Leukocyte Adhesion Deficiency

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Introduction

Fig.1(2009) Leukocyte adhesion deficiency (LAD) is defined as a defect for the leukocyte adhesion process, a disorder in leukocytosis and the constant recurrence of infections (Erzioni, 2005). LAD has been seen to affect about one in a million individuals. It is mainly characterized by ongoing bacterial and fungal infections of mucous membranes and the skin, lack of pus formation, the delay of umbilical cord separation, granulocytosis and the poor healing of wounds. An example of recurrence of bacterial infections can be seen in figure 1 (Akbari and Zadeh, 2001). Leukocyte adhesion deficiency is a genetic disease which is explained in the next section.

Genetics

Over the last 20 years, certain defects have been observed which are needed in order for leukocytes to be recruited to the sites of infection. LAD had three types LAD I, LAD II and LAD III. LAD I and LAD II are autosomal recessive disorders whereas the process of LAD III is unknown. LAD I is caused by specific mutations in a ITGB2 gene which is found on chromosome 21. This gene is responsible for expressing CD18 which also plays a part in the β2 integrin molecule subunit (Erzioni, 2005). This specific subunit is also involved in the synthesis of proteins such as LFA-1, Integrin alphaXbeta2 and Mac-1/CD3. These proteins are therefore non-functioning which causes problems in leukocyte adhesion. LAD II is a less common form of the disease and is caused by a defect on chromosome 11 which is responsible for encoding for the Golgi GDP-fucose transporter. This leads to less expression of fucosylated proteins, for example, sialyl Lewis X (sLeX), which are ligands responsible for initiating phagocytic cells which attach to endothelial cells, this process is called rolling. The

Fig. 2 (Knutsen, 2009)specific genetic defect for the LAD III variant is unknown but has been narrowed down to several genes that are involved in the integrin activation process. The probable defect for this form of the disease lies with a disorder in the activation of Rap-1 which is responsible for integrin activation (Knutsen, 2009). All the types of leukocyte adhesion deficiency are outlined in figure 2 along with the associated protein defects. This section has shown what causes the disease to occur, the following section will go into detail showing how the disease acts upon the immune system.

Pathophysiology

In normal cases, neutrophils are recruited to sites of inflammation by the production of bacterial attractants, specific inflammatory cytokines and other host cell factors. These chemical signals initiate the rolling of neutrophils along the sites of infection allowing white blood cells to undergo adhesion and extravasation. Rolling of neutrophils is caused by certain members of the selectin family, E-selectin, P-selectin and L-selectin. E- selectin and P-selectin are expressed on endothelial cells whereas L-selectin is expressed on neutrophils. The structure I mentioned earlier, Sialyl - Lewis X has been recognised as having ligands E and P-selectin present on its subunits. For leukocyte adhesion deficiency II to occur this carbohydrate molecule is absent. Due to the absence of sLeX, the specific selectins cannot bind leading to no neutrophil recruitment to sites of infection and injury. Also rolling is mediated by the adhesion molecules LFA-1 and Mac-1. It is a defect in these two molecules which results in the disease leukocyte adhesion deficiency I. This defect is due to a disorder in the β subunit of the CD18 molecule (Etzioni et al, 1992). As this disease has different types, certain diagnostic techniques need to be carried out.

Diagnosis

To fully diagnose leukocyte adhesion deficiency a range of laboratory tests are carried out. This is because not only does the disease need to be diagnosed but which type of leukocyte adhesion deficiency the patient has. The main test carried out is a CDC count which reveals the level of leukocytosis in the absence of infection. This is because during infections the level of leukocytosis increases dramatically. The presence of β2 integrins is tested on leukocytes and myeloid cells by using a process called flow cytometry. This allows for the detection and measurement of CD18, LFA-1 and Mac-1. Leukocyte adhesion deficiency II can be detected by taking a blood test. This test determines whether or not the Bombay blood group is present which is only found in LAD II. Also genetic analysis can be a key diagnostic tool for the diagnosis of this disease to determine whether any gene mutations are present (Nervi, 2009). There are specific treatments for this disease which will be outlined in the following section.

Treatment

The majority of patients with leukocyte adhesion deficiency I will die within the first year. Many of these deaths are associated with untreated bacterial and viral infections. The prognosis for patients with leukocyte adhesion deficiency II is usually better due to a longer life expectancy. Complications can occur causing mental retardation, a slower developmental rate, neurological impairment and a shorter stature (Nervi, 2009). The main line of therapy for this disease is the constant control and treatment of infections. Antibodies should be administered even when an acute infection is present. In severe cases of leukocyte adhesion deficiency I, bone marrow transplants are carried out. With regards to leukocyte adhesion deficiency II, fucose supplementation is strongly advised (Erzioni, 2005)

Conclusion

The autoimmune disease, leukocyte adhesion deficiency, causes many problems in early life due to a weaker leukocyte system. Mutations on specific genes cause defects on CD18 which is needed for leukocyte adhesion at inflammatory and infection sites. This means that bacterial and viral infections find it easier to gain access and multiply within the host. Treatments are available in severe cases of the disease but close clinical attention is required due to the recurrence of infections.

Word Count - 951

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