Genetic variants near the tumor necrosis factor-α-induced protein 3 gene (TNFAIP3) at the chromosomal region 6q23 demonstrated significant associations with multiple autoimmune diseases.
Ablation of A20/Tnfaip3, a critical regulator of NF-κB activation, in DCs leads to constitutive DC activation and development of systemic autoimmunity.
These data showed that autoimmune disease-associated risk variants, TT>A, of the TNFAIP3 locus play a protective role in the pathogenesis of brucellosis.
Previous studies have found that the polymorphisms of tumor necrosis factor-α induced protein 3 (TNFAIP3) were associated with several autoimmune diseases.
Tumor necrosis factor, α-induced protein 3 (TNFAIP3) which encodes a ubiquitin-modifying enzyme (A20), acts as a negative regulator of the NF-κB pathway, and in lymphoma and autoimmune diseases it is frequently inactivated by mutations and/or deletions.
Loss of TNFAIP3 mRNA and its encoded protein, A20, impaired tumor necrosis factor-α-induced receptor-mediated downregulation of nuclear factor-κB signaling, a hallmark of autoimmunity.
To replicate a single nucleotide polymorphism (SNP) of known genes for lupus (IRF5 rs10488631, PTPN22 rs2476601, BLK rs2736340 and TNFAIP3rs5029939) and other autoimmune diseases (CD28 rs1980422, IL2RA rs2104286 and KIF5A rs1678542) on a newly studied Egyptian cohort to investigate the genetic disparity with different studied ethnic groups in relation to lupus susceptibility.
Variations in two genes of the tumour necrosis factor (TNF) alpha pathway have been implicated in the pathogenesis of autoimmune diseases: polymorphisms in the TNFRSF1A gene, encoding TNF receptor 1, showed significant association with MS in genomewide association scans, and variation in or near the TNFAIP3 gene, coding for a negative regulator of NFkB, was associated with MS, systemic lupus erythematosus, diabetes and rheumatoid arthritis.
Genetic studies have shown an association between multiple autoimmune diseases and TNFAIP3 (A20) and TNIP1 (ABIN1), both repressors of NF-κB and of IKBKE (IKKε), which is an NF-κB activator.
Polymorphisms of TNFAIP3, which encodes the A20 protein that plays a key role in controlling nuclear factor κB activation, have been associated with several autoimmune diseases.
B cells lacking the tumor suppressor TNFAIP3/A20 display impaired differentiation and hyperactivation and cause inflammation and autoimmunity in aged mice.
Because genetic polymorphisms in TNFAIP3 are associated with human autoimmune disorders, these findings identify A20-mediated control of DC activation as a crucial checkpoint in the development of systemic autoimmunity.