Abstract
Trace elements play important roles in human health, but little is known about their functions in humoral immunity. Here, we show an important role for iron in inducing cyclin E and B cell proliferation. We find that iron-deficient individuals exhibit a significantly reduced antibody response to the measles vaccine when compared to iron-normal controls. Mice with iron deficiency also exhibit attenuated T-dependent or T-independent antigen-specific antibody responses. We show that iron is essential for B cell proliferation; both iron deficiency and α-ketoglutarate inhibition could suppress cyclin E1 induction and S phase entry of B cells upon activation. Finally, we demonstrate that three demethylases, KDM2B, KDM3B and KDM4C, are responsible for histone 3 lysine 9 (H3K9) demethylation at the cyclin E1 promoter, cyclin E1 induction and B cell proliferation. Thus, our data reveal a crucial role of H3K9 demethylation in B cell proliferation, and the importance of iron in humoral immunity.
Highlights
Trace elements play important roles in human health, but little is known about their functions in humoral immunity
We conducted a clinical investigation at the Zhejiang Provincial Center for Disease Control and Prevention to assess the correlation between iron metabolism and antibody responses to the measles vaccine (MV) in humans
Consistent results were obtained for transferrin saturation
Summary
The iron levels in serum correlate with antibody responses to vaccination in humans. First, we sought to determine whether humoral immunity was influenced by abnormal iron metabolism. Gene expression profiles were similar in 2OG-inhibited B cells and iron-deficient B cells, and induction of cyclin D2 and Bcl-xL in response to BCR or TLR activation remained intact, whereas cyclin E1 induction was severely inhibited (Fig. 7b) These data suggest that JmjC demethylasemediated histone demethylation processes might play roles in Bcell proliferation. We further observed increased H3K9 methylation at the promoter region of cyclin E1 in triple-KD B cells similar as the situation in iron-deficient B cells (Fig. 8d) These results indicated that iron is required for cyclin E1 induction primarily because it alters H3K9me status and that the three demethylases KDM2B, KDM3B, and KDM4C might be involved in this process
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