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Abstract: PO1771

TNIP1/ABIN1 Mutation Contributes to Lupus Nephritis via Chemokine IP-10 Induction

Session Information

Category: Glomerular Diseases

  • 1202 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
  • 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

We previously reported TNIP1 gene variants as risks for lupus nephritis (LN). TNIP1 encodes the protein ABIN1, which is a polyubiquitin binding protein that negatively regulates the prominent immune regulatory transcription factor NF-κB. We reported that transgenic mice with impaired ABIN1 ubiquitin binding function (ABIN1[D485N]) spontaneously develop SLE-associated autoimmunity and LN and that ABIN1 determines the severity of LN via activation of kidney and immune cell inflammation. Interferon gamma-inducible protein -10 (IP-10) is a pro-inflammatory chemokine and NF-κB target that has been implicated in the pathogenesis and as a diagnostic marker of LN. The current project tested a hypothesis that LN development is mediated by induction of IP-10 expression due to loss of cellular ABIN1 activity.

Methods

In order to test our hypothesis, we measured urine and serum IP10 in ABIN1[D485N] mice using ELISA and utilyzed IHC techniques to measure kidney IP10 expression. Additionally, we used ELISA to measure urinary IP10 levels in human subjects with LN (with and without TNIP variant rs4958881) and in healthy controls.

Results

We found that serum, urine, and kidney cell IP-10 expression is enhanced in ABIN1[D485N] mice. We also found that urinary IP-10 levels are higher in LN patients with TINIP1/ABIN1 variant rs4958881 when compare to LN patients without the TNIP1 variant and healthy controls. The rs4958881 variant also correlated with disease severity.

Conclusion

Our findings indicate that TNIIP/ABIN1 mutation contributes to the pathogenesis of LN via kidney and immune cell induction of IP-10 secretion and that serum and urinary IP-10 are promising diagnostic markers for LN especially in patients with TNIP1 variants. Further, successful Phase 2 clinical trials with IP-10 mAb for ulcerative colitis indicate its potential for effective LN treatment.

Funding

  • NIDDK Support