TNIP1/ABIN1 and lupus nephritis: review

Abstract

SLE is a complex autoimmune disease with genetic, epigenetic, immune-regulatory, environmental and hormonal factors. Kidney inflammation and injury, termed lupus nephritis (LN), occurs in over half of patients with SLE and is a leading cause of disability and death. There is a high degree of short-term and long-term side effects associated with current LN therapies and they are not effective for many patients. Thus, novel therapies with reduced toxicity and improved efficacy are drastically needed. Many of the known LN susceptibility genes have functions that mediate inflammation via cytokine/chemokine production and activation of myeloid and B cells. Understanding the cellular and molecular mechanisms mediated by these variant gene products provides valuable insight for the development of improved and personalised diagnostics and therapeutics. This review describes variants in the TNIP1 (tumour necrosis factor α-induced protein 3-interacting protein 1) gene associated with risks for SLE and LN and potential roles for loss of function of its protein product ABIN1 in the activation of myeloid and B-cell-mediated injury in LN.

Keywords: genetic; inflammation; lupus erythematosus; lupus nephritis; polymorphism; systemic.

Figure 1

This diagram shows the location/region for each identified TNIP1 (tumour necrosis factor-α-induced protein 3-interacting protein 1) polymorphism listed in table 1 and colour code for the ethnicity of the cohort for which they were identified.

Figure 2

This is a simplified version of the canonical nuclear factor kappa B cell (NF-κB) pathway that is negatively regulated by A20 binding inhibitor of NF-κB (ABIN1) function. Other reviews describe NF-kB signalling and ABIN1 interactions and NF-κB regulation in greater detail. In brief, ABIN1 negatively regulates NF-kB by binding to polyubiquitin moieties on (TAK1, NEMO) inhibiting phosphorylation and degradation of inhibitor of κB-α (IkB-α), preventing nuclear translocation of NF-kB and inhibiting transcription of target immune regulators. Created with Biorender.com. IKK, IκB kinase; TLR, Toll-like receptor.

Figure 3

This represents a proposed model for how genetic variants for the A20 binding inhibitor of NF-κB (ABIN1) gene TNIP1 (tumour necrosis factor-α-induced protein 3-interacting protein 1) contribute to the development and progression of SLE and lupus nephritis (LN). A number of TNIP1 single-nucleotidepolymorphisms have been identified in association with SLE and LN from large-scale genome-wide association study and replicate studies. ABIN1 is ubiquitously expressed. It is possible that TNIP1 variants result in reduction or loss of ABIN1 cellular function and enhanced activation of nuclear factor kappa B cell (NF-κB). The findings presented herein suggest that loss of ABIN1 function mediates activation of adaptive immune and myeloid cells resulting increased circulating monocytes and elevated blood autoantibody and inflammatory modulator levels. This subsequently results in increased glomerular leucocyte infiltration and immune deposition in LN. iMo, inflammatory monocyte;pMo, patrolling monocyte.