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Colombia University has a very good and current mouse model of PANDAS:

A Murine Model for Neuropsychiatric Disorders Associated with Group A beta-Hemolytic Streptococcal Infection

[edit]
  • 02/18/2004
  • [1]
  • Kurt L. Hoffman, Mady Hornig, Kavitha Yaddanapudi, Omar Jabado, and W. Ian Lipkin
  • The Journal of Neuroscience, February 18, 2004 • 24(7):1780 –1791

Two groups of 6 week old mice were inoculated with GABHS and Complete Freund’s adjuvant (CFS), and then boosted three times with strep and Incomplete Freund’s adjuvant (IFS). The control groups received only the CFS and IFS. The first group of 7 GABHS-immunized and 7 control mice were boosted every 6 weeks. The second group of 16 GABHS-immunized and 13 control were boosted every 4 weeks.

After the second boost, serum from GABHS-immunized mice was found to be immunoreactive to deep cerebellum nuclei (DCN), and to some extent globus pallidus, and thalamus. This anti-DCN immunoreactivity was confirmed to be linked to the GABHS through preabsorption.

IgG deposits in DCN were greater in GABHS-immunized mice with anti-DCN antibodies (average 16.3) than GABHS-immunized mice without anti-DCN antibodies (average 11.7) or control mice (6.6).

GABHS-immunized mice having serum immunoreactivity to DCN also had increased rearing behavior in open-field and hole-board tests (dark box tests were statistically non-significantly elevated) compared with controls and with GABHS-immunized mice lacking serum anti-DCN antibodies.

Rearing behavior suggests increased vigilance and is considered a sign of anxiety. It is also strongly linked to increased dopaminergic and GABAergic activity.

Rearing and ambulatory behavior were correlated with IgG deposits in the DCN and with serum immunoreactivity to GABHS proteins in Western blot. In addition, serum from a GABHS mouse reacted with normal mouse cerebellum in nondenaturing Western blots and immunoprecipitated C4 complement protein and alpha-2-macroglobulin.

These results are consistent with the hypothesis that immune response to GABHS can result in motoric and behavioral disturbances and suggest that anti-GABHS antibodies cross-reactive with brain components may play a role in their pathophysiology.

Passive transfer of streptococcus-induced antibodies reproduces behavioral disturbances in a mouse model of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection

[edit]
  • 08/11/2009
  • https://www.nature.com/articles/mp200977.pdf
  • K Yaddanapudi, M Hornig, R Serge, J De Miranda, A Baghban, G Villar and WI Lipkin
  • Center for Infection and Immunity and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA
  • Molecular Psychiatry (2010) 15, 712–726; doi:10.1038/mp.2009.77; published online 11 August 2009

Demonstrated for the first time that humoral immunity is necessary and sufficient to induce the syndrome through experiments wherein naive mice are transfused with immunoglobulin G (IgG) from PANDAS mice. Depletion of IgG from donor sera abrogates behavior changes. These functional disturbances link to the autoimmunity-related IgG1 subclass but are not attributable to differences in cytokine profiles. The mode of disrupting blood–brain barrier integrity differentially affects the ultimate CNS distribution of these antibodies and is shown to be an additional important determinant of neuropsychiatric outcomes.

Donor mice were immunized with inactivated GABHS, complete Freund’s adjuvant (CFA) and phosphate-buffered saline (PBS) while a control group was immunized with only CFA/PBS. One set of donor mice were immunized at 4 weeks consisting of 44 GABHS and 38 PBS. A second set of donor mice were immunized at 6 weeks consisting of 33 GABHS and 35 PBS. Both groups were boosted three times at three week intervals with either GABHS/IFS/PBS (GABHS groups) or just IFA/PBS (Control groups).

24 GABHS mice were chosen to contribute to a GABHS serum pool. 20 control mice were chosen to contribute to a PBS serum pool. Concentrations of Ig subclasses of 17 GABHS mice (of the 24) that contributed to the GABHS serum pool were analyzed as were 17 mice (of the 20) that contributed to the PBS pool.

