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Diminished neonatal antibody responses following infection or immunization may stem in part from intrinsic characteristics of neonatal B cells. In this study, we used B-cell subset sorting combined with gene expression assays to investigate major differences in the expression of host genes in neonatal and adult naïve B cells. We discovered significantly reduced expression of the interleukin (IL)-4 receptor alpha chain and reduced IL-4-induced signalling in neonatal B cells. Neonatal naïve B cells were susceptible to more rapid and more profound levels of apoptosis when cultured in vitro. They also exhibited a limited response to IL-4 treatment compared with adult cells. The expression level of the IL-13 receptor alpha 1 chain, a key component of the IL-13 receptor/IL-4 type II receptor, and the response to IL-13 treatment for protection against apoptosis in neonatal B cells were similar to those of the adult B cells. These studies suggest a possible mechanism underlying the limited magnitude and durability of neonatal antibody responses.