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Abstract: SA-PO827

A Role for Lung Foxp3+ T-Regulatory (Treg) Cells in Modulating Lupus Autoantibody Production Exacerbated by Silica Dust Exposure

Session Information

Category: Glomerular Diseases

  • 1401 Glomerular Diseases: From Inflammation to Fibrosis

Authors

  • Foster, Mary H., Duke University, Durham, North Carolina, United States
  • Kumar, Advika, Duke University, Durham, North Carolina, United States
  • Abe, Koki, Duke University, Durham, North Carolina, United States
  • Souma, Tomokazu, Duke University, Durham, North Carolina, United States
  • Tighe, Robert Matthew, Duke University, Durham, North Carolina, United States
  • Fee, Lanette, Duke University, Durham, North Carolina, United States
Background

Gene-environment (GxE) interactions promote systemic autoimmunity and induction of autoantibodies (autoAb) that destroy kidneys in SLE and ANCA vasculitis. In mice, inhalation of crystalline silica (cSi) dust, an exposure compellingly linked to human autoimmune diseases, induces local tertiary lymphoid structures (TLS) enriched in T and B cells. In lupus and other autoimmune-prone strains, cSi inhalation increases local and systemic autoAb and accelerates nephritis. To test the hypothesis that immune control is defective in GxE-influenced tissue microenvironments in lupus, we measured cells expressing transcription factor forkhead box protein 3 (Foxp3), a key marker of regulatory T cells (Treg), in cSi-exposed lupus BXSB and non-autoimmune C57BL/6J (B6) mice.

Methods

Lungs harvested from female mice 7-9 weeks after cSi exposure were sectioned and stained with anti-Foxp3 and anti-B220 (B cell) antibodies and visualized using a Zeiss Axio Imager. TLS-associated Foxp3+ nuclei were enumerated in n=16 TLS per mouse using Zeiss Zen software, with TLS identified as loci of densely packed nuclei overlapping B220+ clusters. In situ hybridization was performed using RNAScope on FFPE tissue sections from cSi and vehicle (V) exposed autoAb transgenic (Tg) B6 mice, using Foxp3 and control probes.

Results

Foxp3+ nuclei were identified within TLS in lung tissue of all cSi-exposed mice. In one of three BXSB mice, a single TLS had an exceptionally high Foxp3+ cell count, highlighting the potential for microniche heterogeneity. Exclusion of this outlier revealed significantly fewer Foxp3+ cells/TLS in BXSB vs B6 mice: 4.6±0.2 in BXSB vs 8.1±4.6 in B6 (mean±SD), p<0.05. Immunofluorescence and RNAScope imaging showed that Foxp3+ cells also localized to TLS regions in cSi-exposed autoAb Tg mice, whereas only a few scattered Foxp3+ cells were identified in V-exposed lung.

Conclusion

Foxp3+ Treg are recruited to lungs after cSi inhalation and localize to lymphocyte-rich TLS, suggesting a role in regulation of local autoimmune responses. The relative paucity of Foxp3+ cells in BXSB TLS may contribute to autoimmunity in this lupus-prone strain. Understanding the composition and contribution of local tissue immune niches in GxE-influenced pulmonary-renal diseases such as lupus may identify novel approaches to therapy.

Funding

  • Other NIH Support