Somatic mutations and T-cell clonality in patients with immunodeficiency

Area of Science:

• Immunology
• Genetics
• Cell Biology

Background:

• Common variable immunodeficiency (CVID) and other late-onset immunodeficiencies frequently present with autoimmunity and lymphoproliferation.
• The underlying causes are often unknown, with only a few cases linked to known genetic mutations.

Purpose of the Study:

• To investigate the association between somatic mutations in CD4+ and CD8+ T cells and immunodeficiency.
• To explore the role of these mutations in patients with CVID and other immunodeficiencies, particularly those with co-occurring autoimmunity and lymphoproliferation.

Main Methods:

• Deep sequencing of 2533 immune-associated genes in CD4+ and CD8+ T cells from 17 patients and 21 healthy controls.
• T-cell receptor beta sequencing to analyze T-cell receptor repertoires.
• Analysis of somatic mutation prevalence, including clonal hematopoiesis-associated variants.

Main Results:

• Somatic mutations were found in 65% of immunodeficiency patients (75% in CVID) compared to 48% in controls.
• Mutations were identified in genes critical for immune function and proliferation (e.g., STAT5B, C5AR1, KRAS, NOD2).
• Patients with CVID showed altered T-cell receptor repertoire dynamics, suggesting immune dysregulation.

Conclusions:

• Somatic mutations in immune-associated genes are prevalent in CD4+ and CD8+ T cells of patients with immunodeficiency.
• These mutations may contribute to the pathogenesis of immune dysregulation, autoimmunity, and lymphoproliferation in a subset of patients.