AbstractBackgroundFamilial eosinophilia (FE) is a rare autosomal dominant inherited disorder characterized by the presence of lifelong peripheral eosinophilia (>1500/μL). Mapped to chromosome 5q31‐q33, the genetic cause of FE is unknown, and prior studies have failed to demonstrate a primary abnormality in the eosinophil lineage.ObjectiveThe aim of this study was to identify the cells driving the eosinophilia in FE.MethodsMicroarray analysis and real‐time PCR were used to examine transcriptional differences in peripheral blood mononuclear cells (PBMC), and in purified cell subsets from affected and unaffected family members belonging to a single large kindred. Cytokine levels in serum and PBMC culture supernatants were assessed by suspension array multiplexed immunoassays.ResultsWhereas IL‐5 mRNA expression was significantly increased in freshly isolated PBMC from affected family members, this was not accompanied by increased mRNA expression of other Th2 cytokines (IL‐4 or IL‐13). Serum levels of IL‐5 and IL‐5 receptor α, but not IgE, were similarly increased in affected family members. Of note, IL‐5 mRNA expression was significantly increased in purified CD3+ CD4+, CD14+, CD19+, and ILC2 cells from affected family members, as were IL‐5 protein levels in supernatants from both stimulated PBMC and ILC2 cultures.ConclusionsThese data are consistent with the hypothesis that the eosinophilia in FE is secondary to dysregulation of IL‐5 production in PBMC (and their component subsets).