303 - HLA-B and KIR in Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS)

Publication Number: 2293.303

Noelle Schlenk, Stanford University School of Medicine, Olathe, KS, United States; Kerry Kizer, University of California, San Francisco, School of Medicine, San Francisco, CA, United States; Cindy Manko, Stanford University School of Medicine, Palo Alto, CA, United States; Bahare Farhadian, Lucile Packard Children's Hospital Stanford, Palo Alto, CA, United States; Meiqian Ma, Stanford University School of Medicine, Palo Alto, CA, United States; Yuhuan Xie, Stanford Medicine, Stanford, CA, United States; Paula Tran, Stanford University School of Medicine, Palo Alto, CA, United States; Melissa Silverman, Stanford University School of Medicine, Stanford, CA, United States; Margo Thienemann, Stanford University School of Medicine, Redwood City, CA, United States; Marcello M. Fernandez Vina, Stanford University School of Medicine, Stanford, CA, United States; Jill Hollenbach, University of California, San Francisco, School of Medicine, San Francisco, CA, United States; Jennifer Frankovich, Stanford University School of Medicine, Palo Alto, CA, United States

Background: Pediatric acute-onset neuropsychiatric syndrome (PANS), Sydenham chorea (SC), and other post-infectious psychiatric deteriorations are believed to result from autoimmune/inflammatory processes. Autoantibody, imaging, and sleep studies in PANS suggest that the pathogenic mechanism involves immune-mediated basal ganglia dysfunction. While there is compelling evidence for a high rate of heritability among these conditions, their underlying genetic components remain largely unexplored.

Objective: Our objective is to investigate genotypes in the HLA-B or KIR region that are associated with PANS.

Design/Methods: We used next-generation sequencing (NGS) to characterize human leukocyte antigen (HLA) and related killer immunoglobulin-like receptor (KIR) associations among 112 consecutive patients with PANS seen at a single center and a control cohort of 1,364 ancestry-matched controls.

Results: The Bw4 allotype with residues IALR in HLA-B positions 80-83, a high-affinity ligand for inhibitory KIR receptor KIR3DL1, displayed a significant association in our PANS cohort (p, 0.002; OR, 2.47; 95% CI, 1.67-3.66). Further investigation of coexisting Bw4-80I and KIR3DL1 loci revealed a stand-out signal at KIR3DL1*004 (p, 0.002; OR, 2.50; 95% CI, 1.47-4.10), with the Bw4-80I/KIR3DL1*004 genotype observed in 20% of patients and 9% of controls.

Conclusion(s): The significance of the Bw4-80I and KIR3DL1*004 interaction implicates a role for NK cells and possibly CD8+ T cells in PANS pathology.