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Kidney Week

Abstract: FR-PO1061

Kidney-Targeted Autoimmunity Exposed in Human Immune System Mice

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Ord, Jeffrey R., Duke University Medical Center, Durham, North Carolina, United States
  • Clark, Amy G., Duke University Medical Center, Durham, North Carolina, United States
  • Birukova, Anastasiya, Duke University Medical Center, Durham, North Carolina, United States
  • Fee, Lanette, Duke University Medical Center, Durham, North Carolina, United States
  • Asfaw, Yohannes G., Duke University Medical Center, Durham, North Carolina, United States
  • Tighe, Robert Matthew, Duke University Medical Center, Durham, North Carolina, United States
  • Foster, Mary H., Duke University Medical Center, Durham, North Carolina, United States
Background

Lupus and anti-GBM nephritis are paradigmatic systemic and organ-specific autoimmune diseases, respectively, in which kidney and other organ injury is induced by pathogenic autoantibodies. Gene-environment interactions are implicated in disease induction, yet mechanisms by which this occurs in man are poorly understood. We explored the utility of an in vivo human immune system model (HuHSC-NSG) to study autoimmune regulation by inhaled crystalline silica, an environmental exposure compellingly linked to multiple human autoimmune diseases with a prominent humoral component.

Methods

Conditioned immunodeficient NOD-scid-gamma (NSG) mice were intravenously injected with CD34+ human hematopoietic stem cells (HSC) from two different donors and monitored for reconstitution with a human immune system. Three months after engraftment, mice were exposed to crystalline silica (Si) or vehicle (V, saline) by oropharyngeal aspiration. Tissue was collected 1-3 months post-aspiration. Chimerism was determined by flow cytometry, and lung pathology and lymphocytic infiltrates were scored by investigators blinded to experimental conditions. Serum autoantibodies that bound DNA or the NC1 domain of the alpha3 chain of collagen IV were measured using enzyme linked immunosorbent assay. Data are reported as mean±SD.

Results

HuHSC-NSG mice (n=29) demonstrated mean spleen chimerism of 57.6±28.4%, with the human CD45+ subset composed of 70.7±18.6% B cells and 19.4±20.1% T cells. Si-exposed subjects developed significantly greater lung injury and inflammation than did their V-exposed counterparts, with composite lung pathology score 2.8±2.2 vs 0.7±1.7, Si vs V, p<0.05. Focal infiltrates of human CD45+ leukocytes were observed in Si-exposed lungs. All mice developed circulating human IgM and IgG, and a subset had detectable circulating human anti-DNA or anti-alpha3(IV)NC1 collagen autoantibodies.

Conclusion

NSG mice reconstituted with a human immune system develop Si-induced lung injury and circulating autoantibodies with specificities relevant to human antibody-mediated nephritis. This model should be useful in studying gene-environment interactions that promote pathogenic autoimmunity in humans, without putting volunteers or patients at risk.

Funding

  • Other NIH Support