1. Katherine Caras Pacific Lutheran University

2.  Dr. Tom Carlson  Dr. Rosalind Billharz  PLU Biology Department

3. Epidemiology of TS 3% of school-age children (Du et al. 2010) 30% special needs children (Eapen et al. 1997). Giles de La Tourette 19 th Century: Psychiatric causes of tics 20 th Century: Genetic and neurobiological etiologies Giles de La Tourette (http://www.baillement.com/lettres/tourette.html)

4. Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infection (PANDAS) Coined by Swedo et al. (1998) Group A βeta Hemolytic Streptococcal Infection (GABHS) Group A Beta hemolytic streptococci (http://www.health-writings.com/tags/beta/1/)

5. Detection of association between GABHS and TS and OCD (Church et al. 2003 ) Investigate immune mechanisms of PANDAS and of TS Association between immune dysfunction and symptoms of TS and OCD (Zhang et al. 2012)

6. Controls noninfectious neurological disease (NNID) uncomplicated streptococcal infection Healthy Assays for immune markers Antistreptolysin O titer (ASOT) Western immunoblotting Indirect immunofluorescence

7. Recent streptococcal infection and anti-basal ganglia autoimmunity are more common in TS subjects (Church et al. 2003). High ASOTs IgGs bind 60 kDA antigen Localized IgG binding to large basal ganglia neurons IgG 60 kDA Figure 1: Western immunoblot against basal ganglia homogenate detects IgG reactivity to basal ganglia antigens (Church et al. 2003) 60 kDA Positive Control TSSydenham’s Chorea (SC) MW IgG

8. Church et al. supports PANDAS hypothesis, but study has its limitations. Connects GABHS infection with cross-reactive ABGA s No temporal associations Does not explain specific autoimmune mechanisms Figure 2: Indirect immunofluorescence shows ABGA binding to basal ganglia neurons (Church et al. 2003)

9. Detection of association between GABHS and TS and OCD (Church et al. 2003) Investigate immune mechanisms of PANDAS and of TS Association between immune dysfunction and symptoms of TS and OCD (Zhang et al. 2012)

10. Investigate whether Ig-class and antigen influenced the production of symptoms Detect deposits of fluorescent IgMs in brains Determine if IgMs increased the number of immunoreactive Fos cells in brains

11. Behaviors that increased significantly after IgM injection differed from those that were positively correlated with IgGs IgM-associated symptoms were not the general effects of IgMs

12. IgM reactivity was detected in the brains of mice. IgMs Localize with Fcα/µ receptors Increase number of Fos cells Affected brain areas Cortico-striato-thalamo- cortical circuit (CSTC) Motor Cortex Figure 3: The number of immunoreactive Fos cells in sections of the motor cortex (M1, M2) increased after injection with IgMs (Zhang et al. 2012).

13. Post-infectious IgMs are linked with behavioral symptoms of PANDAS. Ig class and antigen influence the production of behavioral symptoms of PANDAS Findings of IgM reactivity in the CNS were consistent with behavioral observations of mice. Figure 4: Fluorescently labeled IgM deposits in motor cortex

14. Detection of association between GABHS and TS and OCD (Church et al. 2003) Investigate immune mechanisms of PANDAS and of TS Association between immune dysfunction and symptoms of TS and OCD (Zhang et al. 2012)

15. Future PANDAS research can have important clinical implications. Topics for future research Crossing of blood brain barrier (BBB) by antibodies Immune dysfunction –TS v. PANDAS Clinical Implications Diagnosis Immunotherapies

16. Future PANDAS research can have important clinical implications. Topics for future research Crossing of blood brain barrier (BBB) by antibodies Immune dysfunction –TS v. PANDAS Questions? Clinical Implications Diagnosis Immunotherapies