bioRxiv : the preprint server for biologySep 2, 2025

Ongoing Immune Imbalance after COVID-19 Includes Antibodies Targeting Virus Outer and Core Proteins

Long Covid Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jan 19, 2026

Abstract

PASC participants exhibited persistently elevated IgG titers for SARS-CoV-2 Envelope and Nucleocapsid proteins over 6 months.

Compared to convalescent individuals, those with PASC had significantly higher IgG levels for specific SARS-CoV-2 proteins.
IgG responses to Spike protein were notably lower in the PASC cohort, with a bias towards IgG1 and IgG3 classes.
Elevated numbers of circulating T follicular helper cells and mucosa-associated invariant T cells were observed in PASC participants.
There was a correlation between high anti-Envelope IgG titers and increased levels of circulating T follicular helper cells.
PASC participants displayed increased serum cytokines, including LIF, IL-11, Eotaxin-3, and HMGB-1, indicating persistent immune activation.
Higher rates of autoantibodies were found in participants with PASC.

Simplified

Post-Acute Sequelae of SARS-CoV-2 infection (PASC) syndrome or "Long COVID" represents a widespread health challenge that necessitates the development of novel diagnostic approaches and targeted therapies that can be readily deployed. Immune dysregulation has been reported as one of the hallmarks of PASC, but the extent of PASC immune dysregulation in patients over time remains unclear. We therefore assessed SARS-CoV-2-specific antibody responses, peripheral immune cell profiles, autoantibody profiles and circulating cytokines for up to 6 months in participants with a SARS-CoV-2 infection who either convalesced or developed PASC. Compared to convalescent, PASC participants with a broad range of PASC phenotypes exhibited persistently elevated IgG titers for SARS-CoV-2 Envelope and Nucleocapsid proteins over the 6 months of study duration. In contrast, the IgG responses to Spike protein were significantly lower in the PASC cohort with predominantly IgG1 and IgG3 class-switched bias. Using CyTOF analysis, we show elevated numbers of circulating T follicular helper cells (cTFH) and mucosa-associated invariant T cells (MAIT), which also correlated with high anti-Envelope IgG titers. Persistent immune activation was accompanied by augmented serum cytokine profiles with LIF, IL-11, Eotaxin-3, and HMGB-1 in PASC participants, who also demonstrated significantly higher rates of autoantibodies. These findings highlight the persistence of immune dysregulation in PASC, underscoring the need to explore targeted therapies addressing viral persistence, dysregulated antibody production, and autoimmunity.

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Funding

Competing interests

Disclosures: Jerry A. Krishnan, MD, PhD, reports grants from National Institutes of Health during the conduct of the study; research grants from the American Lung Association, BioVie Pharma, COPD Foundation, and Patient Centered Outcomes Research Institute outside the submitted work; and personal fees from AstraZeneca, Inogen, MedImmune, RespirAI, and Verona Pharma.

PubMed

Ongoing Immune Imbalance after COVID-19 Includes Antibodies Targeting Virus Outer and Core Proteins

Abstract

Full Text

Funding

Competing interests

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Abstract

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Funding

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