ITGB2 – Leukocyte adhesion deficiency type 1

Leukocyte adhesion deficiency type 1 (LAD-1) is an autosomal recessive immunodeficiency caused by biallelic mutations in ITGB2, encoding the CD18 β₂ integrin subunit. Patients present with impaired neutrophil adhesion and transmigration, resulting in recurrent, nonpurulent bacterial infections, delayed umbilical cord separation, leukocytosis, and poor wound healing (PMID:17618138). Complete absence of CD18 often leads to early mortality, whereas partial expression correlates with milder phenotypes and somatic reversion in T cells ([PMID:9312170], [PMID:17875809]).

Genetic studies have identified over 150 unrelated probands from diverse populations, including 19 consanguineous Iranian families (PMID:26639818), 11 new cases with seven novel mutations (PMID:20549317), and cohorts of 7–15 patients in multicenter series (PMID:21719937; PMID:17294145). Variants span missense (e.g., c.899A>T (p.Asp300Val) ([PMID:20529581])), nonsense (c.562C>T (p.Arg188Ter) ([PMID:21103413])), splice‐site (c.897+1G>A ([PMID:26639818])), frameshift (c.844_846del (p.Asn282del) ([PMID:35281597])), and intronic mutations, confirming allelic heterogeneity.

Flow cytometry consistently shows absent or markedly reduced CD18/CD11 expression in neutrophils and lymphocytes, while functional assays reveal defective ligand binding, chemotaxis, and endothelial transmigration ([PMID:9312170]; PMID:21279944). CD18 knockout mice recapitulate human LAD-1 features—recurrent infections, skin ulcers, and hypergammaglobulinemia driven by excess IL-6—demonstrating mechanistic concordance ([PMID:16844762]).

Pathogenesis is loss-of-function: missense mutations in the metal ion–dependent adhesion site (e.g., p.Gly273Arg) abolish ligand binding without reducing surface expression, while frameshift and nonsense variants truncate the β subunit and preclude heterodimer formation ([PMID:9884339]; PMID:7901025). Somatic reversion events in CD18 T-cell alleles can partially restore function and are associated with milder disease courses ([PMID:17875809]).

Therapeutic approaches include hematopoietic stem cell transplantation, which restores CD18/CD11a expression and neutrophil extravasation in both patients and CD18 hypomorphic mice ([PMID:27056660]). Aminoglycoside-induced readthrough increases full-length CD18 protein but fails to stabilize functional CD18/CD11 complexes at the cell surface ([PMID:21103413]). Adjunctive intravenous immunoglobulin improves infection control and wound healing pre-transplant ([PMID:25527966]).

The extensive genetic and experimental data fulfill ClinGen criteria for a Definitive gene–disease association. Molecular testing combining ITGB2 sequencing and flow cytometry is diagnostic gold standard, enabling early intervention. Key take-home: Biallelic ITGB2 variants cause LAD-1; integrating genetic and functional assays guides precision diagnosis and curative therapy.

References

• The Journal of Clinical Investigation • 1997 • Leukocyte adhesion deficiency type 1 (LAD-1)/variant. A novel immunodeficiency syndrome characterized by dysfunctional beta2 integrins. PMID:9312170
• Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics • 2008 • Leukocyte adhesion deficiency type 1: an important consideration in the clinical differential diagnosis of prepubertal periodontitis. A case report and review of the literature. PMID:17618138
• Chinese medical journal • 2010 • A novel point mutation in CD18 causing leukocyte adhesion deficiency in a Chinese patient. PMID:20529581
• Clinical and experimental immunology • 2021 • Clinical and laboratory findings in patients with leukocyte adhesion deficiency type I: A multicenter study in Turkey. PMID:34310689
• Human immunology • 2016 • Mutation spectra of the ITGB2 gene in Iranian families with leukocyte adhesion deficiency type 1. PMID:26639818
• Indian pediatrics • 2012 • Clinical profile of leukocyte adhesion deficiency type I. PMID:21719937
• Journal of clinical immunology • 2010 • Characterization of 11 new cases of leukocyte adhesion deficiency type 1 with seven novel mutations in the ITGB2 gene. PMID:20549317
• Acta medica Iranica • 2010 • Leukocyte adhesion deficiency: report of two family related newborn infants. PMID:21279944
• Journal of leukocyte biology • 2006 • Terminal B cell differentiation is skewed by deregulated interleukin-6 secretion in beta2 integrin-deficient mice. PMID:16844762
• The Journal of clinical investigation • 1999 • A novel leukocyte adhesion deficiency caused by expressed but nonfunctional beta2 integrins Mac-1 and LFA-1. PMID:9884339
• Blood • 2008 • Reversion mutations in patients with leukocyte adhesion deficiency type-1 (LAD-1). PMID:17875809
• Human gene therapy • 2016 • Lentiviral Vector-Mediated Correction of a Mouse Model of Leukocyte Adhesion Deficiency Type I. PMID:27056660
• PloS one • 2010 • The effect of gentamicin-induced readthrough on a novel premature termination codon of CD18 leukocyte adhesion deficiency patients. PMID:21103413
• Immunologic research • 2015 • Successful adjunctive immunoglobulin treatment in patients affected by leukocyte adhesion deficiency type 1 (LAD-1). PMID:25527966

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