Leukocyte Adhesion Deficiency (LAD) is a rare, inherited immune system disorder that severely impairs the body’s ability to fight infections. The condition involves a failure in how white blood cells (leukocytes) leave the bloodstream and travel to sites of infection in the body’s tissues. Because these immune cells cannot reach invading pathogens, individuals with LAD suffer from recurrent, life-threatening bacterial and fungal infections starting in infancy. The deficiency is categorized into three main subtypes—LAD-I, LAD-II, and LAD-III—all stemming from defects in the molecular machinery necessary for immune cell movement.
Understanding Normal Leukocyte Adhesion
The body’s defense relies on the swift movement of white blood cells, particularly neutrophils, to the site of injury or infection. This process, known as leukocyte extravasation, requires interactions between the immune cells and the inner lining of the blood vessel walls, called the endothelium. Leukocytes use the bloodstream primarily as a transport system, but their work of fighting infection happens in the tissues outside the vessels.
This migration is a multi-step process involving a sequence of molecular interactions between proteins on the leukocyte surface and proteins on the endothelial cells. The initial step is a weak, transient contact called “rolling,” which slows the leukocyte along the vessel wall. This rolling is mediated by a family of surface proteins called selectins and their carbohydrate ligands, such as sialyl Lewis X.
After rolling, the leukocyte must stop and firmly attach itself to the blood vessel wall, a process called “tight adhesion.” This firm attachment is facilitated by another class of surface proteins on the leukocyte, known as integrins, which bind to adhesion molecules on the endothelium. The adhered leukocyte then squeezes through the gaps between the endothelial cells and moves into the surrounding tissue to confront the infection.
The Genetic Cause of Leukocyte Adhesion Deficiency
Leukocyte Adhesion Deficiency is an inherited condition following an autosomal recessive pattern. This means an individual must inherit a mutated gene copy from both parents to develop the disorder. The specific gene affected determines the subtype of the condition, with each subtype disrupting a different stage of the adhesion process.
Leukocyte Adhesion Deficiency Type I (LAD-I) is the most common form, caused by mutations in the ITGB2 gene. This gene provides instructions for making the beta-2 integrin subunit, also known as CD18. A defect or absence of CD18 prevents the formation of beta-2 integrins (such as LFA-1 and Mac-1) on the leukocyte surface, blocking the tight adhesion step of extravasation.
LAD-II is caused by mutations in the SLC35C1 gene, which codes for a GDP-fucose transporter. This defect results in the absence of the sialyl Lewis X ligand, needed for the rolling step mediated by selectins. Leukocyte Adhesion Deficiency Type III (LAD-III) is caused by mutations in the FERMT3 gene, which encodes the protein kindlin-3. Kindlin-3 is necessary for the activation of multiple integrins, including the beta-2 integrins, leading to immune dysfunction and a bleeding tendency.
Recognizing Clinical Manifestations and Symptoms
The failure of white blood cells to migrate out of the circulation results in distinct clinical manifestations, often beginning shortly after birth. One of the earliest signs of LAD-I is a delayed separation of the umbilical cord, which persists for three weeks or more, well past the normal one-to-two-week period. This delay is often accompanied by omphalitis, an infection of the umbilical cord stump.
Affected individuals experience recurrent, severe bacterial and fungal infections in soft tissues like the skin, gums, and muscles. These infections are challenging to control and can rapidly become life-threatening, often spreading widely. A hallmark feature of LAD-I is the lack of pus formation at infection sites, as pus is composed primarily of dead white blood cells that cannot reach the area.
The impaired immune response also leads to severe inflammation of the gums, known as periodontitis, which can cause early loss of primary and permanent teeth. A routine blood count often shows a persistent elevation in the number of circulating white blood cells, a condition called leukocytosis. This occurs because the cells are trapped in the bloodstream and cannot exit to the tissues. LAD-II patients may present with additional features not seen in LAD-I, including growth and intellectual disabilities.
Diagnosis and Management Options
The first indication of LAD can be a complete blood count (CBC) showing a significantly high number of white blood cells, especially neutrophils. The specific diagnosis is confirmed through laboratory tests that assess the expression of adhesion proteins on the surface of the leukocytes.
Flow cytometry is the standard method used to measure the quantity of beta-2 integrin (CD18) on the surface of neutrophils. Absent or severely reduced CD18 expression is diagnostic for LAD-I, and the degree of deficiency often correlates with disease severity. Genetic testing of the ITGB2, SLC35C1, or FERMT3 genes can confirm the specific subtype and mutation.
Management of LAD focuses on preventing and aggressively treating infections, including the continuous use of prophylactic antibiotics. While supportive care, such as antibiotic therapy, can manage symptoms, the only definitive treatment for severe LAD-I and LAD-III is hematopoietic stem cell transplantation (HSCT), also known as a bone marrow transplant. HSCT replaces the defective blood-forming stem cells with healthy ones, correcting the underlying genetic defect and restoring normal immune function.