AIOLOS-Associated Inborn Errors of Immunity

• Published in: Journal of clinical immunology Vol. 44; no. 6; p. 128
• Main Authors: Yamashita, Motoi, Morio, Tomohiro
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.08.2024; Springer Nature B.V
• Subjects: Animal models; Animals; B-lymphocytes; Biomedical and Life Sciences; Biomedicine; Cell differentiation; Cells; Disease Models, Animal; family; Gene expression; genes; Genetic Predisposition to Disease; Haploinsufficiency; heterozygosity; Humans; Ikaros protein; Ikaros Transcription Factor - genetics; Immune system; Immunity; Immunity - genetics; Immunodeficiency; Immunology; Infectious Diseases; Internal Medicine; L-selectin; loss-of-function mutation; lymph; Lymph nodes; Lymphocytes; Lymphopenia; Medical Microbiology; Mice; Molecular modelling; mutants; Mutation - genetics; pathogenesis; Phenotype; Phenotypes; Proteins; Review; Transcription factors; zinc finger motif; Zinc finger proteins; IKZF; Inborn errors of immunity; AIOLOS; IKAROS; IKZF3
• ISSN: 0271-9142; 1573-2592; 1573-2592
• DOI: 10.1007/s10875-024-01730-9

AIOLOS, encoded by the IKZF3 gene, belongs to the Ikaros zinc finger transcription factor family and plays a pivotal role in regulating lymphocyte development. Recently, heterozygous missense loss-of-function variants within the DNA-binding domain of the IKZF3 gene (G159R, N160S, and G191R) have been identified in patients with inborn errors of immunity (IEI). Additionally, a missense and a truncating variant (E82K and Q402X) leading to the AIOLOS haploinsufficiency have been documented. The majority of individuals with AIOLOS-associated IEI manifest recurrent sinopulmonary infections, as well as various bacterial and viral infections. The patients carrying the AIOLOS N160S variant exhibit severe immunodeficient phenotypes. In contrast, patients harboring AIOLOS haploinsufficient variants predominantly present with clinical phenotypes associated with immune dysregulation. A varying degree of B-lymphopenia and hypoimmunoglobulinemia was noted in approximately half of the patients. Mouse models of AIOLOS G159R and AIOLOS N160S variants (Aiolos G158R and Aiolos N159S  in mice, respectively) recapitulated most of the immune abnormalities observed in the patients. Among these models, Aiolos G158R mice prominently exhibited defects in early B cell differentiation resulting from mutant Aiolos interfering with Ikaros function through heterodimer formation. In contrast, Aiolos N159S mice did not manifest early B cell differentiation defects. However, they displayed a distinct immune abnormality characterized by impaired induction of CD62L expression in lymphocytes, which is likely attributable to dysfunction of Ikaros, leading to defective lymphocyte homing to lymph nodes. Considering the diverse clinical phenotypes observed in the reported cases and the distinct molecular pathogenesis associated with each variant, further studies with more patients with AIOLOS-associated IEI would contribute to a better understanding of the clinical spectrum and underlying molecular mechanisms associated with this disorder.