IKZF-associated inborn errors of immunity

IKAROS, HELIOS, and AIOLOS are transcription factors predominantly expressed in hematopoietic cells, where they form heteromeric and homodimeric complexes and facilitate transcriptional regulation. IKZF proteins also associate with non-IKZF family proteins, which vary between different immune cell subtypes and their differentiation stages. Heterozygous germline loss-of-function variants in IKZF1, IKZF2, and IKZF3 cause IKAROS, HELIOS, and AIOLOS deficiencies, respectively, leading to inborn errors of immunity (IEI). Heterozygous gain-of-function (GOF) variants in IKZF1 result in IKAROS-GOF disease, characterized by autoimmune and allergic manifestations, whereas dominant-negative IKAROS and AIOLOS variants are associated with combined immunodeficiency. Importantly, patients with IKZF-associated IEI exhibit varying degrees of immunodeficiency, immune dysregulation, and occasional malignancies, and so, disease manifestations differ significantly among the variant types. Therefore, each variant often causes phenotypic heterogeneity, which possibly stems from diverse protein complexes formed by IKZF proteins. Besides immunoglobulin supplementation for patients with B cell defects and hematopoietic cell transplantation for severe cases, molecularly targeted therapies have been investigated for treating IKAROS-GOF disease.