IFNAR2Deficiency Causing Dysregulation of NK Cell Functions and Presenting With Hemophagocytic Lymphohistiocytosis

We describe a 2 year old boy with two previously undescribed frameshift mutations in the interferon (IFN)alpha/beta receptor 2 (IFNAR2) gene presenting with hemophagocytic lymphohistiocytosis (HLH) following measles-mumps-rubella vaccination. Functional analyses show the absence of response to type I IFN in the patient's cells, as revealed by the lack of phosphorylation of STAT1 and the lack of induction of interferon-stimulated genes uponex vivostimulation with IFN alpha. HLH has been reported in patients with inborn errors of type I IFN-mediated immune responses following vaccination with live-attenuated viruses. The relation between HLH and defective type I IFN-mediated responses is unclear. We show that in patient's natural killer (NK) cells stimulated with IFN alpha the expected increase in degranulation and inhibition of IFN gamma production were affected. These data support a role for NK cell function dysregulation and lack of inhibition of IFN gamma production as contributors to the development of HLH in patients with impaired type I IFN signaling.