# Prevention Center U01: Early Targets for Antigen-Specific Tolerance Induction in Preclinical Rheumatoid Arthritis

> **NIH NIH U01** · UNIVERSITY OF COLORADO DENVER · 2020 · $627,429

## Abstract

It is now known that rheumatoid arthritis (RA)-related autoantibodies, including autoantibodies to citrullinated
peptide/protein antigens (ACPA) and rheumatoid factors (RF), are found in asymptomatic individuals for an
average of 3-5 years prior to the development of clinically apparent arthritis. This autoantibody positive but
asymptomatic phase is characterized by progressive epitope spreading and the development of increased
systemic inflammation, ultimately culminating in classified RA. The understanding of this process has
progressed such that an NIH-funded, double blind, placebo controlled prevention trial in very high risk
asymptomatic ACPA+ individuals has been initiated. The investigative group for this application now proposes
to focus efforts on understanding the molecular mechanisms that underlie the initiation, development and
evolution of RA-related autoimmunity in this preclinical period, with the goals of identifying the inciting
antigen(s) and developing tolerance strategies that could be utilized in these early disease phases. As outlined
within the proposal, ongoing studies have strongly suggested that the immune process ultimately manifesting
clinically as RA is initiated at mucosal sites and is associated with local inflammation and local autoantibody
production, which in a subset of individuals evolves to become systemic autoimmunity detected through blood-
based autoantibody biomarkers. Major preliminary findings have included that the peripheral blood plasmablast
pool in the at-risk population is uniquely characterized by expanded IgA isotype expressing cells and dual
IgA/IgG clonal families. Additionally, sampling the lung and gut mucosa in at-risk subjects through studies of
sputum and feces, respectively, has revealed that an elevated proportion of individuals locally express IgA
ACPA, and only a small subset of bacterial families is specifically recognized by locally produced IgA. With
these findings, it should now be possible to identify the citrullinated epitopes to which pathogenic B and T cells
respond locally and systemically, as well as understand how local mucosal immune responses to a subset of
bacteria influence development of RA-related autoimmunity. This knowledge is critical to our understanding of
the immunologic mechanisms that underlie disease development as well as the design of tolerance-inducing
therapies. Notably, the Co-Investigators in this CSGADP application, Drs. Kuhn, Robinson and Buckner, have
developed novel approaches to characterize the mucosal immune response and also identify antigen-specific
B and T cell responses to citrullinated and other RA-related autoantigens. To advance our understanding of the
immune and autoimmune responses at these earliest time points, the investigators propose to utilize these
techniques in at-risk subjects to characterize the antigen reactivity of dual IgA/IgG plasmablasts and mucosally
produced IgA/IgG, determine which citrullinated antigens and microbial spe...

## Key facts

- **NIH application ID:** 9965813
- **Project number:** 5U01AI101981-09
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Vernon Michael Holers
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $627,429
- **Award type:** 5
- **Project period:** 2012-07-05 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9965813

## Citation

> US National Institutes of Health, RePORTER application 9965813, Prevention Center U01: Early Targets for Antigen-Specific Tolerance Induction in Preclinical Rheumatoid Arthritis (5U01AI101981-09). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9965813. Licensed CC0.

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