AIOLOS-Associated Inborn Errors of Immunity.

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• AIOLOS, encoded by IKZF3, is a transcription factor crucial for lymphocyte development.
• Heterozygous loss-of-function variants in AIOLOS have been linked to inborn errors of immunity (IEI).
• Identified variants include missense (G159R, N160S, G191R) and haploinsufficiency-causing (E82K, Q402X) mutations.

Purpose of the Study:

• To investigate the clinical spectrum and molecular pathogenesis of IEI associated with AIOLOS variants.
• To correlate specific AIOLOS mutations with distinct immunodeficient or immune dysregulation phenotypes.
• To utilize mouse models to elucidate the functional consequences of AIOLOS variants on immune cell development and function.

Main Methods:

• Analysis of clinical data from patients with AIOLOS-associated IEI.
• Characterization of heterozygous missense and truncating variants in the IKZF3 gene.
• Generation and analysis of mouse models mimicking human AIOLOS variants (AiolosG158R and AiolosN159S).

Main Results:

• AIOLOS variants cause recurrent sinopulmonary, bacterial, and viral infections.
• The AIOLOS^N160S variant is associated with severe immunodeficiency.
• AIOLOS haploinsufficiency leads to immune dysregulation, B-lymphopenia, and hypoimmunoglobulinemia in some patients.
• Mouse models recapitulated immune abnormalities, with Aiolos^G158R affecting B cell differentiation and Aiolos^N159S impairing lymphocyte homing via CD62L expression defects.

Conclusions:

• AIOLOS variants represent a significant cause of IEI with varied clinical presentations.
• Distinct AIOLOS mutations result in different molecular mechanisms underlying immune defects.
• Further patient studies are needed to fully delineate the clinical spectrum and pathogenic mechanisms of AIOLOS-associated IEI.