Multi-Omic Signatures of Overactive Autoantibody Activation after Pediatric Traumatic Brain Injury

Document Type

Conference Proceeding

Publication Date

3-2026

Publication Title

Critical Care Medicine

Abstract

Introduction: Evidence grows that autoantibody-mediated secondary injury in traumatic brain injury (TBI) can result in long-term outcomes. We implemented a multi-omic (transcriptomic, metabolomic, and immune-repertoire) workflow to identify early signals forecasting broad autoantibody expansion correlated to prolonged rehabilitation in pediatric TBI.

Methods: Samples were collected on days 0, 2, and 9 from seventeen children (median age13.1 y) with severe TBI (GCS < 8, mean ISS of 31), critically ill patients. Whole-blood RNA-seq, untargeted LC-MS metabolomics, and immunoglobulin heavy-/light-chain (IGH, IGK, IGL) repertoire modeling were assessed relative to clinical recovery.

Results: IGH clonal expansion was significantly elevated at day 9 (2.4 ± 1.2 clones/clonotype, p = 0.02) compared to controls (1.4 ± 0.2), day 0 (1.3 ± 0.2), and day 2 (1.3 ± 0.2). The patient with the longest rehab showed pronounced IGH activation at day 9 (6.0 clones/clonotype, z-score = 5.4), with 3,505 IGH clonotypes linked to brain antigens including Amyloid-beta, S100B, Synapsin I, NMDAR, MOG, Aquaporin-4, GAD65, and GFAP. This individual had a day 0 response enriched for immune activation (HSA-168256, FDR = 2.5E-7), membrane trafficking (HSA-199991, FDR = 4.2E-6), and Epstein-Barr virus response (hsa05169, FDR = 1.1E-5), alongside elevated lipids (PG 18:0_18:3, LPI 17:0, PE P-20:0/17:1, LPI 14:1). All timepoints showed elevated UFA/PUFA-LPC to SFA-LPC ratios and unconjugated bile acids, with enrichment of nervous system-specific genes (BTO:0001484), alternative splicing (KW-0025), and membrane-bound organelles (GOCC:0043227). Splicing outlier analysis revealed consistent use of NPC2 isoform-201 rather than isoform-207 (average z-score –1.5), resulting in a three–amino acid deletion in a protein linked to brain-lipid damage response.

Conclusions: An isoform switch in the cholesterol-regulating NPC2 may promote lipid buildup and lysosomal stress that prime antigen-presenting cells and B Cell mediated downstream injury. These findings demonstrate the power of multi-omic integration to reveal early molecular drivers of autoantibody amplification in pediatric TBI, offering critical pathways for antibody-targeted diagnostics and immunotherapy.

Volume

54

Issue

3 Suppl

Comments

Society of Critical Care Medicine Critical Care Congress, March 22-24, 2026, Chicago, IL

Helen DeVos Children's Hospital

DOI

10.1097/01.ccm.0001187976.43579.29

ISSN

1530-0293

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