# Elucidating the immunology of autoantibody formation and function in COVID-19

> **NIH NIH R01** · STANFORD UNIVERSITY · 2023 · $750,712

## Abstract

Project Summary
 Surprisingly little is known about the regulation of B cell tolerance during infection; thus,
the overarching goal of our studies is to characterize autoantibodies in COVID-19, focusing on
their inflammatory capacity and abnormal regulation of B cell tolerance during infection. The scale
of the COVID-19 pandemic, synchrony between infection and autoimmune manifestations, and
mobilization of resources has allowed us to generate large numbers of banked samples paired
with well-annotated clinical data - creating a once-in-a-lifetime opportunity to study the
mechanisms involved in regulation of B cell tolerance and generation of IgG autoantibodies (AAb)
and pro-inflammatory immune complexes (IC). The pathogenic roles of AAb in COVID-19 are now
widely recognized with anti-cytokine antibodies targeting type I interferons identified in ~10% of
critically ill patients, and rare in those with milder disease. More than half of patients in our
COVID-19 cohorts have evidence of at least one AAb; the overwhelming majority of those who
are AAb positive during SARS-COV-2 infections have no known cause for autoimmunity. The
clinical correlates and immunologic basis of this loss of tolerance and aberrant AAb formation in
infection are as yet unexplored.
 Elucidating the role of Fc glycosylation and impairments in the establishment of B cell
tolerance in development of AAbs has not yet been attempted but may lead to a paradigm shift
in our understanding of the immune and autoimmune responses to both COVID-19 and viral
infection more broadly. Hence, in cohorts totaling >1300 patients with acute COVID-19 infection
and >3000 samples, we propose to test the hypothesis that patients with severe infections and
poor outcomes have pathogenic IgG AAb that may appear over the course of hospitalization and
become part of the antibody repertoire even in convalescence. We will also test whether IgG
AAbs in patients with severe COVID-19 have different Fc domain repertoires and glycosylation
that favor inflammation. Finally, we postulate that serum AAb in patients with COVID-19 result
from the activation of naïve self-reactive clones that escape early B cell tolerance checkpoints.
We will determine if naïve B cell selection defects are induced by infection or are likely already
present at the time of acute infection.
Hence, our work may ultimately inform the role of early immune-modulating interventions
not only in COVID-19, but in severe infections and ARDS more broadly, particularly pneumonia
in ICU settings.

## Key facts

- **NIH application ID:** 10639707
- **Project number:** 1R01AI175771-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Eric Meffre
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $750,712
- **Award type:** 1
- **Project period:** 2023-07-11 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10639707

## Citation

> US National Institutes of Health, RePORTER application 10639707, Elucidating the immunology of autoantibody formation and function in COVID-19 (1R01AI175771-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10639707. Licensed CC0.

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