Leukocyte adhesion deficiency

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Introduction0:00–0:18

Leukocyte adhesion deficiency is a rare inherited immunodeficiency which develops because a group of immune cells called phagocytes fail to bind to the blood vessel wall, and therefore cannot get to the site of inflammation or tissue injury.

Physiology0:18–2:20

Normally, phagocytes, which are mostly neutrophils, circulate in the blood waiting for a signal that something’s wrong somewhere in the body.
As soon as this signal comes, in the form of cytokines which are pro-inflammatory molecules, they try to speed over to the affected tissue.
But to get there, they first have to pass through the endothelial cells that line the blood vessel wall. Getting through the endothelial cells is known as extravasation and involves multiple steps.
First, the endothelium expresses molecules called selectins, which binds to sialyl-Lewis X, a carbohydrate that’s found on the surface of phagocytes, making them slow down and roll along the vessel wall.
Second, is a step called adhesion. That’s basically a tight interaction between cellular adhesion molecules on the surface of endothelial cells, and integrins on the surface of the phagocytes.
Third, phagocytes manage to transmigrate or squeeze around the endothelial junctions, which are the sites of connection between two adjacent endothelial cells.
Fourth, the phagocytes use the concentration gradient of the cytokine signals to move towards the area of inflammation. This process is critical for destroying invading pathogens, in particular bacteria and fungi.
In fact, after a long battle with bacterial or fungal cells, phagocytes, especially neutrophils, die and can form a collection of pus, which can accumulate in a closed tissue space, developing into an abscess.
The process of extravasation is also essential for wound healing, where phagocytes help remove dead and damaged cells. In addition to typical settings of wound healing, this function of phagocytes is required soon after birth.
That’s because once the umbilical cord is cut, the cells within the cord being to die, and these dead cells are engulfed by phagocytes.
That process helps the dry umbilical cord separate from the baby’s abdomen. In leukocyte adhesion deficiency, there’s a mutation in a gene that encodes some of the molecules that mediate the interaction between phagocytes and endothelial cells.

Pathology2:20–4:04

There are two major types, based on the step that’s affected. Leukocyte adhesion deficiency type I is by far the most common and results from a failure to express CD18, which is a subunit of integrin molecules.
Without integrins, the second step of the extravasation process called adhesion cannot happen - in other words, phagocytes can’t firmly bind to the blood vessel wall.
Leukocyte adhesion deficiency type II is extremely rare and is caused by the absence of sialyl-Lewis X, which is essential for the process of rolling, or the first step of the extravasation process.
In both cases, an increased number of phagocytes get trapped in the circulation and can’t make their way into infected or damaged tissue.
This allows pathogens like bacteria and fungi, to spread uncontrollably and cause tissue injury. Meanwhile, without the help of phagocytes, tissue debris cannot be removed so that slows down wound healing.
This is also the reason why the umbilical cord in infants with leukocyte adhesion deficiency remains attached for a prolonged period of time.
As it turns out, both Leukocyte adhesion deficiency type I and II are inherited in an autosomal recessive pattern, meaning that an affected individual must have two copies of the mutated gene.
Typically, both parents of this individuals carry a single copy of the mutated gene, but neither of them shows any sign or symptom of the condition.

Symptoms4:04–4:46

Symptoms of leukocyte adhesion deficiency include having recurrent or chronic bacterial or fungal infections of the skin or mucosal membranes, such as the moist lining of the nose and mouth, which are never accompanied by pus or abscess formation.
At the same time, wounds are also slow to heal, leading to poorly formed, thin, and bluish scars. Infants have a delay in umbilical cord sloughing, so it typically lingers for a couple of months.
Unfortunately, because of these problems, the life expectancy without treatment is often extremely shortened, with many individuals not surviving past infancy.

Diagnosis4:46–5:02

Diagnosis is based on the elevated number of phagocytes, especially neutrophils, in the blood. In the case of leukocyte adhesion deficiency type I, flow cytometry can be used to look for the expression of CD18 on the leukocyte membrane.

Treatment5:02–5:28

The most effective treatment of leukocyte adhesion deficiency is a hematopoietic stem cell transplant. That’s where the immune system is wiped out and rebooted with immature stem cells that can give rise to all types of blood cells, including new leukocytes that are able to extravasate normally.
Additionally, prophylactic antibiotics are often given to help avoid serious infections. All right, as a quick recap, leukocyte adhesion deficiency is a genetic disorder that occurs when phagocytes lack specific molecules that enable them to pass through the endothelium of the blood vessel wall in order to reach the site of inflammation or tissue injury.

Review5:28–6:33

This results in a form of immunodeficiency and often appears just after birth with serious bacterial and fungal infections and delayed separation of the umbilical cord.