock-out mice deficient in complement regulatory proteins or Fc receptors required for IgG-dependent cell-mediated cytotoxicity, histological, immunohistochemical and electronmicroscopic analyses of ganglionic tissues, and time lapse fluorescence photomicroscopic recording of ENS development stages in GFP transgenic mice exposed in utero to AChR-IgG. Insights anticipated from these studies will improve the diagnosis and aid classification of idiopathic G.l.dysmotilities, and justify early consideration of immunomodulatory therapies. The proposed research also has high clinical relevance to cancer immunity.
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