What is Leukocyte Adhesion Deficiency?
Leukocyte adhesion deficiency (LAD) is a condition where certain molecules in your cells that help them stick together don’t work properly, causing various health problems. It’s a type of immune deficiency disorder that affects both B cells (which make antibodies to fight off infections) and T cells (which directly attack infected cells).
Here are some key things you should know about LAD:
- One characteristic of LAD is an inability to form pus, which is a thick substance your body produces when fighting infection.
- There’s a lack of certain sugar-coated proteins like LFA-1/Mac-1 and glycoprotein 150/95. These proteins help your immune cells move around and do their job.
- Your immune cells, called leukocytes, can’t move to where infections are to eliminate harmful bacteria. This is because of changes in a protein called CD18.
- If you have LAD, your body doesn’t respond to inflammation (swelling and redness) normally, which can lead to repeated bacterial infections. This is because there’s a shortage of special molecules called adhesion molecules that usually help with inflammation and fighting off germs.
What Causes Leukocyte Adhesion Deficiency?
Leukocyte Adhesion Deficiency (LAD) is a disorder which primarily prevents white blood cells, or leukocytes, from moving from the blood to tissues that have been attacked by harmful microorganisms. The process by which these white blood cells continually scan for foreign antigens or harmful substances in the body is also affected.
There are three types of LAD:
* Type I – Leukocytes find it hard to remain attached to the inner surfaces of blood vessels due to alterations in a gene called CD18. This results in flaws or deficiencies in a type of protein called beta-2 integrin.
* Type II – There’s an absence of a particular molecule called Sialyl Lewis X, which usually binds to a protein known as E-selectin.
* Type III – Defects are present in beta integrins 1, 2, and 3 proteins, hampering the series of events that activates these integrins. Specifically, an alteration in the kindlin-3 gene is responsible for this type of LAD.
LAD is typically inherited in an autosomal recessive manner – meaning, a person must inherit two copies of the altered gene (one from each parent), for the disorder to manifest.
Additionally, seven new changes in the ITGB2 gene, which creates the beta2 integrin family of proteins, have been identified. They consist of three frame shift deletions (alterations that disrupt the reading of the gene), two splicing alterations (changes in how the gene is read), and three missense alterations (a single alteration in the gene that changes one amino acid in the protein).
Risk Factors and Frequency for Leukocyte Adhesion Deficiency
Leukocyte adhesion deficiency type-1 (LAD-I) is a very rare inherited disorder that weakens the immune system. It affects about 1 in 1 million people every year and often manifests as repeated and persistent bacterial infections.
A review of patients with LAD-I typically shows the most common problems like repeated infections seen in 93.3% of patients and difficulty with wound healing found in 86% of patients. All patients with LAD-I have a defect in a part of their immune cells known as CD18.
- LAD-I is a very rare, inherited disorder weakening the immune system.
- It affects 1 in 1 million people every year.
- The disorder often shows up as persistent bacterial infections.
- Common issues associated with LAD-I include repeated infections (93.3% of patients) and wound healing problems (86% of patients).
- All LAD-I patients have a defect in the part of their immune cells called CD18.
The disease can sadly be severe, with about 75% of serious cases resulting in death by the age of 2, according to a research study from 1988. People with moderate versions of the disease (those with 2% to 30% of their immune cells expressing CD18) can live beyond childhood, but they still face repeated infections on the skin and within the body. The mortality rate for these individuals can exceed 50% by age 40.
Signs and Symptoms of Leukocyte Adhesion Deficiency
Leukocyte adhesion deficiency is a health condition observed by repeat bacterial infections, delayed shedding of the umbilical cord, and defects in the way white blood cells stick together, which in turn affect their ability to fight off infection. People with this condition often experience severe and life-threatening infections from birth, including inflammation of the newborn’s umbilical stump (omphalitis), lung infection (pneumonia), gum disease (gingivitis), and inflammation of the abdomen’s lining (peritonitis). The body struggles to fight these infections because the immune cells can’t move properly to the infection site.
This disease usually presents itself in three types, each with unique symptoms:
- LAD I: Delayed shedding of the umbilical cord, repeat skin infections starting in the first few weeks of life, infections usually caused by Staphylococcus aureus and Pseudomonas aeruginosa, lack of pus formation, and gum disease.
- LAD II: Recurrent skin infections, pneumonia, bronchiectasis, tuberculosis, dental abnormalities, and generally less severe and fewer infections compared to LAD I.
- LAD III: Omphalitis, features similar to osteoporosis in bones, bleeding complications, bone marrow failure.
Other possible symptoms can include:
- Vaginitis
- Peritonitis
- Osteomyelitis
- Perianal abscesses
- Sinusitis
- Tracheobronchitis
- Necrotic soft tissue infections
- Otitis media
- Meningitis
- Reactions to grafts versus hosts
- Repeated tonsillitis
- Conjunctivitis
- Granuloma
- Oral candidiasis
- Aphthous stomatitis
- Urinary tract infections
- Lymphocytic interstitial pneumonitis
- Glomerulonephritis
- Hemolytic-uremic syndrome
- Nail dystrophy
- Persistent hyperinsulinemic hypoglycemia of infancy
- Pyoderma gangrenosum
- Megakaryocytic acute myeloid leukemia
Testing for Leukocyte Adhesion Deficiency
If someone is thought to have leukocyte adhesion deficiency, a condition where white blood cells can’t properly move and fight infection, several tests may be done to confirm the diagnosis.
