Iron-dependent histone 3 lysine 9 demethylation controls B cell proliferation and humoral immune responses

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.

Iron Deficiency Anemia at Time of Vaccination Predicts Decreased Vaccine Response and Iron Supplementation at Time of Vaccination Increases Humoral Vaccine Response: A Birth Cohort Study and a Randomized Trial Follow-Up Study in Kenyan Infants

“…Thus, adequate iron availability may be critical for adaptive immunity. If ID critically limits iron availability to responding lymphocytes ( 10 ), this may explain our findings that ID and anemia during early infancy are associated with an impaired response to vaccination. If ID limits the development of memory B-cells ( 10 ) it may reduce long-term immunity ( 32 ).…”

“…If ID critically limits iron availability to responding lymphocytes ( 10 ), this may explain our findings that ID and anemia during early infancy are associated with an impaired response to vaccination. If ID limits the development of memory B-cells ( 10 ) it may reduce long-term immunity ( 32 ). Recent studies showing impaired antigen-specific immune responses in hypoferremic mice and lower antibody concentrations in patients with iron-refractory IDA support this concept (Joe Frost et al, personal communication 2020).…”

“…In some animal and cell models, ID reduces the proportion of mature T-cells and impairs T-cell activation and proliferation, although in many cell models iron chelators have been used (5,9,31). Some studies have also shown detrimental effects of ID on B-cell numbers or function, but others have not (5,(9)(10)(11)31). In humans, studies on ID and immune function show varying results depending on what aspect of immunity is measured and the severity of ID, age and/or underlying nutritional status (5,9).…”

“…Anemia is particularly common in infants age <1 y in Sub-Saharan Africa: >70% of infants may be anemic at time of routine vaccination in the first year (7,8). ID not only causes anemia, but also may impair adaptive immunity and thereby vaccine efficacy, although the data are equivocal (5,9,10). ID in mice attenuates T-cell dependent and independent antigen-specific antibody responses, and impairs cyclin E1 induction and S-phase entry during B-cell proliferation (10).…”

“…ID not only causes anemia, but also may impair adaptive immunity and thereby vaccine efficacy, although the data are equivocal (5,9,10). ID in mice attenuates T-cell dependent and independent antigen-specific antibody responses, and impairs cyclin E1 induction and S-phase entry during B-cell proliferation (10). Data from observational studies in humans are contradictory, in some, ID was associated with defective immune function, particularly T-cell immunity (5,9).…”