How animal models inform potential therapies for immune dysfunction in PANDAS/PANS Dritan Agalliu, Ph.D. Departments of Neurology, Pathology & Cell Biology and Pharmacology Columbia Translational Neuroscience Initiative Columbia University Medical Center
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How animal models inform potential therapies for immune dysfunction in PANDAS/PANS
Dritan Agalliu, Ph.D. Departments of Neurology, Pathology & Cell Biology
and Pharmacology Columbia Translational Neuroscience Initiative
Engelhardt & Ransohoff, 2012 Trends Immunol Huppert, J. et al., 2010 FASEB Okada & Khoury, 2012 JCI Risau W. et al., 1990 JCB
Hypothesis 1: Destruction of tight junctions between endothelial cells
Zhang, D. et al., 2012 Brain Behav Immun Abuqayyas & Balthasar, 2012 Mol Pharmaceutics Okun, E. et al., 2010 Neuromol Med Diamond, B. et al., 2013 Ann Rev Immunol
Hypothesis 2: Selective transport of antibodies from endothelial cells into the brain
Group A β-hemolytic Streptococcus pyogenes causes a plethora of autoimmune diseases
Implicated in autoimmunity Scarlet fever
Rheumatic fever
Glomerulonephritis
Sydenham’s chorea PANDAS
heart
kidney
Skin (viral toxin)brain
Neurological symptoms in SC and PANDAS
Chorea Hypotonia
Cardiac involvement Hyperactivity Obsessions
time
sym
ptom
sev
erity
Choreiform movements Tics
Severe separation anxiety Urinary frequency
Food refusal / anorexia
Emotional lability OCD-like symptoms
Contamination fears
SC PANDAS
S. pyogenes activates both arms of the immune system: humoral (antibodies) and cellular (Th17 cells).
S. pyogenes
Generation of Th17 cells after multiple intranasal infections
% o
f CD
4+ 2
W T
cel
ls
with
Cyt
okin
e ph
enot
ype
Perc
enta
ge o
f T
cells
IFNγ
Dileepan et al., (2011). PLoS Pathogens
Patients’ serum autoantibodies bind neurons and activate neuronal signaling
100%C
aMK
II A
ctiv
atio
n
PANDAS non-PANDASSC
p < 0.0001
CaM kinase
TH-(P)
Dopamine
Dopamine release Unwanted movement
Autoantibody
Kirvan, C. et al. (2006), J Neuroimmunol Kirvan, C. et al. (2003), Nat Med
Autoantibodies can bind post-synaptic D1R and D2R receptors
D1R D1RD2R
SC: D2R, D1R or ratio of D2R/D1R titers correlate with symptoms
PANDAS: D2R; Mixed reportsdopamine
Ben-Pazi, H. et al., 2012 J Mol Neurosci Ben-Pazi, H. et al., 2013 PLoS One Brilot, F. et al., 2011 Neurology Dale, R. C. et al., 2012 Brain Kirvan, C. et al., 2006 J Neuroimm Kirvan, C. et al., 2003 Nat Med
Access to the brain?
Outline
1. What is the role of S. pyogenes-specific Th17 lymphocytes in post-infectious basal ganglia encephalitis?
2. Are Th17 lymphocytes necessary for the development of disease in the brain?
GAS or PBS
Intranasal
Weekly i.n. GAS or PBS
i.v. tracer, sac
Experiment day 0 7 14 21 28 30
A novel rodent model to understand the impact of the immune system on the brain after S. pyogenes infections
GAS T cells
Dileepan T et al., (2011) PLoS Pathogens; Dileepan T., Smith E. et al., 2016 J Clin Invest
Hypothesis: Dysregulated Th17 immune response to S. pyogenes infections is key to understanding “autoimmune” complications associated with this pathogen.