Leukocytes, or white blood cells, are a major component of the body's immune system. White blood cells fight against infections within the body.
Leukocyte adhesion deficiency (LAD) is a very rare genetic disorder that impairs the body's immune system, making the patient susceptible to recurrent infections. LAD is considered a primary immunodeficiency (PI) and it is not contagious. Primary immune deficiencies, unlike secondary immune deficiencies, occur because part of the body's immune system does not function properly. These disorders are caused by intrinsic or genetic defects in the immune system.
LAD occurs when a patient's body is unable to produce glycoproteins that are found on the outside of leukocytes. These glycoproteins enable the leukocytes to adhere to the blood vessel walls as they migrate towards sites of inflammation during a process called chemotaxis.
There are two different genotypes that cause the disease - type I and type II.
LAD I is characterized by recurrent bacterial infections, defects in neutrophil adhesion and a delay in umbilical cord sloughing (shedding). Defects in adhesion prevent the neutrophils from congregating toward a site of infection (chemotaxis) and from performing phagocytosis (process of engulfing harmful microbes that enter the body). Most LAD I patients die by age five, unless they are successfully treated with a bone marrow transplant. Bacterial infections are responsible for most deaths. However, patients who experience moderate symptoms may survive into young adulthood without a transplant.
Patients who have LAD II do not usually die from infections. LAD type II patients typically have severe mental retardation, neurologic impairment, and short stature. Dental periodontitis (inflammation of the gums) and rarely colitis (inflammation of the large intestine) may be found in older individuals.
Fewer than 200 cases of LAD I have been reported worldwide in medical literature. However, the actual number of cases may be higher because little is known about the disorder. LAD II is even rarer, with only a handful of reported cases worldwide.
Dogs and cattle have also been diagnosed with the disease. The type that affects dogs is called Canine LAD, or CLAD. The type that affects cattle is called Bovine LAD, or BLAD.
LEUKOCYTE ADHESION DURING INFLAMMATION
When inflammation occurs in the body, a signal is sent out from the affected area to the blood vessels where leukocytes reside. In a healthy person, the leukocytes receive the message, activate, and begin to move toward the infected area by adhering to the blood vessel wall with CD18, a glycoprotein that surrounds the cell. This process is called chemotaxis.
The leukocytes in individuals who have LAD are unable to adhere to the blood vessel walls once they are activated because they lack the necessary glycoproteins, such as CD18 or CD11.
LAD is an autosomal recessive disorder. One mutated gene from each parent must be inherited in order for the child to develop the disease. Individuals who only have one mutated gene and do not express symptoms are called carriers.
Carriers have a 50% chance of passing the abnormal gene to each of their children. If both parents are carriers of LAD, there is a 25% chance that each of their children will inherit the disease.
LAD type I: LAD I is the result of mutations in the ITGB2 gene, which is located on chromosome 21. This gene encodes the glycoproteins called beta 2 integrin (CD18). Individuals with the mutated gene have a severe deficiency of the CD18 glycoproteins. The glycoproteins are normally found on the outer surface of leukocytes and they enable the leukocytes to attach to the blood vessel walls during chemotaxis.
LAD type II: LAD II is the result of a genetic defect, located on chromosome 11. The mutated gene encodes the specific Golgi GDP-fucose transporter. As a result, the fucose metabolism is abnormal, and the molecule that normally binds to the adhesion molecules on the leukocytes is not expressed.
Consequently, patients with LAD II are unable to fucosylate other glycoproteins, including the H blood group polysaccharide. Therefore, patients who have type II LAD have the rarest blood type known as Bombay blood type. These individuals do not have the A or B antigens, typically found in the blood. Instead, they produce antibodies to H.
General: Patients who have LAD suffer from recurrent bacterial infections, beginning in the neonatal period because the body is unable to adequately destroy invading pathogens (disease-causing microbes). Infections commonly include omphalitis (an infection of the umbilical stump), pneumonia, gingivitis, abscesses, and periodontitis. These infections are often life threatening when they occur in infants.
