Leukocyte Adhesion Deficiency (LAD)

• Leukocyte Adhesion Deficiency (LAD) is an immunodeficiency disorder that affects both B and T cells
• LAD is characterized by defects in cellular adhesion molecules due to mutations in beta-2 integrins, leading to impaired leukocyte movement into tissues

LAD Types

• There are 3 types of LAD affecting different steps in leukocyte extravasation
• Leukocytes are the predominant cell type affected

LAD Type 1

• This is the most common form of LAD
• It is caused by a mutation in the ITGB2 gene, encoding CD18, a subunit of β2 integrins
• The absence of CD18 prevents the proper formation of integrins like LFA-1 and Mac-1, hindering firm adhesion of leukocytes to endothelial cells
• Patients present with recurrent bacterial infections, poor wound healing, delayed umbilical cord separation, and impaired formation of pus
• LAD Type 1 follows an autosomal recessive inheritance pattern
• All LAD Type 1 patients exhibit defects in CD18, leading to leukocyte dysfunction and impaired immune responses
• In LAD Type 1, a mutation in CD18 prevents firm adhesion, so phagocytes cannot stop rolling and migrate into tissues

LAD Type 2

• LAD Type 2 results from a defect in fucose metabolism, preventing the synthesis of Sialyl-Lewis X (SLeX)
• SLeX is a carbohydrate required for leukocyte rolling on the endothelium
• Defective early adhesion occurs because selectins cannot bind leukocytes
• Patients have severe immunodeficiency, cognitive impairment, and distinct facial features
• Defective fucosylation disrupts proper neuronal connections, leading to intellectual disability and cognitive impairment
• Facial features are affected due improper glycosylation, examples include coarse facial features, flat nasal bridge, prominent forehead, and micrognathia (small jaw)
• LAD Type 2 is inherited in an autosomal recessive manner and is very rare
• Loss of Sialyl-Lewis X prevents rolling, so leukocytes never slow down enough to adhere

LAD Type 3

• LAD Type 3 is caused by a mutation affecting beta-1, beta-2, and beta-3 integrins
• It leads to defective adhesion and signaling
• Platelets are affected, causing bleeding disorders along with immunodeficiency
• Patients present with severe infections, mucosal bleeding, and clotting dysfunction

Epidemiology of LAD

• LAD Type 1 is extremely rare, affecting 1 in 1 million people annually worldwide
• 93% of LAD Type 1 patients experience recurrent bacterial and fungal infections, often starting shortly after birth
• 86% of LAD Type 1 patients have poor wound healing, which leads to chronic ulcers and scarring
• LAD Type 2 is even rarer, with only a handful of cases reported globally

Mechanism of Disease in LAD

• A mutation in the beta subunit of integrins disrupts their function as adhesion molecules, leading to defective leukocyte migration
• CD18 deficiency results in decreased expression of key integrins: LFA-1 and Mac-1
• LFA-1 is critical for T-cell and neutrophil adhesion
• Mac-1 is essential for phagocytosis and immune response activation
• NK cells remain unaffected, as they use different adhesion molecules for migration
• Pus formation is impaired because leukocytes cannot migrate to the infection site
• Abnormal inflammatory responses occur because neutrophils fail to reach the infection site
• Recurrent bacterial infections, particularly by Staphylococcus and Gram-negative bacteria
• This happens because neutrophils cannot properly respond to infections

Extravasation

• Leukocyte migration (extravasation) is critical for immune function, following these steps:
  • Rolling, adhesion, transmigration (diapedesis), and migration to the infection site
• The endothelium expresses selectins, which bind to Sialyl-Lewis X on leukocytes, slowing them down to roll along the vessel wall
• Defective rolling occurs in LAD Type 2, where leukocytes lack Sialyl-Lewis X and cannot interact with selectins
• Leukocyte integrins (like LFA-1 and Mac-1) bind tightly to ICAM-1 on endothelial cells, which stops leukocytes from rolling and prepares them for migration
• Defective adhesion occurs in LAD Type 1, where leukocytes cannot adhere to the vessel wall
• Leukocytes squeeze through endothelial junctions to enter infected tissues
• Without adhesion, transmigration cannot occur effectively, leaving leukocytes trapped in circulation
• Leukocytes follow cytokine gradients to reach the infection site
• When migration is impaired, bacteria and fungi spread uncontrollably
• Extravasation is critical for wound healing and immune defense
  • Without it, infections persist, and healing is severely impaired

Clinical Manifestations

• Uncontrolled bacterial and fungal infections occur due to leukocyte failure to reach infected tissues
• Delayed umbilical cord separation happens because neutrophils cannot clear dead cells from the cord stump, leading to prolonged attachment (>30 days)
• Recurrent skin and mucosal infections are most commonly caused by Staphylococcus species
• Impaired wound healing leads to ulcers with thin, poorly formed, bluish scars

Genetics of LAD

• LAD Type 1 and Type 2 are inherited in an autosomal recessive pattern
• Affected individuals must inherit two copies of the mutated gene, one from each parent
• Carrier parents typically show no symptoms but can pass the defective gene to their offspring