Defects of adhesion of leukocytes

Adhesion between leukocytes and endothelium, other leukocytes and bacteria is necessary to perform the basic phagocytic functions - moving to the focus of infection, communication between cells, the formation of an inflammation reaction. The main adhesion molecules include selectins and integrins. Defects of the adhesion molecules themselves or proteins involved in signal transmission from adhesion molecules lead to pronounced defects of the anti-infective response of phagocytes. In recent years, several such defects have been described, but the first among those described in this group and the most typical in its clinical manifestations is the defect of adhesion of leukocytes I.

Pathogenesis of leukocyte adhesion defects

LAD I is an autosomal recessive disease caused by a mutation of the gene of the common chain of the family of beta-2 integrins - CD18. The gene is called ITGB2 and is located on the long arm of 21 chromosomes, Integrins are transmembrane proteins present on the surface of all leukocytes. They are necessary for the tight adhesion of leukocytes (primarily neutrophils) to the endothelium and their further transendothelial migration to the site of infection. Deficiency of the β-chain of integrins CD18 leads to the absence of expression of the whole receptor, which results in inadequate migration of neutrophils.

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 with pararectal abscesses, pyoderma, otitis, ulcer stomatitis, gingivitis, paradontitis leading to tooth loss are noted. Also, patients suffer from respiratory tract infections, aseptic meningitis, sepsis. The first manifestation of the disease is often the late departure of the umbilical cord (more than 21 days) and omphalitis. Surface infections often lead to necrosis, with a characteristic feature of the disease is the absence of pus formation with severe neutrophilia in the peripheral blood. Often formed chronic, long-term healing ulcers. The main pathogens are S. Aureus and gram-negative bacteria. Some patients have severe fungal lesions. The frequency of viral infections is not increased.

The severity of clinical manifestations is significantly less in patients with certain missense mutations, in which there is a slight expression of CD18 (2.5-10%). These patients, as a rule, are diagnosed later and may not suffer life-threatening infections. Nevertheless, even in mild cases, leukocytosis, poor wound healing and severe periodontitis are noted.

In carriers of mutation, there is a 50% expression of CD18, which is not clinically apparent.

Diagnosis of leukocyte adhesion defects

Pathognomonic sign of the disease is leukocytosis (15 - 160 x 10 ⁹ / l) at 50-90% of neutrophils. Functional tests show violations of neutrophil migration (skin screen), adhesion of granulocytes to plastic, glass, nylon, etc., as well as a significant decrease in complement-dependent phagocytosis, and other tests of neutrophil functions are usually normal.

Floatsitometricheskoe study of neutrophils can detect the absence or significant decrease in the expression of CD18 and associated molecules CD11a, CD11b and CD11c on neutrophils and other leukocytes. However, several cases of normal CD18 expression have been described with its complete dysfunction.

Treatment of leukocyte adhesion defects

TSCA is the therapy of choice. Moreover, patients with LAD syndrome of at least Type I, to a certain extent, are ideal candidates for transplantation, since adhesion molecules play a key role in graft rejection. Accordingly, the defect of these molecules makes it difficult to reject the transplant and ensures its engraftment. Understanding the essence of LAD I led in the early 90s to the development of pharmacological prophylaxis of rejection with monoclonal antibodies (MAT) to LFA1, a method that showed its effectiveness in patients with different indications for TSCS. Thus, the administration of anti-LFAl MAT results in an artificial adhesion defect, that is, in effect, "emulates" the patient's LAD syndrome, 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 lymphogistiosis. In addition to THSC, one of the approaches to treating patients with LAD is to fight infections that require early and massive antibiotic therapy. The use of proactive antibacterial therapy does not lead to a significant reduction in the incidence of infections.

Conducting gene therapy in two patients was unsuccessful.

Forecast

In the absence of TSCA, 75% of children with severe LAD I do not survive to the age of five.

[1], [2]