More than half of newly generated B lymphocytes have some degree of autoreactivity . These immature autoreactive B cells are extreme sensitive to apoptosis because they express high levels of death receptor Fas, a mechanism to eliminate autoreactive B cells . However, the over expressed BAFF and its receptors may subvert the destiny of apoptosis of these autoreactive B lymphocytes by inducing the expression of anti-apoptotic factors and by blocking the function of pro-apoptotic molecule . The rescued autoreactive B lymphocytes could mediate autoimmune disease through either the secreted autoantibodies or antigen presenting . Altered serum BAFF levels and intra-thyroid BAFF and its receptors expression levels have been observed in autoimmune thyroid disease [10, 12, 19]. Different to these researches, we measured BAFF receptors BAFF-R and TACI expression on peripheral blood B lymphocytes in addition to serum BAFF concentrations in this study.
We found elevated serum levels of BAFF in GD patients, suggesting a possible role of BAFF in thyroid autoimmunity. This is in line with other studies describing increased serum BAFF levels in thyroid autoimmune diseases including GD and Hashimoto’s thyroiditis (HT) [10, 12]. Our data showed serum BAFF concentrations correlated positively with free thyroxine concentrations, confirming serum BAFF levels positively correlating with activity of autoimmune diseases. There was no correlation between serum BAFF concentrations and TRAb titers based on our data. The correlation between serum BAFF levels and titers of autoantibodies are controversial as different results have been reported [7, 12, 26]. In our assay, TRAb was measured by a competing electrochemiluminescence immunoassay method . TRAb measured by this method was only that having the same epitope with monoclonal antibody M22, but not the whole TSH receptor autoantibodies in the blood. BAFF levels may correlate with the whole autoantibodies titers, but not the titer of autoantibody with the specific epitope, this could be the reason we did not observe correlation between BAFF levels with TRAb titers in our study.
The most significant finding of our work was the skewed expression of receptors for BAFF on peripheral blood B lymphocytes in GD patients: the BAFF-R expression was increased while the BAFF receptor TACI expression was decreased. Our results were not in line with reports of reduced BAFF-R expression on peripheral blood B cells in other autoimmune disease as SLE . Conflicting results of TACI expression on peripheral B lymphocytes in SLE patients have been reported [5, 15]. However, B lymphocytes infiltrating in thyroid expressed more BAFF-R, these data combined with our results , indicating different expression profiles of receptors for BAFF among autoimmune diseases.
The skewed expression of BAFF-R and TACI in GD may reflect the different functions of these two molecules [2, 3]. BAFF-R and TACI have different binding affinity to BAFF . BAFF-R and TACI oppositely regulates B cell homeostasis [2, 16, 28, 29]. BAFF-R promotes B cells survival while TACI sensitizes B cells to apoptosis. Knocking out TACI led to elevated B cells number and SLE-like symptoms in the presence of over expressed BAFF in mice . TACI activation also mediates immunosuppression through inducing interleukin (IL)-10 production in B lymphocytes [30, 31]. IL-10 is an immunosuppression cytokine. IL-10 secreting B cells are named Bregs (regulatory B cells) or B10 cells. Overexpressed TACI promoted more IL-10 expression in B lymphocytes in SLE patients . Loss of Bregs has been described in GD patients . We may speculate in GD patients, in the context of high levels of BAFF and skewed expression of BAFF-R and TACI on B lymphocytes, BAFF-R pathway activity was enhanced while TACI pathway activity was relatively diminished, which leads to the accumulation of autoreactive B cells and loss of Bregs. The skewed expression of BAFF-R and TACI is the key mechanism leading to autoimmunity in GD. Totally blocking both BAFF-R and TACI signal pathway will only augment inflammation due to the inhibited IL-10 secretion, as observed in multiple sclerosis (MS) patients . To selective inhibit the BAFF-R pathway and to restore the TACI pathway function could be a novel strategy to cue GD. This strategy may eliminate the autoreactive B lymphocytes, thus with the potential to prevent relapse of GD.
Our data indicated steroids targets BAFF and BAFF-R, but not TACI. There were no previous studies reporting effects of steroids on BAFF-R expression in autoimmune diseases in the literature to our knowledge. In large B cell lymphoma, only BAFF-R, rather than BAFF, was an independent prognostic factor for steroids treatment , highlighting BAFF-R is an important target for steroids in eliminating B lymphocytes. Due to the small sample size of patients receiving steroids, the effect of steroids on TACI expression need be studied in the future with larger sample size.