Human genetic studies aimed at understanding and treating pediatric autoimmune disease

Dr. Cutforth’s strong background in genetics has prompted him to take advantage of 21st century breakthroughs in human gene sequencing technology and statistical approaches to ask the basic question: are there discrete genetic loci that predispose a small subset of children to develop PANS/PANDAS or Sydenham’s chorea, collectively known as basal ganglia encephalitis (BGE)? In collaboration with Hakon Hakonarson’s group at the Center for Applied Genomics, Children’s Hospital of Philadelphia, we are in the midst of a large-scale recruitment and sequencing effort, employing both GWAS and whole-exome methods. Our initial candidates arising from the first 60 cases reveal several genes that appear to regulate immune function, and we are using our mouse model for post-streptococcal BGE to validate these candidate genes and determine their mechanistic roles during the course of disease.

In a second project, we have identified a robust serum profile of 19 signature cytokines and growth factors that are associated with PANS/PANDAS, representing the first biomarker for this enigmatic disease and promising to revolutionize its diagnosis, treatment monitoring and ultimately novel therapeutic targets. Many of these biomarkers have been shown to directly open the human blood-brain barrier in our in vitro model that employs endothelial-like cells derived from induced pluripotent stem cells (iPSCs), thus providing a mechanistic link between inflammatory serum components and leakage of pathogenic antibodies into the brain as a likely trigger for BGE as well as many other autoimmune encephalitides.