Defects in leukocyte adhesion

Adhesion between leukocytes and endothelium, other leukocytes and bacteria is necessary for the performance of the main phagocytic functions - movement to the site of infection, communication between cells, formation of the inflammatory reaction. The main adhesion molecules include selectins and integrins. Defects of the adhesion molecules themselves or proteins involved in the transmission of the signal from the adhesion molecules lead to pronounced defects in the anti-infective response of phagocytes. Several similar defects have been described in recent years, but the first of those described in this group and the most typical in its clinical manifestations is leukocyte adhesion defect I.

Pathogenesis of leukocyte adhesion defects

LAD I is an autosomal recessive disorder caused by a mutation in the gene of the common chain of the beta-2 integrin family - CD18. The gene is called ITGB2 and is located on the long arm of chromosome 21. Integrins are transmembrane proteins present on the surface of all leukocytes. They are necessary for tight adhesion of leukocytes (primarily neutrophils) to the endothelium and their subsequent transendothelial migration to the site of infection. A defect in the beta chain of CD18 integrins leads to a lack of expression of the entire receptor, resulting in inadequate neutrophil migration.

Symptoms of Leukocyte Adhesion Defects

To date, more than 600 cases of the disease have been described. Infections mainly affect the skin and mucous membranes. Patients have pararectal abscesses, pyoderma, otitis, ulcerative stomatitis, gingivitis, periodontitis, leading to tooth loss. Patients also suffer from respiratory infections, aseptic meningitis, and sepsis. The first manifestation of the disease is often late loss of the umbilical cord stump (more than 21 days) and omphalitis. Superficial infections often lead to necrosis, with a characteristic sign of the disease being the absence of pus formation with pronounced neutrophilia in the peripheral blood. Chronic, long-term non-healing ulcerative lesions are often formed. The main pathogens are S. aureus and gram-negative bacteria. Some patients have severe fungal infections. The frequency of viral infections is not increased.

The clinical manifestations are significantly less severe in patients with some missense mutations, which show low CD18 expression (2.5-10%). These patients are usually diagnosed later and may not suffer from life-threatening infections. However, even in mild cases, leukocytosis, poor wound healing, and severe periodontal disease are observed.

Mutation carriers have 50% CD18 expression, which is not clinically evident.

Diagnostics of leukocyte adhesion defects

The pathognomonic sign of the disease is leukocytosis (15-160 x 10 ⁹ /l) with 50-90% neutrophils. When conducting functional tests, disturbances in neutrophil migration (skin window), adhesion of granulocytes to plastic, glass, nylon, etc., as well as a significant decrease in complement-dependent phagocytosis are revealed. Other tests of neutrophil functions are usually normal.

Flow cytometric examination of neutrophils reveals the absence or significant reduction of expression of CD18 and associated molecules CD11a, CD11b and CD11c on neutrophils and other leukocytes. However, several cases of normal expression of CD18 in the presence of its complete dysfunction have been described.

Treatment of leukocyte adhesion defects

HSCT is the treatment of choice. Moreover, patients with LAD syndrome, at least type I, are to some extent ideal candidates for transplantation, since adhesion molecules play a key role in graft rejection. Accordingly, a defect in these molecules complicates graft rejection and ensures its engraftment. Understanding the essence of LAD I led in the early 1990s to the development of pharmacological prophylaxis of rejection using monoclonal antibodies (MAbs) to LFA1, a method that has proven effective in patients with various indications for HSCT. Thus, the introduction of anti-LFAl MAbs leads to an artificial adhesion defect, i.e., in fact, "emulates" LAD syndrome in the patient, reducing the likelihood of rejection. This method is especially successful in a group of patients with a priori high rejection potential, for example, in hemophagocytic lymphohistiocyoses. In addition to HSCT, one approach to treating patients with LAD is to combat infections that require early and massive antibacterial therapy. Preemptive antibacterial therapy does not significantly reduce the incidence of infections.

Gene therapy was unsuccessful in two patients.

Forecast

Without HSCT, 75% of children with severe LAD I do not survive past age 5.

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