The GABHS pool and the PBS pool were split, and one of each had their IgG depleted. Various cytokines, interleukins, and chemokines were analyzed.

Passive transfer mice received one of the four serums (GABHS = 9 mice, IgG depleted GABHS = 7 mice, PBS 6 mice, IgG depleted PBS = 7 mice). And then Lipopolysaccharide from E. coli at 15 min. and 24 h to increase blood-brain barrier (BBB) permeability.

Robust Antigen Specific Th17 T Cell Response to Group A Streptococcus Is Dependent on IL-6 and Intranasal Route of Infection

[edit]

Group A Streptococcus intranasal infection promotes CNS infiltration by streptococcal-specific Th17 cells

[edit]
  • 12/14/2015
  • [2]
  • Thamotharampillai Dileepan, Erica D. Smith, Daniel Knowland, Martin Hsu, Maryann Platt, Peter Bittner-Eddy, Brenda Cohen, Peter Southern, Elizabeth Latimer, Earl Harley, Dritan Agalliu, and P. Patrick Cleary
  • J Clin Invest. 2016;126(1):303–317. https://doi.org/10.1172/JCI80792.

Demonstrated a novel pathway for Th17 infiltration to the brain via the nasal bulb. Intranasal challenge of repeatedly GAS-inoculated mice promoted migration of GAS-specific Th17 cells from NALT into the brain, BBB breakdown, serum IgG deposition, microglial activation, and loss of excitatory synaptic proteins under conditions in which no viable bacteria were detected in CNS tissue. CD4+ T cells were predominantly located in the olfactory bulb (OB) and in other brain regions that receive direct input from the OB.

Hello from the Other Side: How Autoantibodies Circumvent the Blood–Brain Barrier in Autoimmune Encephalitis

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A review of the proposed triggers for various autoimmune encephalopathies and their animal models, as well as basic structural features of the BBB and how they differ among various CNS regions, a feature that likely underlies some regional aspects of autoimmune encephalitis pathogenesis. Discussion of the routes that antibodies and immune cells employ to enter the CNS and their implications for AE. Analysis of future therapeutic strategies that may either preserve or restore barrier function and thereby limit immune cell and autoantibody infiltration into the CNS.

Differential binding of antibodies in PANDAS patients to cholinergic interneurons in the striatum.

[edit]
  • 03/01/2018
  • [4] (Abstract only)
  • Frick LR, Rapanelli M, Jindachomthong K, Grant P, Leckman JF, Swedo S, Williams K, Pittenger C
  • Brain Behav Immun. 2018 Mar;69:304-311. doi: 10.1016/j.bbi.2017.12.004. Epub 2017 Dec 9.

Sera from children with well-characterized PANDAS (n = 5) from a previously described clinical trial (NCT01281969), and matched controls, were infused into the striatum of mice; antibody binding to interneurons was characterized using immunofluorescence and confocal microscopy. Antibodies from children with PANDAS bound to ∼80% of cholinergic interneurons, significantly higher than the <50% binding seen with matched healthy controls. There was no elevated binding to two different populations of GABAergic interneurons (PV and nNOS-positive), confirming the specificity of this phenomenon.


Th17 lymphocytes drive vascular and neuronal deficits in a mouse model of postinfectious autoimmune encephalitis

[edit]
  • 06/16/2020
  • [5]
  • Maryann P. Platt, Kevin A. Bolding, Charlotte R. Wayne, Sarah Chaudhry, Tyler Cutforth, Kevin M. Franks, and Dritan Agalliu

Demonstrate how Th17 lymphocytes are critical for autoantibodies against neuronal receptors and synaptic proteins to enter into the CNS, persistent microglia activation, and neurophysiological deficits in odor processing, in a mouse model of postinfectious autoimmune encephalitis triggered by multiple infections with group A Streptococcus.



In 2010, a mouse model of PANDAS demonstrated that blood serum from donor mice that have been inoculated and triple boosted with Group A β-hemolytic streptococcus (GABHS), when passively transferred to naive mice, reproduced the increased rearing and passive social behavior of donor mice (but had no impact on motor coordination).

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