Increased susceptibility to organic dust exposure-induced inflammatory lung disease with enhanced rheumatoid arthritis-associated autoantigen expression in HLA-DR4 transgenic mice
Abstract
Immunogenetic as well as environmental and occupational exposures have been linked to the development of rheumatoid arthritis (RA), RA-associated lung disease, and other primary lung disorders. Importantly, various inhalants can trigger post-translational protein modifications, resulting in lung autoantigen expression capable of stimulating pro-inflammatory and/or pro-fibrotic immune responses. To further elucidate gene-environment interactions contributing to pathologic lung inflammation, we exploited an established model of organic dust extract (ODE) exposure with and without collagen-induced arthritis (CIA) in C57BL/6 wild type (WT) versus HLA-DR4 transgenic mice. ODE-induced airway infiltration driven by neutrophils was significantly increased in DR4 versus WT mice, with corresponding increases in bronchoalveolar lavage fluid (BALF) levels of TNF-⍺, IL-6, and IL-33. Lung histopathology demonstrated increased number of ectopic lymphoid aggregates comprised of T and B cells following ODE exposure in DR4 mice. ODE also induced citrullination, malondialdehyde acetaldehyde (MAA) modification, and vimentin expression that co-localized with MAA and was enhanced in DR4 mice. Serum and BALF anti-MAA antibodies were strikingly increased in ODE-treated DR4 mice. Coupling ODE exposure with Type II collagen immunization (CIA) resulted in similarly augmented pro-inflammatory lung profiles in DR4 mice (relative to WT mice) that was accompanied by a profound increase in infiltrating lung CD4+and CD8+T cells as well as CD19+CD11b+autoimmune B cells. Neither modeling strategy induced significant arthritis. These findings support a model in which environmental insults trigger enhanced post-translational protein modification and lung inflammation sharing immunopathological features with RA-associated lung disease in the selected immunogenetic background of HLA-DR4 mice.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jun 18, 2022
- Source ID
- 10.1186/s12931-022-02085-8
Entities
People
- Amy J. Nelson
- Ananya Mitra
- Bryant R England
- Carlos Hunter
- Dana P. Ascherman
- Geoffrey M. Thiele
- Jill A. Poole
- Michael J. Duryee
- Rohit Gaurav
- Ted R Mikuls
- Todd A. Wyatt
Organizations
- National Institute for Occupational Safety and Health
- National Institute of Environmental Health Sciences
- National Institute of General Medical Sciences
- National Institute on Alcohol Abuse and Alcoholism
- United States Department of Defense
- United States Department of Veterans Affairs