Leukocyte Adhesion Deficiency

Leukocyte adhesion deficiency (LAD) disorders are primary immune deficiency syndromes that affect the leukocyte adhesion process. There are three types of LAD – 1, 2, and 3. LAD1 is the most common type.

Diagnosis

Indications for Testing

  • Child with delayed separation of the umbilical cord or recurrent infections in whom more common immunodeficiencies have been ruled out
  • Tissue infections with absence of pus and/or high peripheral neutrophil counts

Laboratory Testing

  • Initial screening
    • General immunodeficiency screening
      • CBC with differential
      • Comprehensive metabolic profile
      • Quantitative serum immunoglobulins (IgA, IgG, IgM)
      • Lymphocyte subset analyses – depending on clinical presentation
    • Rule out other diseases associated with immunodeficiency
      • HIV-1,2 testing
      • Plasma cell disorders – monoclonal protein detection, quantitation, and characterization with serum protein electrophoresis (SPEP), immunofixation electrophoresis (IFE), IgA, IgG, IgM
      • Cystic fibrosis – sweat chloride testing using an accredited cystic fibrosis center
    • Rule out diseases associated with protein losses (eg, protein-losing enteropathy, nephropathy)
  • More specific screening – based on initial screening results
  • Flow cytometric analysis
    • Assess presence of beta 2 (β2) integrins CD11 and CD18
      • Decreased/absent expression of CD11/CD18 – consistent with leukocyte adhesion deficiency-1 (LAD1)
        • 2-10% expression – moderate deficiency; reasonable survival rate into adulthood
        • >10% expression – mild deficiency; may not be recognized until late teen years
        • <2% – severe deficiency; majority die in infancy unless bone marrow transplant is performed
      • Normal expression of CD11/CD18 – consistent with LAD2 or LAD3
    • Assess presence of CD15 – indicated if LAD2 is suspected
      • Absent expression of CD15 – consistent with LAD2
    • Other testing
      • Neutrophil rolling, neutrophil adherence, neutrophil motility – performed only in specialized laboratories
      • Bombay blood group phenotype testing – present in LAD2
      • Platelet aggregation – abnormal in LAD3
      • Molecular sequence analysis – defines exact molecular defect

Differential Diagnosis

Background

Epidemiology

  • Incidence/prevalence – rare
    • LAD1 – most common type
  • Age – usually identified in infancy or early childhood

Inheritance

LAD Syndromes
  LAD1 LAD2 LAD3

Inheritance

Autosomal recessive

Autosomal recessive

Autosomal recessive (very rare)

Mutation Defect

Mutation of CD18 gene (ITGB2) – defect in expression of common chain (CD18) of β2 integrin family

Mutation of FUCT1 gene (GDP-fucose transporter 1) – defect in fucose metabolism leading to absence of sialyl-Lewis X (sLeX) ligand from phagocytes (CD15a)

Mutation of KINDLIN-3 gene – defect in inside-out signaling of β1, β2, and β3 integrins on leukocytes and platelets

Pathophysiology

  • LAD involves defects in integrin and selectin expression
    • Blood neutrophils – the first line of defense against bacterial and fungal infection
    • Blood leukocytes migrate into the site of inflammation
      • Requires expression of P and E selectins on the endothelial cells with their ligands on leukocytes, which requires the family of integrins be present
        • CD18 – essential component of the β2 integrins (CD11a/CD18, CD11b/CD18, and CD11c/CD18)
    • Lack of integrin and selectin expression leads to defective adhesion of neutrophils that in turn leads to increased susceptibility to bacterial and fungal infections
    • Other LAD-like syndromes with defects in adhesion/chemotaxis have been identified (eg, RAC-2, which regulates actin cytoskeleton; leukocyte hyperadhesion syndrome)

Clinical Presentation

Signs and Symptoms Based on LAD Type
  LAD1 LAD2 LAD3

Delayed separation of umbilical cord

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Recurrent soft tissue infections/ulcers

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Chronic periodontitis later in life

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Leukocytosis with neutrophilia

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Impaired wound healing

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Absence of pus

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Bleeding tendency

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Developmental abnormalities

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ARUP Laboratory Tests

Use to diagnose type I and II leukocyte adhesion deficiency syndromes

Panel includes CD11b, CD15, CD18

Related Tests

Evaluate patients with suspected inherited qualitative platelet disorders or patients with lifelong platelet-type bleeding

Studies include platelet aggregation studies, ADP; collagen; AA; ristocetin

Medical Experts

Contributor

References

Additional Resources