Autoantibodies in Long COVID

Investigating the autoimmune and immune dysregulation mechanisms underlying Long COVID to improve diagnosis, treatment, and biological understanding of persistent symptoms.
Completed Other Adaptive Immunity Autoantibodies Autoantigens Biological & Mechanistic Biomarker Discovery Experimental Platforms & Models Human Cohorts Immune Profiling T Cell Biology Translational & Clinical

Funding Year: 2022

Project Overview

Long COVID causes persistent symptoms — including pain, fatigue, cognitive dysfunction, and disability — in a significant proportion of individuals following COVID-19 infection, but its biological drivers remain poorly understood. This project analyzed blood samples from Long COVID patients to identify biomarkers and autoantibodies that may explain ongoing symptoms. Key findings include elevated ANA positivity in Long COVID compared to healthy controls, associations between specific autoantibodies (histone 2B, histone 1, nucleolin) and more severe symptoms in those with severe acute COVID, elevated Spike-specific CD8+ T cell activation in a subset of patients, and no evidence of neural autoantibodies driving cognitive symptoms — pointing instead to alternative mechanisms including viral RNA-induced type I interferon activity and reduced circulating serotonin levels.

Impact & Innovation

Mapping the immune roots of Long COVID.

 

By identifying elevated ANA positivity, disease-associated autoantibodies, and Spike-specific T cell activation in Long COVID patients, this project builds a biological framework for understanding persistent post-viral immune dysregulation — and points toward new diagnostic and therapeutic strategies.

  • Establishes that autoimmune and immune dysregulation mechanisms — including specific autoantibodies and altered serotonin levels — are measurable features of Long COVID, opening new paths for diagnosis and treatment
  • Catalyzed over $2.1M in follow-on funding across NIH, Good Shepherd Penn Partners, and the Polybio Research Foundation, and laid the biological foundation for the University of Pennsylvania’s Long COVID research program
  • Advances the Consortium’s Shared Mechanisms Across Autoimmune Diseases pillar by connecting post-viral immune dysregulation, autoantibody production, and persistent inflammation to broader mechanisms relevant across autoimmune conditions
Research Approach

A framework designed for discovery

This project combined clinical phenotyping, biomarker profiling, and autoantibody analysis of blood samples from Long COVID patients to characterize the immune and autoimmune mechanisms underlying persistent post-COVID symptoms. The work integrates biological sample collection with clinical measures to build a foundational dataset for Long COVID research.

Blood sample collection and biological specimen banking from Long COVID patients; ANA testing and autoantibody profiling including histone 2B, histone 1, and nucleolin; Spike-specific CD8+ T cell activation analysis; standardized physical and cognitive assessments including MoCA and ADL measures; and analysis of serotonin levels and type I interferon activity as potential drivers of persistent symptoms.

Blood samples and biological specimens from Long COVID patients at the Post-COVID Assessment and Recovery Clinic at Penn; standardized clinical assessment datasets; autoantibody and ANA profiling datasets compared against healthy controls and severe acute COVID patients; and longitudinal follow-up data from acute to 12-18 months post-discharge.

Identification of autoimmune and immune dysregulation signatures in Long COVID, with translational goals including improved diagnostics, therapeutic target identification, and clinical care strategies for individuals with Long COVID. Findings have been foundational to Penn’s Long COVID research program and have catalyzed inter-departmental, inter-university collaborations and over $2.1M in follow-on grant funding.

Investigators & Institutions

Powering the science

Principal Investigator

Benjamin Abramoff, MD, MS, Colton Consortium Member

Associate Professor, Department of Physical Medicine and Rehabilitation, Perelman School of Medicine, University of Pennsylvania

Colton Centers & Institutions

Colton Center for Autoimmunity at the University of Pennsylvania

Perelman School of Medicine

Research Outputs

From insight to impact

Publications

Serotonin reduction in post-acute sequelae of viral infection

Cell
Wong, AC; Devason, AS; Umana, IC; Cox, TO; Dohnalová, L; Litichevskiy, L; Perla, J; Lundgren, P; Etwebi, Z; Izzo, LT; Kim, J; Tetlak, M; Descamps, HC; Park, SL; Wisser, S; McKnight, AD; Pardy, RD; Kim, J; Blank, N; Patel, S; Thum, K; Mason, S; Beltra, JC; Michieletto, MF; Ngiow, SF; Miller, BM; Liou, MJ; Madhu, B; Dmitrieva-Posocco, O; Huber, AS; Hewins, P; Petucci, C; Chu, CP; Baraniecki-Zwil, G; Giron, LB; Baxter, AE; Greenplate, AR; Kearns, C; Montone, K; Litzky, LA; Feldman, M; Henao-Mejia, J; Striepen, B; Ramage, H; Jurado, KA; Wellen, KE; O'Doherty, U; Abdel-Mohsen, M; Landay, AL; Keshavarzian, A; Henrich, TJ; Deeks, SG; Peluso, MJ; Meyer, NJ; Wherry, EJ; Abramoff, BA; Cherry, S; Thaiss, CA; Levy, M October 2023
Animal ModelsBiological & MechanisticBiomarker DiscoveryCytokine SignalingExperimental Platforms & ModelsHuman CohortsNeuro-Immune InteractionsTranslational & ClinicalOtherUniversity of Pennsylvania

Additional Outputs

  • NIH U19AI082630 — $500,000, 5 years (Benjamin Abramoff, PI)
  • Good Shepherd Penn Partners — $40,000, 1 year (Benjamin Abramoff and Monica Kuns, Co-PIs)
  • NIH R01-HD108312-01A1 — $1,500,000, 3 years (Timothy Dillingham, PI)
  • Polybio Research Foundation — $71,000, 2 years (Sara Cherry, PI).

Impact of Post-Acute Sequelae of SARS-CoV-2 (PASC) on Health-Related Quality of Life

More Than MoCA: Its Limitations in Detecting Functional Cognitive Impairment

Investigating the Role of Autoantibodies and Circulating Biomarkers in the Pathophysiology of Long COVID.