Pulmonary disease is a frequent complication of systemic autoimmune diseases, often requiring aggressive treatment with high dose immunosuppression or lung transplantation. Despite the significant clinical impact, little is understood about the pathogenesis of lung disease in autoimmune conditions. As a pulmonary and critical care physician at the University of California, San Francisco, Dr. Anthony Shum is establishing himself as an investigator in the mechanisms of autoimmune-mediated lung disease. With the highly regarded Immunology Training Program and an internationally recognized mentoring team, UCSF provides the ideal environment for the critical studies and intensive training necessary for Dr. Shum's development towards his long-term goal of a career as a physician-scientist. The primary mentor, Dr. Mark Anderson, is a leading expert in central immune tolerance, and co-mentor, Dr. Harold Chapman, Professor and Chief of the Pulmonary Division, is a renowned authority on lung injury and tissue remodeling. A major barrier to research on lung autoimmunity has been the lack of animal models in which to study disease pathogenesis. Using the Aire (Autoimmune Regulator) deficient mouse, Dr. Shum's research presents the unique opportunity to define basic mechanisms of autoimmune lung disease in a novel model of a known human autoimmune syndrome. Autoimmune Polyglandular Syndrome 1 (APS1) arises from mutations in the AIRE gene and like their human counterparts, Aire deficient mice develop autoimmunity to multiple organs, including the lung, due to a critical breakdown in central immune tolerance. Importantly, Aire deficient mice develop interstitial lung disease spontaneously in a pattern strikingly similar to APS1 patients. Furthermore, Dr. Shum has identified a novel lung autoantigen in the Aire deficient mouse that may be the key to initiating disease. Thus, we hypothesize that pulmonary disease in Aire KO mice is due to a failure to tolerize thymocytes to a critical lung antigen, resulting in the escape of autoreactive T cells that target and injure the lung. To address this hypothesis, the proposed specific aims are to: (1) determine the cell populations that mediate lung disease in Aire KO mice;(2) establish the role of our lung antigen in the pathogenesis of pulmonary disease in the mouse model;and (3) establish the role of the human homolog of

Public Health Relevance

(Seeinstructions). In this project we will learn how lung damage occurs in systemic autoimmune diseases like rheumatoid arthritis or scleroderma. We will identify the cells that are attacking the lung, which lung proteins they are targeting, and how they cause injury. In doing so, we will be able to develop blood tests to help physicians diagnose patients with autoimmune lung disease and determine their prognosis. We also seek to design therapies made specifically for the lung to effectively treat patients with these disorders.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL095659-04
Application #
8286951
Study Section
Special Emphasis Panel (ZHL1-CSR-O (F1))
Program Officer
Colombini-Hatch, Sandra
Project Start
2009-07-01
Project End
2014-04-30
Budget Start
2012-07-01
Budget End
2013-04-30
Support Year
4
Fiscal Year
2012
Total Cost
$121,770
Indirect Cost
$9,020
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Watkin, Levi B; Jessen, Birthe; Wiszniewski, Wojciech et al. (2015) COPA mutations impair ER-Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis. Nat Genet 47:654-60
Lee, Joyce S; Kim, Eunice J; Lynch, Kara L et al. (2013) Prevalence and clinical significance of circulating autoantibodies in idiopathic pulmonary fibrosis. Respir Med 107:249-55
Shum, Anthony K; Alimohammadi, Mohammad; Tan, Catherine L et al. (2013) BPIFB1 is a lung-specific autoantigen associated with interstitial lung disease. Sci Transl Med 5:206ra139
Shum, Anthony K; DeVoss, Jason; Tan, Catherine L et al. (2009) Identification of an autoantigen demonstrates a link between interstitial lung disease and a defect in central tolerance. Sci Transl Med 1:9ra20