CNS Autoimmune Disease after Streptococcus Pyogenes Infections: Animal Models, Cellular Mechanisms and Genetic Factors

Abstract

Streptococcus pyogenes infections have been associated with two autoimmune diseases of the CNS: Sydenham's chorea (SC) and pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections (PANDAS). Despite the high frequency of pharyngeal streptococcus infections among children, only a small fraction develops SC or PANDAS. This suggests that several factors in combination are necessary to trigger autoimmune complications: specific S. pyogenes strains that induce a strong immune response toward the host nervous system; genetic susceptibility that predispose children toward an autoimmune response involving movement or tic symptoms; and multiple infections of the throat or tonsils that lead to a robust T_h17 cellular and humoral immune response when untreated. In this review, we summarize the evidence for each factor and propose that all must be met for the requisite neurovascular pathology and behavioral deficits found in SC/PANDAS.

KEYWORDS:

• autoantibodies
• autoimmunity
• blood–brain barrier
• gene set analysis
• MHC
• PANDAS
• pathway-based genomic studies
• Streptococcus pyogenes
• Sydenham's chorea
• T_h17 cell

Financial & competing interest disclosure

T Cutforth and D Agalliu are supported by grants from the NIH/NHLBI (R01 HL116995–01) and National Multiple Sclerosis Society (RG4673A1/1) and a generous donation from Newport Equities, LLC. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Acknowledgement

T Cutforth and D Agalliu thank Holly and Mark Kerslake from Newport Equities, LLC for their generous financial support that enabled our laboratory to develop a new animal model for SC/PANDAS by means of intranasal S. pyogenes infections.

Additional information

Funding

T Cutforth and D Agalliu are supported by grants from the NIH/NHLBI (R01 HL116995–01) and National Multiple Sclerosis Society (RG4673A1/1) and a generous donation from Newport Equities, LLC. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.