Abstract
Systemic autoimmune rheumatic disorders (SARD) represent important causes of morbidity and mortality in humans. The mechanisms triggering autoimmune responses are complex and involve a network of genetic factors. Mercury-induced autoimmunity (HgIA) in mice is an established model to study the mechanisms of the development of antinuclear antibodies (ANA), which is a hallmark in the diagnosis of SARD. A.SW mice with HgIA show a significantly higher titer of antinucleolar antibodies (ANoA) than the B10.S mice, although both share the same MHC class II (H-2). We applied a genome-wide association study (GWAS) to their Hg-exposed F2 offspring to investigate the non-MHC genes involved in the development of ANoA. Quantitative trait locus (QTL) analysis showed a peak logarithm of odds ratio (LOD) score of 3.05 on chromosome 3. Microsatellites were used for haplotyping, and fine mapping was conducted with next generation sequencing. The candidate genes Bank1 (B-cell scaffold protein with ankyrin repeats 1) and Nfkb1 (nuclear factor kappa B subunit 1) were identified by additional QTL analysis. Expression of the Bank1 and Nfkb1 genes and their downstream target genes involved in the intracellular pathway (Tlr9, Il6, Tnf) was investigated in mercury-exposed A.SW and B10.S mice by real-time PCR. Bank1 showed significantly lower gene expression in the A.SW strain after Hg-exposure, whereas the B10.S strain showed no significant difference. Nfkb1, Tlr9, Il6 and Tnf had significantly higher gene expression in the A.SW strain after Hg-exposure, while the B10.S strain showed no difference. This study supports the roles of Bank1 (produced mainly in B-cells) and Nfkb1 (produced in most immune cells) as key regulators of ANoA development in HgIA.
Highlights
Failure to recognize self with non-self-antigens results in a disorder of the innate and adaptive immune systems, leading to the development of autoantibodies, but the details of this process are still unclear [1]
Since Bank1 is a B-cell specific protein [24, 28] and Bank1 and Nfkb1 genes are associated with the development of higher antinucleolar antibodies (ANoA) titer, we investigated the intracellular pathway by studying gene expression in spleen and believe that our findings mainly resemble what occurs in B-cells
The data for the susceptible B10.S strain are in concordance with what was found in human systemic lupus erythematosus (SLE) patients, but we found that higher expression of the short Δ2 isoform of Bank1 is associated with a higher ANoA titer
Summary
Failure to recognize self with non-self-antigens results in a disorder of the innate and adaptive immune systems, leading to the development of autoantibodies, but the details of this process are still unclear [1]. Systemic autoimmune rheumatic disorder (SARD) is characterized by autoantibodies reactive with nuclear or subcellular organelles. It includes systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and rheumatoid arthritis (RA). Serum antinuclear antibodies (ANA) are used as serological markers in clinical practice and as laboratory tools in diagnostics of autoimmune diseases [2]. Systemic autoimmune disorders are triggered by genetic factors (such as MHC class II) [3], immunodeficiency [4], and environmental factors [5,6,7,8], making susceptible individuals more prone to developing the disease. Genome-wide association study (GWAS) is a tool for investigating genetic associations with autoimmune traits, and it is used to identify genetic risk factors for SARDs [9, 10]
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