Response to the Comments on “Dendritic Cells and Monocyte/Macrophages That Create the IL-6/APRIL-Rich Lymph Node Microenvironment Where Plasmablasts Mature”

In their letter to the editor, Belnoue et al. highlight an important difference between the cell types in mouse and human that produce APRIL at sites of Ab production. Belnoue et al. report an immunohistological study of APRIL expression in human lymph nodes where neutrophils are comfortably the highest constitutive producers of APRIL protein. This contrasts with our study of mouse lymph nodes published in the February 15, 2009 issue of The Journal of Immunology, where the main source of APRIL mRNA was found to be Gr1⁺CD11b^highF4/80⁺ monocyte/macrophages recruited after immunization with alum-precipitated OVA (1). In addition, in our mouse model, Gr1^highCD11b^high neutrophils were the only nonstromal source of BAFF (Blys) mRNA identified in the lymph node. Other studies in humans have demonstrated the ability of neutrophils to produce BAFF (2). BAFF is more active in B cell homeostasis, while APRIL is particularly associated with plasma cell maturation and survival. These data point to human neutrophils’ capacity to influence B cell biology at a number of levels through their production of BAFF and/or APRIL, whereas in mice these different functions seem to involve distinct cell subsets. This apparent discrepancy may prove useful in understanding the mechanisms underlying the regulation of BAFF/APRIL expression during the differentiation of cells of myeloid lineage. It should be noted that in humans, in addition to neutrophils, a number of other cells including CD14⁺ blood monocyte-derived nurse-cells (3), osteoclasts, monocyte/macrophages (4), and dendritic cells can deliver an effective APRIL signal to plasma cells involved in myeloma or autoimmune diseases (see Ref. 5 for review). Untangling the heterogeneity in the cellular composition of plasma cell sustaining niches as well as their functional specificities is an important issue that requires further studies.