The main test is the flow cytometry analysis. This is a laboratory technique that assesses the characteristics of individual cells in a sample of blood. In this case, doctors look for two specific markers on the surface of the white blood cells: CD18 and a related molecule (as part of the LAD I variant of the disease) or a substance called sialyl Lewis X (in the case of LAD-II variant) . If these are missing, it could indicate leukocyte adhesion deficiency.
Another method involves sequence analysis using genetic testing to define the exact molecular defect in a subunit of the white blood cells.
Doctors might also measure levels of certain blood proteins called immunoglobulins. These proteins play a vital role in fighting off infections. The levels of certain types of immunoglobulins — IgG, IgM, IgA, and IgE — are tested.
Doctors might then check the immune system’s response to certain vaccines (like tetanus, diphtheria, polio), and common infectious diseases like rubella, measles, and chickenpox. They’ll do this by checking if there are specific IgG antibodies in the blood.
Other tests might involve checking for anti-blood type antibodies, overall white blood cell counts, and how well certain cells can move and fight infection.
Complement system evaluation tests are done as well. The complement system is part of your immune system that enhances the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism. It also promotes inflammation and attacks the pathogen’s cell membrane.
They would check levels of various specific proteins, perform hemolytic assays (tests that determine the ability of organisms to withstand attack by the immune system), and carry out complement system functional studies.
In addition, doctors might carry out several microbiological studies where they take samples from different parts of the patient’s body (like the nose, throat, and blood) to check if there’s any unusual bacteria or viruses present. Further diagnostic tests, such as chest x-rays, liver function tests, bone marrow biopsies, and blood chemistry, could also be conducted.
Treatment Options for Leukocyte Adhesion Deficiency
LAD-I, also known as Leukocyte adhesion deficiency-I, is a serious condition that can be fatal in severe cases if not treated by the age of 2 years. One of the main ways to treat it is by doing a transplant of certain types of stem cells, known as an ‘allogeneic hematopoietic stem cell transplant.’
Scientists are exploring other potential treatment options as well. Ustekinumab, a type of drug that targets specific parts of our immune system, has been shown to be effective in treating periodontitis (gum disease) and sacral ulcers (sores on the lower back) in patients with a mild form of LAD-I. This drug has also been used to manage other health conditions in the past, however, we need more studies to confirm its safety and usefulness, especially for people with severe LAD-I.
An additional treatment option used is ‘recombinant human interferon-gamma.’ This is a type of protein usually made in the lab, designed to harness and direct our immune system. Then, doctors also recommend trying fucose supplementation in every patient diagnosed with a form of this disease known as LAD II.
For LAD III, recombinant factor VIIa, a medicine that helps our blood clot, is considered effective in treating and preventing severe bleeding, especially in pediatric patients. The success has also been noted in the use of prophylactic immunoglobulin therapy (treatment that boosts the patient’s immune response) in two patients with severe forms of LAD.
Generally, the treatment approach leans on the more conservative side – targeting the specific infectious agents causing the health problems. For instance, common bacteria causing infections in patients with LAD include Proteus, Klebsiella, Staphylococcus aureus, Pseudomonas aeruginosa, and enterococci. These infections can usually be effectively treated with antimicrobial therapy. Importantly, patients should receive proactive and aggressive treatment, for example when undertaking dental procedures, to prevent complications and infections from arising.
What else can Leukocyte Adhesion Deficiency be?
When a doctor suspects leukocyte adhesion deficiency, it’s important to rule out other conditions that might cause similar symptoms. These include:
- Bare lymphocyte syndrome
- Chronic granulomatous disease
- Chediak-Higashi syndrome
- Hyper IgE syndrome
All these conditions are related to the immune system and can show similar features like irregular chemotaxis (movement of cells) or unusual respiratory burst activity (a method that cells use to kill bacteria). However, each of these can be differentiated through clinical examination and specific tests, including immunohistochemistry and molecular biology techniques.
What to expect with Leukocyte Adhesion Deficiency
Leukocyte adhesion deficiency, or LAD for short, is a disease whose outcomes can dramatically change based on how severe the disease is. LAD can sadly cause fatality before the child reaches one year of age. However, individuals with a milder form of LAD can live beyond their thirties when they follow appropriate antimicrobial therapy, a medical treatment that fights off harmful micro-organisms in the body.
Patients who have been able to successfully receive a special treatment known as an allogeneic hematopoietic stem cell transplant – this involves getting healthy stem cells from another person – can often improve their life quality significantly.
Possible Complications When Diagnosed with Leukocyte Adhesion Deficiency
The key risks faced are infections affecting various parts of the body like the skin, breathing system, digestive system, mouth, and some major organs. A condition called Leukocyte adhesion deficiency is also commonly seen, which has a high chance of being fatal.
Common Complications:
- Infections in the skin
- Infections in the respiratory (breathing) system
- Infections in the gastrointestinal (digestive) system
- Infections in the oral cavity (mouth)
- Infections in some internal organs
- Leukocyte adhesion deficiency, a condition with a high mortality rate
Preventing Leukocyte Adhesion Deficiency
Couples who are closely related and have a child with a health condition should be informed about the chances of having another child with the same condition. They should also be guided on how to take care of the affected child, both when they’re healthy and when they’re dealing with the condition.
