Transcript GABA and Autoimmunity

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
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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.