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

Details

• Personal Author:
  Ascherman DP ; Duryee MJ ; England BR ; Gaurav R ; Hunter C ; Mikuls TR ; Mitra A ; Nelson AJ ; Poole JA ; Thiele GM ; Wyatt TA
• Description:
  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-a, 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. [Description provided by NIOSH]
• Subjects:
  Antibodies Dust Environmental Exposure Laboratories Lung Lung Diseases Occupational Exposure Occupational Health Pathology Respiratory System Respiratory Tract Diseases Safety

  More +
• Keywords:
  Organic dusts; Lung disease; Rheumatoid disorders; Laboratory animals; Environmental exposure; Occupational exposure; Lung disorders; Proteins; Pathology; Neutrophils; Antibodies
• ISSN:
  1465-9921
• Document Type:
  Text
• Funding:
  Cooperative Agreement ; Grant
• Genre:
  Journal Article
• Place as Subject:
  Nebraska ; OSHA Region 3 ; OSHA Region 7 ; Pennsylvania
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  23
• NIOSHTIC Number:
  nn:20065421
• Citation:
  Respir Res 2022 Jun; 23:160
• Contact Point Address:
  Jill A. Poole, Department of Internal Medicine, College of Medicine, University of Nebraska Medical Center, Omaha, NE
• Email:
  japoole@unmc.edu
• CAS Registry Number:
  Acetaldehyde (CAS RN 75-07-0) ; Malonaldehyde (CAS RN 542-78-9)
• Federal Fiscal Year:
  2022
• NORA Priority Area:
  Agriculture, Forestry and Fishing
• Performing Organization:
  University of Nebraska Medical Center - Omaha
• Peer Reviewed:
  True
• Start Date:
  20110901
• Source Full Name:
  Respiratory Research
• End Date:
  20270831
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:dc9eb92f2df0909cd0d1557892399725478a9c584a321fc920119e083f9c4cd908c952c47643762a95b9752f4a371e5424d4d274344e8acee069e8f7e92ee911
• Download URL:
  https://stacks.cdc.gov/view/cdc/249431/cdc_249431_DS1.pdf
• File Type:
  [PDF - 2.12 MB ]