title: Immunological GABAergic interactions and therapeutic applications in autoimmune diseases.
abstract: Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain. However, it is also produced in other sites; notably by pancreatic β cells and immune cells. The function of GABA in the immune system is at an early stage of study, but it exerts inhibitory effects that are relevant to autoimmune diseases. The study of GABAergic interactions in the immune system has centered on three main aspects: 1) the expression of GABA and the relevant GABAergic molecular machinery; 2) the in vitro response of immune cells; and 3) therapeutic applications in autoimmune diseases. T cells and macrophages can produce GABA, and express all the components necessary for a GABAergic response. There are two types of GABA receptors, but lymphocytes appear to express only type A (GABAAR); a ligand-gated chloride channel. Other immune cells may also express the type B receptor (GABABR); a G-protein coupled receptor. Activation of GABA receptors on T cells and macrophages inhibits responses such as production of inflammatory cytokines. In T cells, GABA blocks the activation-induced calcium signal, and it also inhibits NF-κB activation. In preclinical models, therapeutic application of GABA, or GABAergic (agonistic) drugs, protects against type 1 diabetes (T1D), experimental autoimmune encephalomyelitis (EAE), collagen-induced arthritis (CIA) and contact dermatitis. In addition, GABA exerts anti-apoptotic and proliferative effects on islet β cells, which may be applicable to islet transplantation. Autoimmunity against glutamic acid decarboxylase 65 (GAD65; synthesizes GABA) occurs in T1D. Antigen therapy of T1D with GAD65 or proinsulin in mice has protective effects, which are markedly enhanced by combined GABA therapy. Clinically, autoantibodies against GAD65 and/or GABA receptors play a pathogenic role in several neurological conditions, including stiff person syndrome (SPS), some forms of encephalitis, and autoimmune epilepsy. GABAergic drugs are widely used in medicine, and include benzodiazepines, barbiturates, anticonvulsants, and anesthetic drugs such as propofol. Native GABA can be administered orally to humans as a drug, and has few adverse effects. However, the immune effects of GABAergic drugs in patients are not well documented. GABAergic immunobiology is a recent area of research, which shows potential for the development of new therapies for autoimmune diseases.
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada; Department of Laboratory Medicine and Keenan Research Centre for Biomedical Science, St. Michael's Hospital, 30 Bond Street, Toronto M5B1W8, Canada. Electronic address: prudhommeg@smh.ca.
authors.forename: Gérald J
authors.initials: GJ
authors.lastname: Prud'homme
authors.affiliation: Keenan Research Centre for Biomedical Science, St. Michael's Hospital, 30 Bond Street, Toronto M5B1W8, Canada. Electronic address: glinkay@smh.ca.
authors.forename: Yelena
authors.initials: Y
authors.lastname: Glinka
authors.affiliation: Department of Endocrinology and Metabolism, Huashan Hospital, Medical College, Fudan University, Shanghai 200040, China; Department of Physiology, Faculty of Medicine, University of Toronto, Canada; Department of Medicine, Faculty of Medicine, University of Toronto, Canada; Division of Endocrinology and Metabolism, Keenan Research Centre for Biomedical Science of St. Michael's Hospital, 30 Bond Street, Toronto, Ontario M5B 1W8, Canada. Electronic address: wangq@smh.ca.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Wang
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007167:Immunotherapy; D018079:Receptors, GABA / Q000276:immunology; D005680:gamma-Aminobutyric Acid / Q000276:immunology*
chemical_list: D007166:Immunosuppressive Agents; D018079:Receptors, GABA; D005680:gamma-Aminobutyric Acid
keywords: Diabetes; EAE; GABA; GAD65; Immunotherapy; Inflammation; Ion channel