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Abstract: PO1429

Environmental Factors Influence Site and Magnitude of Myeloperoxidase and DNA Autoimmunity in BXSB Murine Lupus

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Fee, Lanette, Duke University, Durham, North Carolina, United States
  • Tighe, Robert Matthew, Duke University, Durham, North Carolina, United States
  • Foster, Mary H., Duke University, Durham, North Carolina, United States
Background

SLE is a systemic autoimmune disease with devastating clinical manifestations and complex origins linked to gene-environment interactions. To better understand the role of environmental factors, we exposed lupus-prone female mice to crystalline silica (Si) or vehicle (V) by oropharyngeal aspiration (OPA), mimicking an inhalational exposure compellingly linked to human autoimmunity. Si but not V exposed mice developed chronic lung inflammation, tertiary lymphoid structures (TLS), and elevated autoantibody (autoAb) levels. Si-exposed BXSB mice, a strain that develops vasculitis and glomerulonephritis, uniquely demonstrated elevated anti-myeloperoxidase (MPO) as well as anti-DNA Ig levels in bronchoalveolar lavage fluid (BALF). Herein we extend our studies in BXSB lupus to quantify local autoAb production and assess the impact of environmental co-exposure, using Toll-like receptor ligand (TLR-L) stimulation to mimic microbial infection.

Methods

BXSB mice were exposed to Si or V by OPA and organs harvested 2-3 months later. A subset of mice were injected with TLR4-L i.p. 1-2 days prior to harvest. Lung injury and TLS were quantified and autoAbs in serum, BALF, and cell culture supernatants (±TLR4 or TLR7/9 L) measured by ELISA; mean±SD.

Results

Si but not V exposed BXSB mice developed chronic lung injury (scores 5.0±4 vs 0.1±0.4) and lung TLS (counts 36±19 vs 0±0), n=13/grp, p<0.0001. Levels of anti-DNA and anti-MPO IgM and IgG in BALF and anti-DNA IgG in serum were elevated in Si vs V exposed mice (p<0.05, for each). Splenocytes produced little anti-MPO or anti-DNA Ig when cultured with medium and abundant anti-MPO IgM and anti-DNA IgM after TLR-L stimulation, regardless of Si vs V exposure (p=NS; n=13/grp). Anti-DNA IgG levels were higher from stimulated splenocytes of Si-exposed mice (OD 0.082±0.054 Si vs 0.035±0.011 V, TLR4-L, p=0.0009). Lung cells from Si but not V exposed mice produced abundant autoAb after TLR-L stimulation (OD 1.232±1.100 Si vs 0.025±0.043 V, anti-MPO IgM; OD 0.212±0.310 Si vs 0.001±0.001 V, anti-DNA IgG, TLR7/9-L, p<0.05).

Conclusion

Inhalational Si exposure enhances local and systemic autoimmunity in lupus-prone BXSB mice. Autoreactive B cells with diverse disease-relevant specificities, including anti-MPO and anti-DNA Ig, are recruited to the lungs, where they can be activated by co-exposure to exogenous or endogenous TLR-L.

Funding

  • Other NIH Support