Journal Article

Increased susceptibility to organic dust exposure-induced inflammatory lung disease with enhanced rheumatoid arthritis-associated autoantigen expression in HLA-DR4 transgenic mice

Duryee, Michael J., Poole, Jill A., Mitra, Ananya, Hunter, Carlos, Mikuls, Ted R., Gaurav, Rohit, Nelson, Amy J., Thiele, Geoffrey M., Wyatt, Todd A., Ascherman, Dana P., England, Bryant R.

2022

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Nature Publishing Group,BMC
• Subject: Acetaldehyde / Animals / Antibodies / Arthritis / Arthritis, Rheumatoid / Autoantigens / Autoimmune diseases / Bronchus / CD11b antigen / CD19 antigen / CD4 antigen / CD8 antigen / CD8-Positive T-Lymphocytes - metabolism / Chemokines / Citrulline / Collagen / Collagen (type II) / Dust / Exposure / Gender differences / Genetic aspects / Genotype-environment interactions / Health aspects / Histocompatibility antigen HLA / Histocompatibility antigens / Histopathology / HLA histocompatibility antigens / HLA-DR4 Antigen - metabolism / Immunization / Immunogenetics / Inhalants / Interleukin 6 / Lavage / Leukocytes (neutrophilic) / Lung - metabolism / Lung diseases / Lung Diseases - metabolism / Lymphocytes / Lymphocytes B / Lymphocytes T / Medicine / Medicine & Public Health / Mice / Mice, Inbred C57BL / Mice, Transgenic / Neutrophils / Occupational health / Outdoor air quality / Peptides / Pneumoconiosis - metabolism / Pneumology/Respiratory System / Pneumonia - metabolism / Post-translation / Proteins / Rheumatoid arthritis / Risk factors / Transgenic mice / Translation / Tumor necrosis factor / Tumor necrosis factor-TNF / Vimentin