TNIP1/ABIN1 mutation contributes to lupus nephritis via chemokine IP-10 induction

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Abstract Systemic lupus erythematosus (SLE) is a chronic autoimmune disease. Kidney inflammation or lupus nephritis (LN) is the most common and severe complication of SLE and mechanisms of pathogenesis are not clearly defined and current therapies are toxic and ineffective. We previously reported TNIP1 gene variants as risks for 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-like 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 P-10 expression due to loss of cellular ABIN1 ubiquitin binding activity. 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. 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.