Preprint Persistent Immune Dysregulation during Post-Acute Sequelae of COVID-19 … Antibodies Targeting Envelope and Nucleocapsid Proteins, 2025, Kwisa et al.

[Chandelier]

Persistent Immune Dysregulation during Post-Acute Sequelae of COVID-19 is Manifested in Antibodies Targeting Envelope and Nucleocapsid Proteins​

https://www.biorxiv.org/content/10.1101/2025.08.18.670908v1

Abstract​

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.

Competing Interest Statement​

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.

Spoiler: Authors

Marcin Kwissa, Manikannan Mathayan, Satyajeet S. Salunkhe, Velavan Bakthavachalam, Zijing Ye, Mark A. Sanborn, Samantha Condo, Aditi Upadhye, Athulith Nemakal, Justin M. Richner, Sanjib Basu, Richard M. Novak, Jeffrey R. Jacobson, Balaji B Ganesh, Martha Cerda, Paul J. Utz, Jerry A. Krishnan, Bellur S. Prabhakar, Jalees Rehman

 

[Chandelier]

Ryan Hisner posted an analysis of this paper on Bluesky:

Page by Ryan Hisner | @ryanhisner.bsky.social

A fascinating new preprint w/one very unexpected finding suggests, I believe, that a large proportion of Long Covid may be due to chronic infection in a particular bodily niche, which could be crucial for finding effective LC treatments. It requires some explaining. 1/33

skywriter.blue

This preprint not only adds to the evidence pointing to persistent infection but hints that cryptic viral reservoirs in the deep lung may be involved in LC. Much remains mysterious, but I think this is a possibility worth pursuing.

 

[Yann04]

 

[SNT Gatchaman]

Small cohorts 20 PASC vs 10 CONV, with unbalanced sex: 90% female in PASC and 50% female in CONV.

Nevertheless quite a lot of discussion on MAIT T cells, aberrant class switching (IgG1 and IgG3 dominant in PASC, IgG2 and IgG4 dominant in CONV).

We further evaluated potential changes in the Ig heavy, kappa, and lambda variable chains in plasma of PASC and CONV cohorts (Figure 2C). Fold-change analysis revealed that multiple variable region peptides were significantly upregulated in individuals with PASC compared to convalescent controls (CONV). As shown in the volcano plot (Figure 2C), numerous IGHV, IGKV, and IGLV chains exhibited elevated expression, highlighting a broader shift in variable region usage or expansion of specific B cell clones in the PASC group.

My arrow highlights IGHV3-30-3, which was the gene usage discussed in Deep sequencing of BCR heavy chain repertoires in myalgic encephalomyelitis/chronic fatigue syndrome (2025)