The effects of iron deficiency on lymphocyte cytokine production and activation: preservation of hepatic iron but not at all cost

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Abstract
Worldwide, over 40% of children have iron deficiency anaemia, frequently associated with infections. Certain cytokines are involved in both immune activation/response to infection and iron transport/metabolism. We therefore assessed the relations among iron deficiency, cytokine production and lymphocyte activation markers in 142 hospitalized Malawian children. We examined peripheral blood lymphocyte antigens/cytokine production using four- colour flow cytometry and serum transferrin receptor (TfR) levels, an inverse measure of iron status unaffected by acute illness or infection, with an enzyme-linked immunosorbent assay. Wilcoxon rank sum tests and logistic regression analyses (LRA) were performed. Iron deficiency (TfR ≥ 10 μg/ml) versus TfR < 10 μg/ml, was associated with higher percentages of lymphocytes producing: (a) induced or spontaneous IL-6 (medians: induced, 15·9% for iron-deficient children versus 8·8% for iron-replete children, P= 0·002; spontaneous, 24·4% versus 13·0%, P < 0·001) and (b) induced IFN-γ (medians:18·4% versus 12·4%, P= 0·006). The percentages of CD8+ T cells spontaneously producing IL-6 and of all lymphocytes producing induced TNF-α and IFN-γ in the same cell had the strongest relationships to iron deficiency (b = + 0·0211, P= 0·005 and b =+ 0·1158, P= 0·012, respectively, LRA) and were also positively related to the co-expression of the T cell activation markers HLA DR and CD38. Severe iron deficiency (TfR ≥ 30 μg/ml) was associated with the percentage of lymphocytes producing induced IL-4 (medians: 0·5% versus 1·6%, P < 0·010). The cytokine patterns associated with iron deficiency in our study would preserve iron stores but also preferentially retain the activation capabilities of T cells, albeit not necessarily other immune cells, until a critical level of iron depletion is reached.