Tu149 - Plasma from Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) Induces Increased BBB Permeability Through Disruption of Tight Junction Proteins

Tuesday, June 21, 2022

6:15 PM – 7:45 PM PT

Presenting Author(s)

AM

Ayan Mondal, PhD

Postdoctoral Researcher
Standard University
Stanford, California, United States

Co-Author(s)

Shamma S. Rahman, PhD

Postdoctoral Scholar
Stanford University
San Mateo, California, United States
AK

Agnieszka Kalinowski, n/a

Stanford University
Stanford, California, United States
TW

Theresa Willett, n/a

Stanford University
Stanford, California, United States
MS

Melissa Silverman, n/a

Stanford University
Stanford, California, United States
MT

Margo Thienemann, n/a

Stanford University
Stanford, California, United States
LC

Laurie Columbo, n/a

Stanford University
Stanford, California, United States
JF

Jennifer Frankovich, n/a

Stanford University
Stanford, California, United States
BT

Binu Tharakan, PhD

Associate Professor
Morehouse School of Medicine
Atlanta, Georgia, United States
EM

Elizabeth D. Mellins, n/a

Professor
Stanford University
Stanford, California, United States

Pediatric acute-onset neuropsychiatric syndrome (PANS) is characterized by abrupt onset of obsessive-compulsive disorder (OCD) or severe food restriction and concurrent abrupt onset of other neuropsychiatric symptoms- thought to be caused by a post-infectious inflammation. Diagnosis of PANS is particularly challenging due to lack of specific biomarkers. We have identified increased circulating inflammatory and anti-inflammatory monocyte subsets, the latter also in cerebral spinal fluid (CSF) in PANS in various clinical states (e.g., flare, improvement). Immune cells, including monocytes, are impermeable to the healthy blood brain barrier (BBB). Anatomically, brain microvascular endothelial cells (BEC) is the main constituent of the BBB, forming a selective semipermeable border that prevents solutes in the blood circulation from non-selectively crossing into the extracellular fluid of the central nervous system. BECs are tightly regulated by tight junction proteins (TJPs), specifically claudin 5, claudin 12, occludin and Zonula occludens-1 (ZO1), and act as gatekeepers of the central nervous system. Disruption of the BBB allows infiltration of leukocytes, resulting in brain edema and inflammatory injury. In the present study, we found that PANS flare plasma at 1% volume increased the permeability to 10 kDa dextran of a human brain endothelial cell (hBEC) monolayer by >2-fold in 24hr as compared to healthy control plasma. Furthermore, PANS flare plasma at 1% volume decreased expression of TJPs (claudin 5, ZO-1) and adherent junction protein, VE-Cadherin, in 24hr. Decreased TJP expression is the hallmark of compromised BBB function and may allow blood leukocytes to cross the BBB in diseased conditions.