A Germline Heterozygous Dominant Negative IKZF2 Variant Causing Syndromic Primary Immune Regulatory Disorder and...

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• Monogenic defects in immune regulation cause severe autoimmunity and atopy.
• Understanding these disorders offers insights into immune homeostasis and precision medicine.
• ICHAD syndrome presents with immune dysregulation, craniofacial anomalies, hearing impairment, atheila, and developmental delay.

Purpose of the Study:

• To provide a detailed immunological assessment of a pediatric patient with ICHAD syndrome.
• To investigate the molecular and cellular mechanisms underlying the immunodysregulation in ICHAD syndrome.
• To explore the role of HELIOS (IKZF2) in immune homeostasis and its deficiency in disease pathogenesis.

Main Methods:

• Multi-parameter flow cytometry analysis of peripheral blood mononuclear cells.
• Single-cell RNA sequencing of lymphocyte subsets.
• Genetic analysis to identify variants in IKZF2 (HELIOS).

Main Results:

• The patient had a de novo germline heterozygous variant in IKZF2, leading to reduced HELIOS expression and dominant-negative interference.
• Impaired natural killer cell differentiation and function, with increased CD8+ T cell activation.
• Hyperactive CD4+ T cells with elevated T helper cytokine production and proliferation; aberrant cytokine production by regulatory T cells.
• Single-cell RNA sequencing revealed naive CD4+ T cells enriched in activation and differentiation genes.

Conclusions:

• This study describes the immunological phenotype of a germline dominant-negative HELIOS deficiency, expanding understanding of ICHAD syndrome.
• It elucidates the single-cell level pathogenesis of autoimmune hemolytic anemia in this context.
• Provides critical insights into HELIOS function across diverse lymphocyte subsets and its role in immune homeostasis.