An Autoimmune Disease-Associated Risk Variant in the TNFAIP3 Gene Plays a Protective Role in Brucellosis That Is Mediated by the NF-κB Signaling Pathway

Abstract

Naturally occurring functional variants (rs148314165 and rs200820567, collectively referred to as TT>A) reduce the expression of the tumor necrosis factor alpha-induced protein 3 (TNFAIP3) gene, a negative regulator of NF-κB signaling, and predispose individuals to autoimmune disease. In this analysis, we conducted a genetic association study of the TT>A variants in 1,209 controls and 150 patients with brucellosis, an infectious disease, and further assessed the role of the variants in brucellosis. Our data demonstrated that the TT>A variants were correlated with cases of brucellosis (P = 0.002; odds ratio [OR] = 0.34) and with individuals who had a positive serum agglutination test (SAT) result (titer of >1/160) (P = 4.2 × 10−6; OR = 0.23). A functional study demonstrated that brucellosis patients carrying the protective allele (A) showed significantly lower expression levels of the TNFAIP3 gene in their peripheral blood mononuclear cells and showed increased NF-κB signaling. Monocytes from individuals carrying the A allele that were stimulated with Brucella abortus had lower mRNA levels of TNFAIP3 and produced more interleukin-10 (IL-10), IL-6, and IL-1β than those from TT allele carriers. These data showed that autoimmune disease-associated risk variants, TT>A, of the TNFAIP3 locus play a protective role in the pathogenesis of brucellosis. Our findings suggest that a disruption of the normal function of the TNFAIP3 gene might serve as a therapeutic target for the treatment of brucellosis.

A20 Inhibits Intraocular Inflammation in Mice by Regulating the Function of CD4+T Cells and RPE Cells

“…One SNP associated with SLE is present in the coding region of TNFAIP3 and causes a missense mutation that reduces A20 function ( 26 ). Some of the risk SNPs near the coding regions of the TNFAIP3 gene have been shown to reduce both A20 mRNA and protein expression ( 48 ). In our previous study, a significantly increased prevalence of the TC genotype at rs9494885 was found in BD patients, but the TC genotype had no influence on A20 mRNA expression in PBMCs ( 47 ).…”

Prognostic Value of Serum Fibrinogen Level in Determining the Severity of Appendicitis Inflammation in Adult and Pediatric Patients Undergoing Appendectomy in Two Local Centres in Tehran

“…The proteins associated with fibrinogen are essential in the aggregation of leukocytes and cellular remodelling. These proteins play an essential role in old mononuclear phagocytes and damages caused by coagulation or fibrinolysis in inflamed tissues [3].…”