Combined immunodeficiency associated with DOCK8 mutations.

Area of Science:

• Immunology
• Genetics
• Infectious Diseases

Background:

• Some combined immunodeficiency variants present with recurrent sinopulmonary and cutaneous viral infections and high IgE levels.
• The genetic basis for these specific immunodeficiency variants remained unidentified.
• This study investigates the genetic cause of a particular combined immunodeficiency phenotype.

Purpose of the Study:

• To identify the genetic cause of recurrent sinopulmonary and cutaneous viral infections with elevated IgE.
• To characterize the clinical and immunological features of patients with this immunodeficiency variant.
• To understand the role of DOCK8 protein in lymphocyte function.

Main Methods:

• Longitudinal clinical data collection from 11 patients across eight families.
• Comparative genomic hybridization arrays and targeted gene sequencing to identify genetic variants.
• Quantitative reverse-transcriptase-polymerase-chain-reaction assays, immunoblotting, in vitro lymphocyte assays, and flow cytometry to confirm and evaluate mutations and their effects.

Main Results:

• Patients experienced recurrent sinopulmonary infections, severe skin infections, and persistent viral infections like molluscum contagiosum and human papillomavirus.
• Common findings included severe atopy, anaphylaxis, hypereosinophilia, low T and B cell counts, low IgM, and impaired CD8 T cell expansion.
• Novel homozygous or compound heterozygous mutations in the DOCK8 gene were identified, leading to DOCK8 protein absence in lymphocytes.

Conclusions:

• Autosomal recessive DOCK8 deficiency is identified as a novel cause of combined immunodeficiency.
• This deficiency presents with a distinct clinical phenotype including severe infections and atopy.
• DOCK8 protein is crucial for normal lymphocyte function and immune homeostasis.