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Abstract: FR-PO578

Enhanced Neutrophil Activity in Lupus Nephritis Patients With TNIP1 Variant rs4958881

Session Information

Category: Glomerular Diseases

  • 1302 Glomerular Diseases: Immunology and Inflammation

Authors

  • Powell, David W., University of Louisville School of Medicine, Louisville, Kentucky, United States
  • Brady, Makayla, University of Louisville School of Medicine, Louisville, Kentucky, United States
  • Tandon, Shweta, University of Louisville School of Medicine, Louisville, Kentucky, United States
  • Rane, Madhavi J., University of Louisville School of Medicine, Louisville, Kentucky, United States
  • Barati, Michelle T., University of Louisville School of Medicine, Louisville, Kentucky, United States
  • Caster, Dawn J., University of Louisville School of Medicine, Louisville, Kentucky, United States
Background

There is need for understanding cellular and molecular mechanisms of lupus nephrits (LN) to define novel diagnostics and therapeutic. We previously reported the TNIP1 variant rs4958881 as risks for LN. TNIP1 encodes ABIN1, which negatively regulates the immune regulatory NF-κB. Glomerular neutrophil accumulation has been shown in LN patients and we have shown that transgenic mice with loss of ABIN1 function also develop glomerular influx of neutrophils. Release of neutrophil extracellular traps (NETs) is implicated in loss of immune tolerance in SLE and enhanced serums levels of NETs and antibodies against NET components have been reported in LN patients. Thus, we hypothesize that LN patients with the TNIP1 rs4958881 risk variant have increased NET production/release and recruitment of neutrophils due to NF-κB over activation.

Methods

We tested our hypothesis by performing in vitro transwell migration (chemotaxis) and supernatant DNA measurements (NET release) assays with neutrophils isolated from 6 LN patients with and 6 LN patients without the TNIP1 variant rs4958881 and 6 healthy control subjects. Neutrophil functions were measured in response to known positive activators (FMLF for chemotaxis and PMA for NET production). Interferon (IFN)-γ is prominent activator of neutrophils that was recently implicated in LN and we found that serum levels of IFN-γ are enhanced in LN patients with the rs4958881 variant. Thus, stimulation with IFN-γ was also assessed.

Results

IFN-γ did not activate chemotaxis of neutrophils from healthy controls or LN patients without the TNIP1 variant rs4958881, but cells from LN patients with the TNIP1 variant had a robust response to IFN-γ. NET production was enhanced in response to PMA and IFN-γ in neutrophils from LN patients with the TNIP1 variant as compared to the response in cells from LN patients without the and healthy controls.

Conclusion

Our findings indicate that LN patients’ neutrophils have an altered response to an LN relevant stimulus compared to healthy control individuals. These data also suggests that the presence of TNIP1 variant rs4958881 further exacerbates this altered response. This suggests this increased neutrophil activation is a contributing factor to inflammatory development in these patients and that targeting and suppressing neutrophil activity could potentially alleviate their LN.

Funding

  • NIDDK Support