# Interaction of environment and genetics in predisposition to inflammatory arthritis

> **NIH VA I01** · PORTLAND VA MEDICAL CENTER · 2021 · —

## Abstract

Arthritis, a chronic immune-mediated disease involving painful destruction of the joints, presents a
considerable medical challenge to our US Veteran population due to incomplete understanding of its
pathogenesis. An emerging paradigm proposes that self-reactive (or autoreactive) T cells influenced by
genetic-environmental interactions initiate and perpetuate disease. Understanding how these factors
contribute to generation of autoreactive T cells and their subsequent expansion and ability to cause disease is
centrally important in determining the etiology of arthritis. This project aims to address this critical question in
the field of autoimmunity by focusing on the relationships between autoreactive T cells, the epithelial cells
within the thymus, and the innate immune receptor Nod2. T cell development and “education” occurs within the
thymus, a primary lymphoid organ that serves a critical role in eliminating self-reactive T cells and preventing
autoimmune disease. In the unfortunate event that autoreactive T cells leave the thymus and enter the
periphery, they can become activated and differentiate into IL-17-secreting T cells (Th17 cells), a subset of
cells known to cause arthritis. The proposed studies utilize a unique experimental mouse model of arthritis in
SKG mice, which are genetically predisposed to produce autoreactive T cells (due to impaired selection within
the thymus). We have expanded on the SKG model by genetically-modifying mice to also lack expression of
Nod2, which has uncovered an entirely novel role for the innate immune receptor Nod2 in protection against of
arthritis. This discovery bears clinical relevance to humans, as patients with mutations in NOD2 develop an
inherited form of arthritis called Blau syndrome. Nod2 is a member of the cytosolic NOD-like receptor (NLR)
family of innate immune receptors known to directly sense microbial, or foreign, motifs within the body. By
understanding how Nod2 regulates autoreactive T cells in arthritis, we hope to better understand how extrinsic,
or environmental, signals can contribute to clinical arthritis; thereby specifically investigating how a genetically
determined shift of T cell-repertoire coupled with environmental stimuli facilitates the differentiation of
autoreactive Th17 cells and drives disease. These findings, in both humans and rodents, underscore an
essential homeostatic role for Nod2 in joint disease; the key observation we have made linking Nod2
specifically with control over T cell responses in arthritis, is the basis of this application. The goal of this
application is two-fold: (1) To determine whether Nod2 influences development arthritogenic T cells within the
thymus; and (2) To elucidate the immunoregulatory effects of Nod2 on peripheral activation of arthritogenic
Th17 cells that cause arthritis. Experiments have been designed to examine T cell-intrinsic functions of Nod2
at the cellular and molecular level as well as in vivo functionality of peripheral v...

## Key facts

- **NIH application ID:** 10085189
- **Project number:** 5I01BX002180-08
- **Recipient organization:** PORTLAND VA MEDICAL CENTER
- **Principal Investigator:** HOLLY Lallman ROSENZWEIG
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2014-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10085189

## Citation

> US National Institutes of Health, RePORTER application 10085189, Interaction of environment and genetics in predisposition to inflammatory arthritis (5I01BX002180-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10085189. Licensed CC0.

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