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PHM142 Fall 2016 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson GABA and Autoimmunity Emily Huang, Su Lee, Amy Tian, Michelle Weng November, 8th, 2016 Gamma -Aminobutyric Acid Four-carbon non-protein amino acid Inhibitory neurotransmitter in mammalian central nervous system Depresses ganglionic action potentials Inhibits ACh release from stimulation Synthesized through decarboxylation of glutamate GABA receptors GABA Signalling System- Immune and CNS Autoimmunity Class of diseases where the host immune system fails to differentiate between foreign and self Human immune system is full of checkpoints where autoreactive lymphocytes can be aborted Failure of control mechanisms results in autoimmune disease Can be organ-specific or systemic Targets a specific organ Targets autoantigens - normal cellular constituents like nucleic acids Function of GABA receptors in autoimmunity Immune system expresses the necessary components for GABA signalling Antigen-presenting cells have functional GABA receptors GABAergic activity decreases inflammatory cytokine production and cytotoxic immune responses Expression of GABA-A receptors on T cells GABA interacts with GABA-A receptors to inhibit T cell responses. How? 1.Activation of GABA-A receptor 2.Influx of Cl- leads to depolarization 3.Reduction in intracellular calcium concentration 4. Decreased calcineurin activity 5. Inhibition of TCR/CD3 gated signal transduction 6. Reduction in IL-2 (cytokine) gene expression. 7. Decreased cytokine release Application of GABA mediated T cell inhibition Treatment with GABA has been shown to decrease T-cell autoimmunity and the development of inflammatory response in a mouse model of type I diabetes (will be discussed in detail in later slides) GABA Mechanism in CNS Autoimmune diseases Multiple Sclerosis Autoimmune encephalitis Type 1 Diabetes Multiple sclerosis Autoimmune attack against myelin results in inflammatory neurodegeneration within the central nervous system Early stages involve inflammation while later stages involve neuronal damage and neurodegeneration http://www.carefecthomecareservices.com/blog/multiple-sclerosis-definition-causes-types-symptoms/ Autoimmune encephalitis Group of disorders in which your own immune system attacks the brain Subtype: Autoantibodies targets receptors, and ion channels Anti-GABAA receptor encephalitis Anti- GABAB receptor encephalitis Both → seizures, cognitive decline, changes in behaviour Anti-GABAA receptor encephalitis Rat hippocampal neurons (in vitro): Total GABA(A) R density decreased Mobility of receptors decreased Amplitude of miniature IPSCs are decreased EPSCs remain unchanged Pathway of GABA in Diabetes Type 1 Diabetes Autoimmune attack against insulin producing beta cells in the islets of Langerhans within the pancreas. Summary Gamma-aminobutyric acid is an inhibitory neurotransmitter that also has an inhibitory role in the immune system GABA-mediated inhibition of T cells occurs via indirect Inhibition of TCR/CD3 gated signal transduction and IL-2 gene expression. GABA works to control motor activity: release of GABA onto the Globus Pallidus Internal (GPi) acts to inhibit the GPi. Therefore with the GPi inhibited, the thalamus is able to release glutamate to stimulate the motor cortex. Multiple sclerosis is an inflammatory neurodegenerative autoimmune disease associated with low levels of GABA Autoimmune encephalitis occurs when autoantibodies bind to GABA receptors and reduces inhibitory neurotransmission regulation Type 1 Diabetes is an autoimmune disease that attacks beta cells of islets of Langerhans within pancreas References Bhat, R., Axtell, R., Mitra, A., Miranda, M., Lock, C., Tsien, R. W., and Steinman, L. (2010). Inhibitory role for GABA in autoimmune inflammation. Proceedings of the National Academy of Sciences of the United States of America, 107(6), 2580–5. Bown, A. W., and Shelp, B. J. (1997). The Metabolism and Functions of [gamma]-Aminobutyric Acid. Plant Physiology, 115(1), 1–5. Eisenberg, R. (2005). Do autoantigens define autoimmunity or vice versa? European Journal of Immunology, 35(2), 367–370. Fox, S. (2012). Human Physiology. Boston, MA:McGraw Hill. Jin, Z., Mendu, S. K., and Birnir, B. (2013). GABA is an effective immunomodulatory molecule. Amino Acids, 45(1), 87–94. Joubert, B., & Honnorat, J. (2015). Autoimmune channelopathies in paraneoplastic neurological syndromes. Biochimica et Biophysica Acta, 1848(10 Pt B), 2665–76. Prud’homme, G. J., Glinka, Y., & Wang, Q. (2015). Immunological GABAergic interactions and therapeutic applications in autoimmune diseases. Autoimmunity Reviews, 14(11), 1048–1056. Journal Article, Research Support, Non-U.S. Gov’t, Review. S.K., M. (2012). Role of GABA and GABA-a Channels in T Lymphocytes and Stem Cells. Tian, J., Chau, C., Hales, T. G., & Kaufman, D. L. (1999). GABA(A) receptors mediate inhibition of T cell responses. J Neuroimmunol, 96(1), 21–28. Tillakaratne, N. J. K., Medina-Kauwe, L., Gibsons, K. M., Courtwright, K. H., and Summers, J. W. (1995). Gamma-aminobutyric acid (GABA) metabolism in mammalian neural and nonneural tissues. Camp. Biochem. Physiol. Biochem. Physiol, 112(112), 247–263. References Quek, A., & O'Toole, O. (2016). Encephalitis associated with autoantibodies binding to γ-aminobutyric acid-A, γ-aminobutyric acid-B and glycine receptors: immunopathogenic mechanisms and clinical characteristics. Neuroimmunology And Neuroinflammation, 3(3), 86-92. Wan, Y., Wang, Q, Prud’homme, GJ. (2015). GABAergic system in the endocrine pancreas: a new target for diabetes treatment. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy, 8(1) 79-87.