# Immune Modulating HLA-Coded Ligands in Rheumatoid Arthritis

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $387,500

## Abstract

ABSTRACT
The shared epitope (SE) is the single most significant risk factor for severe rheumatoid arthritis (RA), yet its
mechanism of action is not completely understood. During budget years 01-05 of this R01 project, we identified
the SE as a signal transduction ligand that specifically interacts with a well-defined binding site on cell surface
calreticulin (CRT) and activates intracellular signaling events that lead to Th17 polarization and osteoclast
activation. When administered to mice with collagen-induced arthritis, a synthetic SE ligand enhanced the
severity of erosive joint destruction. Furthermore, based on structure-function characteristics of SE-CRT
interaction, we have therapeutically targeted the pathway with CRT-binding small molecules that potently
inhibited the arthritogenic pathway with resultant amelioration of experimental arthritis in mice.
Based on preliminary results obtained in the current funding cycle of this project, in years 06 – 10 we will carry
out experiments that will advance our understanding of the molecular mechanisms and functional outcomes of
the SE-activated pathway. Additionally, we will elucidate the signaling and functional effects of a protective
epitope (PE) ligand that we recently discovered. This ligand appears to counteract the SE pathway and may
explain a long-established but poorly understood epidemiologic association between particular HLA-DRB1
alleles and protection against RA.
The hypothesis of this project states that in RA: A. Disease-facilitating and disease-protective HLA-
DRB1alleles code for distinct ligands, which transduce reciprocal cell activation and differentiation signals; B.
The SE pathway activates protein citrullination. The research plan in the coming 5 years will address this
hypothesis with the following specific aims: 1. To delineate the respective signaling pathways activated by the
SE and PE ligands and determine their functional effects on cell differentiation; 2. To analyze signature HLA-
DRB1-coded ligand-activated transcriptomes using an RNA-seq approach; 3. To characterize the mechanism
of a recently discovered SE-activated protein citrullination pathway, and determine its in vivo effects.
Successful completion of the proposed research will illuminate fundamental questions concerning HLA-disease
association, provide important new insights into the pathogenesis and etiology of RA, and set the stage for
designing novel therapeutic strategies.

## Key facts

- **NIH application ID:** 9981415
- **Project number:** 5R01AR059085-10
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Joseph Holoshitz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $387,500
- **Award type:** 5
- **Project period:** 2011-08-18 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9981415

## Citation

> US National Institutes of Health, RePORTER application 9981415, Immune Modulating HLA-Coded Ligands in Rheumatoid Arthritis (5R01AR059085-10). Retrieved via AI Analytics 2026-05-30 from https://api.ai-analytics.org/grant/nih/9981415. Licensed CC0.

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