AIOLOS Variants Causing Immunodeficiency in Human and Mice.

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• AIOLOS, encoded by IKZF3, is an IKAROS family transcription factor.
• Recent studies link heterozygous missense variants in AIOLOS to inborn errors of immunity.
• Specific AIOLOS variants have been associated with distinct immune phenotypes.

Purpose of the Study:

• To investigate the role of AIOLOS variants in human adaptive immune deficiency.
• To characterize the functional consequences of AIOLOS missense variants.
• To establish AIOLOS as a novel disease-causing gene.

Main Methods:

• Analysis of patient genetic variants (AIOLOS G159R, N160S).
• Assessment of B cell counts and subsets (CD21, CD23) in patients.
• Functional studies of AIOLOS variants.
• Validation in mouse models harboring patient variants.

Main Results:

• AIOLOS G159R variant linked to B-lymphopenia and reduced early B-cell progenitors.
• AIOLOS N160S variant associated with hypogammaglobulinemia, PJP susceptibility, and altered B cell populations (CD21lo, CD23 expression).
• Both variants demonstrated loss-of-function, and mouse models recapitulated patient phenotypes.

Conclusions:

• AIOLOS variants disrupt adaptive immunity, leading to distinct immune deficiencies.
• AIOLOS is identified as a novel gene implicated in human immune disorders.
• Understanding AIOLOS function is crucial for diagnosing and potentially treating these conditions.