Published online June 2, 2008
PEDIATRICS Vol. 121 No. 6 June 2008, pp. 1198-1205 (doi:10.1542/peds.2007-2658)
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ARTICLE

Serial Immune Markers Do Not Correlate With Clinical Exacerbations in Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections

Harvey S. Singer, MDa, Colin Gause, BSa, Christina Morris, MSa, Pablo Lopez, PhDb and the Tourette Syndrome Study Group

Departments of a Neurology
b Pharmacology, Johns Hopkins University School of Medicine, Baltimore, Maryland

OBJECTIVE. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections is hypothesized to be a poststreptococcal autoimmune disorder. If clinical exacerbations are triggered by a streptococcal infection that activates cross-reacting antibodies against neuronal tissue or alters the production of cytokines, then a longitudinal analysis would be expected to identify a correlation between clinical symptoms and a change in autoimmune markers.

PATIENTS AND METHODS. Serial serum samples were available on 12 children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections participating in a prospective blinded study: 2 samples before an exacerbation point, 1 during the clinical exacerbation, and 2 after the exacerbation. Six subjects had a well-defined clinical exacerbation in association with a documented streptococcal infection, and 6 had a clinical exacerbation without an associated streptococcal infection. All of the serum samples were assayed for antibodies against human postmortem caudate, putamen, and prefrontal cortex; commercially prepared antigens; and complex sugars. Cytokines were measured by 2 different methodologies.

RESULTS. No correlation was identified between clinical exacerbations and autoimmune markers, including: enzyme-linked immunosorbent assay measures of antineuronal antibodies; Western immunoblotting with emphasis on brain region proteins located at 40, 45, and 60 kDa or their corresponding identified antigens; competitive inhibition enzyme-linked immunosorbent assay to evaluate lysoganglioside GM1 antibodies; and measures of inflammatory cytokines. No differences were identified between individuals with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections with or without exacerbations triggered by streptococcal infections.

CONCLUSIONS. The failure of immune markers to correlate with clinical exacerbations in children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections raises serious concerns about the viability of autoimmunity as a pathophysiological mechanism in this disorder.

Key Words: PANDAS • longitudinal analysis • antineuronal antibodies • cytokines • lysoganglioside GM1

Abbreviations: PANDAS—pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections • GABHS—group A β-hemolytic streptococci • ELISA—enzyme-linked immunosorbent assay • ExWS—exacerbation with streptococcal infection • ExWOS—exacerbation without streptococcal infection • BA10—Brodmann's area 10 • PBS—phosphate-buffered saline • Ig—immunoglobulin • TBS-T—Tris-buffered saline containing 0.1% Tween 20 • BSA—bovine serum albumin • GlcNAc—N-acetyl-β-D-glucosamine • Th—T-helper • IL—interleukin • TNF—tumor necrosis factor • MCP—macrophage chemoattractant protein • RANTES—regulated upon activation, normal T cell expressed and secreted • AUC—area under the curve

Accepted Nov 12, 2007.




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