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Abstract: PO1477

Preexisting Autoimmune Dysregulation Unmasks a Role for Silica Dust Exposure in Nephrotropic Autoantibody Production

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation


  • 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

Pathogenic autoantibodies (autoAb) promote severe glomerulonephritis in ANCA vasculitis and lupus. Genetic susceptibility and environmental exposures, particularly inhalation of silica (Si) dust, are implicated in dysregulated autoimmunity and are targets for therapeutic intervention. Using a mouse reporter system expressing a regulated nephrotropic autoAb transgene (Tg) targeting basement membrane (BM) and instilling Si by oropharyngeal aspiration (OPA), we demonstrated that central B cell tolerance and anergy to BM are preserved in multiple lupus strains despite induction of lung inflammation and ectopic lymphoid tissue. Nonetheless, Si exposure increased local and systemic anti-DNA Ig levels in wildtype (WT) B6 and lupus mice, suggesting subversion of alternative regulatory checkpoints. Herein we leverage the aberrant M7 anti-BM Tg lineage that demonstrates partial escape from tolerance and evidence of glomerular Ig deposition to study the interaction of Si exposure with preexisting defects in autoreactive cell regulation.


M7 Tg mice (WT at Ig light chain, or LC, locus) were exposed to Si or vehicle (V) by OPA, organs harvested at 5-6 weeks, and cells cultured ±Toll-like receptor ligand (TLR-L). To restrict Ig specificity, a subset of mice (Tg/KI) was bred to heterozygosity for the Vk8/Jk5 V8R Ig LC knock-in. Tg autoAb were measured by ELISA; mean OD±SD.


Presence of serum Tg autoAb and induction of high levels of autoAb by TLR-L-stimulated splenocytes (OD 2.612±0.49, TLR7/9, vs 0.063±0.03, medium, p<0.0001) confirmed Tg phenotype, and bronchoalveolar lavage fluid cell counts confirmed exposure (237.1±130 vs 1.8±1.7, x1000, Si vs V, p<0.05). Among Tg/WT mice, more autoAb were produced by TLR7/9-stimulated lung cells from Si vs V exposed mice (OD 0.131±0.15, Si, vs 0.032±0.01, V, p<0.05), indicating that Tg B cells recruited by Si exposure contribute to local autoAb production. Among Si-exposed mice, Tg autoAb levels were higher in Tg/W vs Tg/KI mice: OD 1.239±0.47 for TLR4-L stimulated splenocytes, Tg/W, vs 0.515±0.13, Tg/KI, p<0.05.


An autoAb reporter system reveals that anti-BM autoreactive lymphocytes that escape tolerance can be recruited to the lung after exposure to inhaled silica dust. Anti-BM cell activation by superimposed stimuli, such as TLR-L, can lead to secretion of nephrotropic autoAb.


  • Other NIH Support