LAD D84.8

Leukocyte adhesion defect (LAD) syndromes are a group of rare primary immunodeficiency syndromes (seeprimary immunodeficiencies below) with impaired leukocyte adhesion, marked leukocytosis, and recurrent infections.

To date, three specific defects have been elucidated, leading to three distinct entities (LAD1-LAD3).

• LAD1 is characterized by life-threatening recurrent infections.
• LAD2 is characterized by recurrent infections, severely delayed growth, and intellectual deficits.
• LAD3 (also called LAD1 variant) is characterized by severe bacterial infections along with a severe bleeding tendency.

Prevalence: unknown. To date, < 350 cases have been described.

LAD results from an autosomal recessive inherited migration defect of leukocytes, which is necessary to enable leukocytes to migrate from the vessels to the site of infection. For leukocytes to function normally, it is essential that they are able to move from the blood to the site of infection (chemotaxis). Adhesion molecules(selectins and integrins) are responsible for this process; they enable cells in flowing blood to adhere to endothelial cells of postcapillary venules (adhesion) and cross over into tissues(transmigration). The beta2-integrin family of adhesion molecules plays a crucial role in this process. Beta integrins are heterodimers from a common beta2 chain, CD18, which can be associated with 3 different alpha- integrins (CD11a-c, CD11a/CD18 = LFA1, CD11b/CD18 = MAC-1; CD11c/CD18 = gp150,95). CD18/CD11 integrins are selectively expressed on leukocytes and are involved in other functions besides adhesion and transmigration, such as phagocytosis and cytotoxicity.

LAD1 is caused by autosomal recessive mutations in the ITGB2 gene (21q22.3), which encodes beta-2 integrin(CD18). Since LFA1 is essential for granulocyte migration, the presence of LAD1 is also referred to as LFA1 deficiency.

LAD2 is caused by mutations in the SLC35C1 gene (11p11.2), which encodes the guanosine 5'-diphosphate (GDP) fucose transporter.

Cause of LAD3 are mutations in the FERMT3 gene (11q13.1), which encodes kindlin-3 of hematopoietic cells.

The first symptoms appear in infancy or early childhood.

Disorders of leukocyte adhesion lead to increased susceptibility to (bacterial) infection. The number of neutrophil granulocytes in the peripheral blood is usually moderately to strongly increased, while it is decreased in the inflamed tissue. So-called "cold abscesses" are typical of the disease and describe a constellation with an inflammatory reaction caused by bacteria, but which remains free of granulocytes. Pus cannot be formed.

Clinical criteria are:

• onset of disease in infancy or early childhood
• unexplained leukocytosis
• Susceptibility to infection

In LAD1 and LAD2 diagnostics, flow cytometry should be performed to detect CD18 and CD15, respectively. Platelet aggregation tests are required if LAD-III is suspected. In all cases, the diagnosis is confirmed by molecular analysis.

Immunodeficiency due to interleukin-1 receptor-associated kinase 4 deficiency(IRAK4 deficiency)

Job's syndrome(Hyper IgE syndrome)

Septic granulomatosis (chronic granulomatosis)

Necessary is the control of infections. Treatment is with antibiotics. Many patients have undergone bone marrow transplantation.

Without hematopoietic stem cell transplantation, patients with severe LAD1 and LAD3 usually die within the first two years of life following a severe infection. After bone marrow transplantation, patients with LAD1 have a survival rate of 75%. Some patients with LAD2 reach adulthood.

1. Jiang X et al (2020) Bioinformatics analysis reveals novel hub gene pathways associated with IgA nephropathy. Eur J Med Res 25:40.
2. Kristóf E et al (2013) Novel role of ICAM3 and LFA-1 in the clearance of apoptotic neutrophils by human macrophages. Apoptosis 18:1235-1251.
3. Orr FW et al (2000) Interactions between cancer cells and the endothelium in metastasis. J Pathol 190: 310-329.
4. Ostermann G et al (2002) JAM-1 is a ligand of the beta(2) integrin LFA-1 involved in transendothelial migration of leukocytes. Nat Immunol 3:151-158.
5. Swaim CD et al (2017) Extracellular ISG15 Signals Cytokine Secretion through the LFA-1 Integrin Receptor. Mol Cell 68: 581-590.e5.
6. Schetler D (2019) Importance of integrin β4 and E-/P-selectin for tumor growth in the prostate carcinoma xenograft model. Dissertation for the degree of Doctor of Medicine at the Medical Faculty of the University of Hamburg.