Katherine Caras Pacific Lutheran University. Dr. Tom Carlson Dr. Rosalind Billharz PLU Biology...
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Transcript of Katherine Caras Pacific Lutheran University. Dr. Tom Carlson Dr. Rosalind Billharz PLU Biology...
Role of Autoimmunity in Cases of Tourette’s Syndrome (TS)
classified as PANDAS
Katherine CarasPacific Lutheran University
Dr. Tom Carlson Dr. Rosalind Billharz PLU Biology Department
Acknowledgements
Epidemiology of TS3% of school-age children (Du et al. 2010)
30% special needs children (Eapen et al. 1997).
Giles de La Tourette 19th Century: Psychiatric causes of tics
20th Century: Genetic and neurobiological etiologies
Tourette’s Syndrome (TS) is characterized by tics.
Giles de La Tourette
(http://www.baillement.com/lettres/tourette.html)
Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infection (PANDAS)
Coined by Swedo et al. (1998)
Group A βeta Hemolytic Streptococcal Infection (GABHS)
The PANDAS hypothesis implicates post-infectious, cross-reactive antibodies in the pathophysiology of neuropsychiatric disorders
Group A Beta hemolytic streptococci (http://www.health-writings.com/tags/beta/1/)
Support for PANDAS is inconclusive, but current findings implicate post-infectious autoimmunity in the onset and modulation of OCD and TS.
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)
Controls
• noninfectious neurological disease (NNID)
• uncomplicated streptococcal infection
• Healthy
Assays for immune markers
• Antistreptolysin O titer (ASOT)
• Western immunoblotting
• Indirect immunofluorescence
Cross-sectional study investigated whether streptococcal infection and autoimmunity were more common in TS subjects (Church et al. 2003).
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
TS Sydenham’s Chorea (SC)
MW
IgG
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)
Associations between GABHS and TS/OCD generates questions about immune mechanisms that trigger PANDAS symptoms.
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)
• 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
Mice were injected with anti-streptococcal immunoglobulins in order to determine the cause of behavioral symptoms of PANDAS (Zhang
et al. 2012).
• 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
Reactions between IgMs and antigens are associated with behaviors that were distinct from symptoms mainly related to IgGs.
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).
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
Both Church et al. and Zhang et al. raise questions about the pathophysiology of PANDAS.
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)
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
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