Autoimmunity/inflammation in a monogenic primary immunodeficiency cohort

Area of Science:

• Immunology
• Genetics
• Clinical Medicine

Background:

• Primary immunodeficiencies (PIDs) are rare genetic disorders affecting immunity, leading to diverse clinical outcomes including infections, autoimmunity, and malignancy.
• Patients with PIDs often present with complex phenotypes, including autoimmune/inflammatory (AI/I) conditions, necessitating comprehensive evaluation.

Purpose of the Study:

• To investigate the clinical, genetic, and immunological characteristics of monogenic PID patients, focusing on the prevalence and nature of AI/I manifestations.
• To identify novel genetic variants associated with PIDs and AI/I diseases.
• To explore the relationship between AI/I manifestations, regulatory T cell (Treg) levels, and treatment responses in PID patients.

Main Methods:

• Clinical, genetic, and immunological phenotyping of a diverse cohort of monogenic PID patients.
• Identification of pathogenic variants using genetic sequencing.
• Analysis of regulatory T cell (Treg) percentages and assessment of treatment outcomes with immunosuppressive agents.

Main Results:

• Novel pathogenic variants were identified in genes including IKBKG, CTLA4, NFKB1, GATA2, CD40LG, and TAZ, alongside known variants in STAT3, PIK3CD, STAT1, NFKB2, and STXBP2.
• Autoimmune/inflammatory (AI/I) manifestations were common in PID patients, often present at initial diagnosis and characterized by multisystem involvement.
• Significantly decreased regulatory T cell (Treg) percentages were observed in PID patients with AI/I manifestations compared to those without.
• Steroid monotherapy provided insufficient long-term control for AI/I in most cases, necessitating additional immunosuppression.

Conclusions:

• Multisystem autoimmunity/inflammation in patients warrants investigation for underlying Primary Immunodeficiency (PID).
• Early assessment of regulatory T cells (Tregs) in PID patients may aid in predicting the risk of developing autoimmune/inflammatory (AI/I) conditions.
• Effective management of AI/I manifestations in PIDs often requires combination immunosuppressive therapy beyond initial steroid treatment.