Leukocyte Adhesion Deficiency (LAD) is a rare, inherited primary immunodeficiency disorder that disrupts the body’s ability to mount an effective defense against invading pathogens, particularly bacteria. This condition is classified as an autosomal recessive disorder, meaning a child must inherit a copy of the mutated gene from both parents to be affected. The core mechanism involves a failure of white blood cells, specifically a type called leukocytes, to properly exit the bloodstream and reach sites of infection. Because the immune system’s front-line defenders cannot reach the infected tissue, individuals with LAD experience severe, recurrent bacterial infections starting in infancy.
Genetic Basis and Molecular Function
The inability of white blood cells to reach the infection site is rooted in genetic mutations affecting specialized adhesion molecules. These molecules allow leukocytes to stick to the inner lining of blood vessels (adherence) before squeezing through the vessel wall into the surrounding tissue (extravasation). The specific genetic defect determines the subtype of the disorder, with three main types recognized: LAD-I, LAD-II, and LAD-III.
Leukocyte Adhesion Deficiency Type I (LAD-I)
Leukocyte Adhesion Deficiency Type I (LAD-I) is the most common form and results from mutations in the ITGB2 gene. This gene provides instructions for making the beta-2 integrin subunit, known as CD18. CD18 pairs with different alpha subunits (like CD11a, CD11b, or CD11c) to form a family of beta-2 integrin adhesion molecules present on the surface of most white blood cells. A deficiency or defect in CD18 means these integrin complexes cannot form correctly, severely impairing the ability of neutrophils to adhere to the endothelial cells lining the blood vessels.
Leukocyte Adhesion Deficiency Type II (LAD-II)
In LAD-II, the genetic defect lies in the SLC35C1 gene, which encodes a guanosine diphosphate (GDP)-fucose transporter. This transporter moves fucose, a necessary sugar molecule, into the Golgi apparatus to build complex carbohydrates on the cell surface. The defect prevents the creation of Sialyl Lewis X, a carbohydrate structure that acts as a ligand for E-selectin and P-selectin molecules on endothelial cells. Since Sialyl Lewis X is absent or deficient, the initial, weak “rolling” adhesion of leukocytes to the vessel wall is impaired.
Leukocyte Adhesion Deficiency Type III (LAD-III)
Leukocyte Adhesion Deficiency Type III (LAD-III) is caused by mutations in the FERMT3 gene, which codes for the protein Kindlin-3. Kindlin-3 is an intracellular protein that plays a role in the “inside-out” signaling pathway required to activate integrins. Although the beta-2 integrins (like CD18) may be present on the cell surface, the Kindlin-3 defect prevents them from shifting into their high-affinity, active state necessary for firm attachment to the blood vessel wall. This results in a functional failure of the adhesion process.
Clinical Presentation and Diagnosis
The failure of neutrophils to migrate from the blood into the tissues leads to characteristic clinical signs beginning shortly after birth. One of the earliest signs of LAD-I is the delayed separation of the umbilical cord stump, often remaining attached for three weeks or longer, accompanied by infection (omphalitis). Affected individuals suffer from severe, recurrent bacterial infections involving the skin, soft tissues, and mucous membranes, such as the mouth and gums, often leading to severe periodontitis and premature tooth loss.
Neutrophilia and Absence of Pus
A hallmark feature of these infections is the absence of pus formation. Pus is a collection of dead white blood cells, and its absence occurs because neutrophils are trapped in the bloodstream and cannot migrate to the infection site. Despite the severe tissue infections, blood tests show a persistent elevation in the white blood cell count, particularly neutrophils, a condition known as neutrophilia. This high count reflects the body’s continued production of white blood cells and their inability to leave the circulation.
Diagnostic Procedures
Diagnosis often begins with the observation of clinical signs combined with persistent neutrophilia revealed by a complete blood count. The primary diagnostic step involves a specialized blood test called flow cytometry. This technique uses fluorescently labeled antibodies specific to adhesion molecules, such as CD18, to determine the level of protein expression on the surface of the patient’s leukocytes. A severe reduction or complete absence of CD18 expression confirms the diagnosis of LAD-I.
For LAD-II and LAD-III, flow cytometry may show normal CD18 levels, requiring functional testing to assess the ability of integrins to activate and adhere. Genetic sequencing of the relevant genes (ITGB2, SLC35C1, or FERMT3) is performed for all subtypes to confirm the diagnosis and identify the specific mutation. The severity of LAD-I correlates directly with the amount of residual CD18 expression; patients with less than one percent of normal expression have the most severe disease.
Treatment and Long-Term Outlook
The immediate management of Leukocyte Adhesion Deficiency focuses on controlling life-threatening bacterial infections. This typically involves using broad-spectrum, often intravenous, antibiotics to treat active infections and initiating prophylactic antibiotics. Prophylactic antibiotics are given continuously to prevent infections, a necessary strategy since the patient’s immune cells cannot effectively clear pathogens on their own.
Hematopoietic Stem Cell Transplantation (HSCT)
For the most severe forms of LAD-I and LAD-III, Hematopoietic Stem Cell Transplantation (HSCT) is the only current treatment that offers a potential cure. HSCT replaces the patient’s defective hematopoietic stem cells with healthy donor cells. These cells then produce functional white blood cells capable of proper adhesion and migration. This procedure is complex and carries risks, including graft-versus-host disease, but it restores immune function and improves the patient’s long-term prognosis.
Long-Term Prognosis
The long-term outlook for individuals with LAD depends on the disease subtype and the availability of curative treatment. Without a successful HSCT, patients with severe LAD-I and LAD-III often have a high mortality rate, succumbing to overwhelming infections within the first few years of life. With successful transplantation, the long-term survival rate is improved, and patients can lead relatively normal lives as immune function is restored. Gene therapy, which aims to correct the genetic defect in the patient’s own cells, is a promising alternative strategy currently under investigation for LAD-I.