ABIN1 Dysfunction as a Genetic Basis for Lupus Nephritis

Abstract

The genetic factors underlying the pathogenesis of lupus nephritis associated with systemic lupus erythematosus are largely unknown, although animal studies indicate that nuclear factor (NF)-kB is involved. We reported previously that a knockin mouse expressing an inactive form of ABIN1 (ABIN1[D485N]) develops lupus-like autoimmune disease and demonstrates enhanced activation of NF-kB and mitogen-activated protein kinases in immune cells after toll-like receptor stimulation. In the current study, we show that ABIN1[D485N] mice develop progressive GN similar to class III and IV lupus nephritis in humans. To investigate the clinical relevance of ABIN1 dysfunction, we genotyped five single-nucleotide polymorphisms in the gene encoding ABIN1, TNIP1, in samples from European-American, African American, Asian, Gullah, and Hispanic participants in the Large Lupus Association Study 2. Comparing cases of systemic lupus erythematosus with nephritis and cases of systemic lupus erythematosus without nephritis revealed strong associations with lupus nephritis at rs7708392 in European Americans and rs4958881 in African Americans. Comparing cases of systemic lupus erythematosus with nephritis and healthy controls revealed a stronger association at rs7708392 in European Americans but not at rs4958881 in African Americans. Our data suggest that variants in the TNIP1 gene are associated with the risk for lupus nephritis and could be mechanistically involved in disease development via aberrant regulation of NF-kB and mitogen-activated protein kinase activity. 24: 174324: -175424: , 201324: . doi: 10.1681 Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by an abnormal immune response leading to autoantibody production, immune complex formation, T cell activation, and inflammatory cytokine release. 1 Multiple factors contribute to the immune response in SLE, including genetic, epigenetic, immunoregulatory, environmental, and hormonal factors. 1 Lupus nephritis (LN) occurs in about 50% of patients with SLE and is a major cause of morbidity and mortality. 2 The incidence of LN varies among different ethnic groups, suggesting that genetic factors play an important role in the pathogenesis. Patients with African ancestry are at Received February 11, 2013. Accepted May 7, 2013 D.J.C. and E.A.K. contributed equally to this work. J Am Soc NephrolPublished online ahead of print. Publication date available at www.jasn.org. LN,4 and that therapy is associated with undesirable short-and long-term adverse effects. Thus, identifying the molecular mechanisms responsible for the pathogenesis of LN is necessary to define more specific diagnostic and therapeutic targets. However, the complex interactions of genetic risks, environmental factors, and molecular events that contribute to the development of LN are only beginning to be defined. The transcription factor nuclear factor-kB (NF-kB) regulates the expression of hundreds of genes that control cell proliferation and survival, the cellular stress r...

Emergence of the A20/ABIN-mediated inhibition of NF-κB signaling via modifying the ubiquitinated proteins in a basal chordate

“…These studies have related the roles of ABIN-1 in anti-inflammation to its UBD, likely by targeting the TLR-signaling pathways that control NF-κB and MAPK activity (27)(28)(29)(30). In this study, both bbtABIN1 and bbtABIN2 proteins, when expressed individually, were found to localize in cytoplasm and form unique punctuated spherical structures of various sizes, suggesting that bbtABIN1 and bbtABIN2 may form complexes with other unidentified proteins.…”

“…In addition to connecting A20 to NEMO to affect NF-κB signaling, as an ubiquitin sensor, a growing number of references have implicated ABIN-1 in embryonic development and in chronic inflammatory and autoimmune diseases, such as psoriasis, rheumatoid arthritis, and lupus nephritis (27)(28)(29). These studies have related the roles of ABIN-1 in anti-inflammation to its UBD, likely by targeting the TLR-signaling pathways that control NF-κB and MAPK activity (27)(28)(29)(30).…”

The TLR and IL-1 signalling network at a glance

“…The mutant B cells also proliferate more rapidly in response to TLR ligands (Nanda et al, 2011). The ABIN(D485N)-expressing mice develop all the hallmarks of autoimmunity and succumb to a disease that resembles Type III and Type IV lupus in humans, termed lupus nephritis (Nanda et al, 2011;Caster et al, 2013). Interestingly, polymorphisms in the human gene encoding ABIN1 predispose individuals to several autoimmune diseases (Han et al, 2009;Nair et al, 2009;He et al, 2010;Gregersen et al, 2012;Yang et al, 2013).…”

Advances in lupus genetics and epigenetics

“…HLA-DR2/DR3 , STAT4 , IRF5/IRF7 , IFIH1 , ITGAM and UBE2L3 ) [78] and/or renal disorders (e.g. ITGAM , STAT4 , TNFSF4, TNFAIP3 and TNIP1 ) [79,80]. In addition, the apolipoprotein L1 nephropathy risk alleles G1/G2 strongly impact the risk and the time of end-stage renal disease (ESRD) in African Americans with lupus nephritis (LN), which may partly explain the increased risk of LN-ESRD in African Americans due to the high frequency of these alleles in African Americans but near absence in European Americans [81].…”