ITGB2 – Leukocyte Adhesion Deficiency

Leukocyte adhesion deficiency (LAD) is a rare primary immunodeficiency characterized by defective neutrophil and lymphocyte extravasation, resulting in recurrent, life-threatening bacterial infections and impaired wound healing. LAD type I, the most common form, is caused by biallelic mutations in ITGB2 encoding the β2 integrin subunit (CD18). The inheritance is autosomal recessive, with patients typically presenting in infancy with delayed umbilical cord separation and marked leukocytosis. Flow cytometry reveals absent or reduced CD11/CD18 expression on leukocytes, confirming impaired β2 integrin assembly and function.

Numerous case reports and series have documented over 300 affected children worldwide with ITGB2‐related LAD (PMID:25858935), underscoring a definitive gene–disease relationship. Mutations span missense, nonsense, splice-site, frameshift, and genomic deletions. A recurrent missense variant, c.850G>A (p.Gly284Ser), was identified in multiple unrelated patients with a moderate phenotype of LAD-I (PMID:7686755). Founder and de novo alleles have also been described in inbred populations, highlighting mutational heterogeneity and hotspot regions.

Segregation studies in compound heterozygous and homozygous families have confirmed autosomal recessive inheritance. Experimental correction by retrovirus-mediated CD18 gene transfer into patient lymphocytes restored normal CD11a/CD18 surface expression and LFA-1-dependent adhesive function (PMID:1972597), providing functional validation of pathogenicity.

Functional assays and animal models further support pathogenic mechanisms. Transfectant analyses of missense mutants (e.g., p.Gly273Arg, p.Ser138Pro) revealed impaired heterodimer assembly or ligand binding, elucidating structure–function relationships in the β2 integrin I-domain. CD18-null mice recapitulate human LAD-I phenotypes, including recurrent infections and skin ulcers, and exhibit dysregulated IL-6 production driving B cell hyperplasia (PMID:16844762).

Collectively, the evidence meets ClinGen criteria for a definitive association: over 300 unrelated probands, multiple variant classes, consistent segregation, and concordant functional data. Genetic evidence is strong with diverse pathogenic alleles reaching cap levels, and functional evidence is moderate based on in vitro complementation and in vivo modeling. Additional published prenatal diagnostic procedures and successful hematopoietic stem cell transplants illustrate broad clinical utility.

Key Take-home: Biallelic ITGB2 mutations cause autosomal recessive leukocyte adhesion deficiency type I through loss or dysfunction of CD18, and molecular diagnosis enables targeted gene therapy and transplant strategies.

References

• Science • 1990 • Correction of CD18-deficient lymphocytes by retrovirus-mediated gene transfer. PMID:1972597
• BMJ Case Reports • 2015 • Leucocyte adhesion deficiency type 1 with developmental delay secondary to CMV infection and filiation questions. PMID:25858935
• Biochemical and Biophysical Research Communications • 1993 • A point mutation associated with leukocyte adhesion deficiency type 1 of moderate severity. PMID:7686755
• European Journal of Immunology • 1992 • Molecular basis for a severe case of leukocyte adhesion deficiency. PMID:1352501
• Journal of Leukocyte Biology • 2006 • Terminal B cell differentiation is skewed by deregulated interleukin-6 secretion in beta2 integrin-deficient mice. PMID:16844762

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