AIOLOS Variants Causing Immunodeficiency in Human and Mice

AIOLOS is encoded by IKZF3 and is a member of the IKAROS zinc finger transcription factor family. Heterozygous missense variants in the second zinc finger of AIOLOS have recently been reported to be found in the families of patients with inborn errors of immunity. The AIOLOS(G159R) variant was identified in patients with B-lymphopenia and familial Epstein–Barr virus-associated lymphoma. Early B-cell progenitors were significantly reduced in the bone marrow of patients with AIOLOS(G159R). Another variant, AIOLOS(N160S) was identified in the patients presented with hypogammaglobulinemia, susceptibility to Pneumocystis jirovecii pneumonia, and chronic lymphocytic leukemia. Patients with AIOLOS(N160S) had mostly normal B cell counts but showed increased levels of CD21(lo) B cells, decreased CD23 expression, and abrogated CD40 response. Both variants were determined to be loss-of-function. Mouse models harboring the corresponding patient’s variants recapitulated the phenotypes of the patients. AIOLOS is therefore a novel disease-causing gene in human adaptive immune deficiency.