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.

• Authors: Jill A Poole, Ted R Mikuls, Geoffrey M Thiele, Rohit Gaurav, Amy J Nelson, Michael J Duryee, Ananya Mitra, Carlos Hunter, Todd A Wyatt, Bryant R England, Dana P Ascherman
• Journal: Respiratory research (Respir Res) Vol. 23 Issue 1 Pg. 160 (Jun 18 2022) ISSN: 1465-993X [Electronic] England
• PMID: 35717175 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s).

Chemical References

• Autoantigens
• Dust
• HLA-DR4 Antigen

Topics

• Animals
• Arthritis, Rheumatoid
• Autoantigens
• CD8-Positive T-Lymphocytes (metabolism)
• Dust
• HLA-DR4 Antigen (metabolism)
• Lung (metabolism)
• Lung Diseases (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Pneumoconiosis (metabolism)
• Pneumonia (metabolism)