Leukocyte adhesion deficiency
Introduction
Leukocyte adhesion deficiency (LAD) is a rare, genetically inherited disorder characterized by defects in the adhesion and migration of White blood cell, primarily neutrophils, which are crucial components of the immune system. This condition leads to recurrent bacterial infections, impaired wound healing, and other immune-related complications. LAD is classified into three main types: LAD I, LAD II, and LAD III, each caused by distinct genetic mutations affecting different aspects of leukocyte function.
Types of Leukocyte Adhesion Deficiency
LAD I
LAD I is the most common form of leukocyte adhesion deficiency and is caused by mutations in the ITGB2 gene, which encodes the beta-2 integrin subunit, CD18. This subunit is essential for the formation of integrins, which are proteins that facilitate leukocyte adhesion to the endothelium and subsequent transmigration into tissues. Patients with LAD I exhibit a range of symptoms, including severe bacterial infections, delayed umbilical cord separation, and impaired pus formation. The severity of the condition correlates with the level of CD18 expression, with complete absence leading to more severe manifestations.
LAD II
LAD II is a rare form of the disorder caused by mutations in the SLC35C1 gene, which encodes a GDP-fucose transporter. This transporter is crucial for the fucosylation of selectins, which are adhesion molecules that mediate the initial rolling of leukocytes on the endothelium. Patients with LAD II present with a distinct set of symptoms, including recurrent infections, growth retardation, and developmental delay. Unlike LAD I, LAD II does not affect the integrin pathway but rather the selectin-mediated adhesion process.
LAD III
LAD III, also known as LAD with associated bleeding disorder, is caused by mutations in the FERMT3 gene, which encodes kindlin-3. Kindlin-3 is a cytoplasmic protein that plays a critical role in integrin activation. This type of LAD is characterized by recurrent infections, severe bleeding tendencies, and leukocytosis. The bleeding disorder is due to the impaired function of integrins in platelets, leading to defective platelet aggregation.
Pathophysiology
The pathophysiology of leukocyte adhesion deficiency involves disruptions in the normal processes of leukocyte adhesion, migration, and activation. In LAD I, the absence or dysfunction of CD18-containing integrins impairs the firm adhesion of leukocytes to the endothelial cells, preventing their migration into tissues where they are needed to combat infections. In LAD II, the lack of fucosylation of selectins disrupts the initial rolling and tethering of leukocytes on the endothelium, hindering their ability to reach sites of infection. LAD III affects the activation of integrins, leading to defects in both leukocyte and platelet functions.
Clinical Manifestations
The clinical manifestations of leukocyte adhesion deficiency vary depending on the type and severity of the condition. Common features across all types include recurrent bacterial infections, particularly of the skin and mucous membranes, poor wound healing, and leukocytosis. In LAD I, infections often begin in the neonatal period, with delayed separation of the umbilical cord being a hallmark sign. LAD II patients may also exhibit developmental delays and distinctive facial features. LAD III is marked by a combination of immunodeficiency and bleeding disorders, with patients experiencing frequent epistaxis, gingival bleeding, and prolonged bleeding from minor injuries.
Diagnosis
The diagnosis of leukocyte adhesion deficiency involves a combination of clinical evaluation, laboratory tests, and genetic analysis. Flow cytometry is commonly used to assess the expression of CD18 on leukocytes in LAD I, while LAD II can be diagnosed by measuring fucosylation levels of selectins. Genetic testing can confirm the presence of mutations in the ITGB2, SLC35C1, or FERMT3 genes, depending on the suspected type of LAD. Additional tests may include complete blood counts, which typically reveal leukocytosis, and functional assays to evaluate leukocyte adhesion and migration.
Treatment
The treatment of leukocyte adhesion deficiency is primarily supportive and focuses on managing infections and preventing complications. Antibiotic therapy is essential for treating bacterial infections, and prophylactic antibiotics may be used to reduce the frequency of infections. In severe cases, hematopoietic stem cell transplantation (HSCT) may be considered as a curative option, particularly for LAD I. Gene therapy is an emerging area of research, with the potential to correct the underlying genetic defects in LAD. For LAD III, management of the bleeding disorder may involve platelet transfusions and other supportive measures.
Prognosis
The prognosis for individuals with leukocyte adhesion deficiency varies depending on the type and severity of the condition. Patients with mild forms of LAD I may have a relatively normal life expectancy with appropriate management, while those with severe forms may experience life-threatening infections and complications. LAD II and LAD III also pose significant challenges, with developmental delays and bleeding disorders impacting quality of life. Early diagnosis and intervention are crucial for improving outcomes in affected individuals.