# Defining the Role of Thymic Tolerance in the Pathogenesis of the COPA syndrome

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $471,675

## Abstract

PROJECT SUMMARY:
 Our lab recently co-discovered the COPA syndrome, an autoimmune disease caused by dominant
mutations in the Coatomer subunit alpha (COPA) gene that manifests as inflammatory arthritis and interstitial
lung disease (ILD). COPA encodes the COPA subunit of coat protein complex I (COPI). COPI is engaged in
the retrograde movement of proteins from the Golgi to the ER and is a vital component of a cell's trafficking
machinery. Patients with the COPA syndrome develop high-titer antinuclear or anti-neutrophil cytoplasmic
autoantibodies, immune-mediated kidney disease and an increase in CD4+ T helper 17 (Th17) cells, an
immune cell subset implicated in autoimmunity. Some patients have findings consistent with rheumatoid
arthritis RA including rheumatoid factors or autoantibodies to cyclic citrullinated peptides. All COPA syndrome
patients eventually develop interstitial lung disease (ILD) in combination with their arthritis. Generalized
immunosuppressive drugs such as mycophenolate have been used to treat patients with limited success,
although the ILD typically progresses on treatment and leads to end stage lung fibrosis.
 We generated a germline point mutant knock-in mouse bearing the exact same E241K mutation as
COPA syndrome patients. Preliminary data demonstrates that CopaE241K/+ mice spontaneously develop
mononuclear lung infiltrates and an examination of peripheral lymphoid tissues reveals a significant increase in
effector memory T cells. Detailed study of developing thymocytes shows a significant increase in mature CD8+
and CD4+ single positive (SP) cell populations, findings that suggest alterations in thymocyte development or
selection. CopaE241K/+ mice bred to a T cell receptor transgenic mouse system revealed a defect in the negative
selection of CD4+ T cells. Interestingly, reciprocal bone marrow chimera experiments map the selection defect
to E241K COPA expression in the thymic stroma. Thus, we hypothesize that a critical precursor to autoimmune
disease in the COPA syndrome is aberrant thymocyte selection caused by mutant COPA expression in the
thymic epithelium. We propose to pursue this hypothesis by 1) Determining the role of mutant COPA in positive
and negative selection of CD4+ and CD8+ T cells 2) Defining the role of the thymic stroma on thymocyte
development in CopaE241K/+ mice and 3) Defining the autoimmune features of CopaE241K/+ mice and COPA
syndrome subjects.
 Through our study we seek to determine the role of thymic tolerance in the pathophysiology of the
COPA syndrome and establish CopaE241K/+ mice as a preclinical model for the disease. Because the COPA
syndrome shares features with other inflammatory joint disorders, our study may provide novel insight into how
impaired vesicular trafficking contributes to the pathogenesis of arthritis and ILD by altering the negative
selection of autoreactive T cells and causing a defect in central immune tolerance.

## Key facts

- **NIH application ID:** 9838719
- **Project number:** 5R01AI137249-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Anthony Shum
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $471,675
- **Award type:** 5
- **Project period:** 2018-01-16 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838719

## Citation

> US National Institutes of Health, RePORTER application 9838719, Defining the Role of Thymic Tolerance in the Pathogenesis of the COPA syndrome (5R01AI137249-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9838719. Licensed CC0.

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