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Abstract: FR-PO996

Gene-Environment Interactions Modulate Anti-DNA and Anti-Myeloperoxidase. Autoimmunity in Lupus

Session Information

Category: Pathology and Lab Medicine

  • 1601 Pathology and Lab Medicine: Basic

Authors

  • Fee, Lanette, Duke University School of Medicine, Durham, North Carolina, United States
  • Ord, Jeffrey R., Duke University School of Medicine, Durham, North Carolina, United States
  • Clark, Amy G., Duke University School of Medicine, Durham, North Carolina, United States
  • Birukova, Anastasiya, Duke University School of Medicine, Durham, North Carolina, United States
  • Tighe, Robert Matthew, Duke University School of Medicine, Durham, North Carolina, United States
  • Foster, Mary H., Duke University School of Medicine, Durham, North Carolina, United States
Background

Autoantibody (autoAb)-mediated glomerulonephritis develops in 60-85% of patients with lupus and ANCA vasculitis. Nephron preservation requires control of the systemic autoimmune response. To better understand factors driving autoimmunity, we used a mouse model system to study interaction of lupus genetic susceptibility and inhalation of crystalline silica (Si), an environmental exposure linked to human lupus. We previously showed that Si induces lung injury, lymphoid aggregates, and autoAbs in mice of genetically diverse backgrounds. Herein we report strain differences in Si-induced autoAb specificity, production site, and co-exposure requirements.

Methods

Wildtype (WT) and autoAb transgenic (Tg) B6, BXSB, MRL, and NZB mice were exposed to Si (Si+) or vehicle (V+) by aspiration; tissues were harvested for immunophenotyping 1 to 3 months later.

Results

Among WT lupus mice exposed to Si, anti-DNA IgG levels are significantly higher in bronchoalveolar lavage fluid (BALF) from Si+ MRL compared to other Si+ strains (mean OD405 1.35 vs 0.07, 0.49, & 0.36 for B6, BXSB & NZB, p<0.05). TLR7/TLR9 ligands induce significantly more anti-DNA IgG from cultured lung cells of Si+ vs V+ MRL (OD405 0.49±0.43 vs 0.11±0.21, n=6-9/grp, p<0.05), and vs lung cells of Si+ B6 and Si+ NZB (OD405 0.02±0.02 & 0.01±0.01). Anti-myeloperoxidase (MPO) Ig are detected only in BALF of Si+ BXSB, and are not found in BALF from V+ BXSB (p<0.05, n=7/grp) or from Si+ B6, MRL, & NZB. To probe the in vivo fate of autoAb-producing lymphocytes after Si exposure, we studied mice of each strain expressing an autoAb Tg. Results suggest that central deletion and anergy are intact: mean spleen B cell numbers (5.7±3.4 mil, n=25) are markedly lower than that for non-Tg counterparts (35±2 mil, n=53) and do not differ for Si+ vs V+ mice in any of the 4 Tg strains; and, the residual autoAb Tg B cells produce little Tg autoAb. However, TLR7/TLR9 stimulation induces Tg autoAb production by splenocytes from Si+ Tg B6 mice.

Conclusion

These results suggest that silica exposure can disrupt local and systemic autoimmune control in a strain-dependent manner, consistent with gene-environment interaction in modulation of the autoimmune response. The results further suggest that Si-induced subtle alterations in autoreactive lymphocyte regulation are unmasked by environmental co-exposure.

Funding

  • Other NIH Support