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Abstract: FR-PO976

Exploring Origins of Autoimmune Nephritis Using HLA DR+ CD34+ Humanized Immune System Mice

Session Information

Category: Pathology and Lab Medicine

  • 1601 Pathology and Lab Medicine: Basic

Authors

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

Autoimmunity causes most glomerulonephritis (GN) and must be controlled to limit nephron destruction. Understanding the origins of the autoimmune response can guide development of targeted intervention. We generated a human immune system (HIS) model to examine interactions of two potent disease susceptibility factors: autoimmune-linked HLA Class II receptor DR4 and inhalation of crystalline silica (Si), an environmental exposure linked to lupus and ANCA vasculitis.

Methods

NOD-scid-gamma mice lacking mouse MHC Class II and transgenic (Tg) for HLA DR4 were infused with T-depleted DR4+ CD34+ human hematopoietic stem cells (HSC) from 1 of 4 cord blood donors. The Tg DR4 is expressed in host thymus to educate human CD4+ T cells, and DR4 is expressed on HSC-derived B cells. 3 mon later mice were exposed by aspiration to Si, vehicle (V), or neither, followed in 0 to 10 wks by adjuvant±PR3 or foreign antigen injection. Organs were harvested 4-8.5 mon post-engraftment.

Results

Among 19 surviving engrafted DR4+/moCIIKO/CD34+HIS mice, mean spleen chimerism was 72.2±27%. Low levels of human anti-PR3 Ig were detected in bronchoalveolar lavage fluid (BALF) from 69% (9 of 13) of immunized HIS mice, representing all 4 HSC donors and each exposure group. Low levels of human anti-DNA Ig were detected in BALF of 3 immunized (1 Si/2V) HIS mice, derived from the same HSC donor; 2 had lung perivascular infiltrates. Among Si-exposed mice, 5 deteriorated clinically 5-9 wks post-exposure, precluding immunization. All 5 had severe lung injury, including findings typical of chronic silicosis with extensive fibrosis and/or alveolar proteinosis in 4 mice. These 5 Si-exposed HIS mice (derived from 3 HSC donors) with 77%-85% spleen chimerism had no detectable serum or BALF anti-DNA & anti-PR3 Ig.

Conclusion

DR+ CD34+ HIS mice provide a useful translational platform to study susceptibility factors and gene-environment interactions that promote human nephritogenic autoimmunity. Our findings suggest that immunization and/or adjuvant, but not silicosis alone, facilitates induction of humoral autoimmunity in the context of HLA DR4. Future models can test the impact on autoimmune control of alternative risk alleles, modifiable host factors, and environmental co-exposures.

Funding

  • Other NIH Support