LAD type I: LAD I is characterized by a delayed separation of the umbilical cord, omphalitis, and severe recurrent infections with no pus formation.
LAD type II: Patients with LAD type II have the rare Bombay blood type and suffer from severe psychological and growth retardation, as well as short stature.
General: A qualified healthcare provider will first evaluate the patient's immune function with a basic examination of the humoral immune system and the cell-mediated immune system. A specific diagnosis is made after monoclonal antibody testing is performed.
White blood cell differential: A white blood cell differential will detect extremely elevated levels of neutrophils in the blood because the cells are unable to leave the blood vessels. Neutrophils make up about 40-60% of a healthy individual's white blood cells.
Complete blood count: A complete blood count will show a high number of white blood cells in the blood in the absence of an infection. Healthy individuals have a white blood count of between 4,500 to 10,000 cells per microliter of blood.
Monoclonal antibody testing: A monoclonal antibody test will show an absence or severe deficiency of adhesive glycoproteins on the surface of leukocytes.
Prenatal testing: Prenatal diagnosis is possible with amniocentesis or chorionic villus sampling. Amniocentesis may be performed to determine whether the fetus has LAD. Amniocentesis is performed at about 15-18 weeks of gestation to determine whether the fetus has any genetic abnormalities. During the procedure, a long, thin needle is inserted into the abdominal wall and into the uterus. A small amount of fluid is then removed from the sac surrounding the fetus. There is a risk of infection or injury to the fetus and a chance of miscarriage.
Chorionic villus sampling may also be performed to determine whether the fetus has LAD. This procedure can be performed between 12 and 13 weeks of pregnancy. During chorionic villus sampling (CVS), a small piece of tissue (chorionic villi) is removed from the uterus during early pregnancy to screen the fetus for genetic defects. Depending on where the placenta is located, CVS can be performed through the cervix (transcervical) or through the abdomen (transabdominal). The risks of infections, fetal damage, or miscarriage are slightly higher than the risks of amniocentesis. Fetal loss occurs about two percent of the time. While the risks are slightly higher for CVS, some patients may choose this procedure if they want results during the first trimester to either cut down on worrying time or possibly terminate the pregnancy early.
Most LAD I patients die by age five, unless they are successfully treated with a bone marrow transplant. However, patients who experience moderate symptoms may survive into young adulthood without a transplant.
Bone marrow transplant: A bone marrow transplant is considered conventional treatment for individuals with severe LAD I. The high rate of success in LAD patients may be attributed to the absence of CD11a/CD18 on lymphocytes. Not all patients are candidates for bone marrow transplants. The transplant must come from a donor whose body tissues are a close biological match to the recipient. Serious health risks are also associated with the surgery. Individuals who are immunocompromised have a risk of developing graft-versus-host disease after surgery. This condition occurs when the transplanted bone marrow attacks the recipient's weakened immune system. Other recipients may experience transplant rejection, which occurs when the body's immune system attacks the donated organ.
In addition, patients who undergo organ transplants must take immunosuppressive medication for the rest of their lives in order to prevent their bodies from attacking the transplanted organs. The most common oral immunosuppressants prescribed in the United States include tacrolimus (Prograf©), mycophenolate mofetil (CellCep©t), sirolimus (Rapamune©), prednisone, cyclosoporine (Neoral©, Sandimmune©, or Gengraf©), and azathioprine (Imuran©). Depending on the transplant, some patients may need to take different combinations and doses of the drugs. In general, patients are typically prescribed two to three medications for long-term immunosuppression.
Oral antibiotics: Oral antibiotics like amoxicillin and clavulanate (Augmentin©), trimethoprim and sulfamethoxazole (Bactrim©), oxacillin (Bactocill©), clarithromycin (Biaxin©), penicillin VK (Veetids©), or minocycline microspheres (Arestin©) are usually taken daily to treat and/or prevent infections in LAD I patients.
Leukocyte transfusion: Leukocyte transfusions, or white blood cells transfusions, have been used to treat severe infections in LAD I patients. The patient receives donated white blood cells to help boost the body's immune system. However, this treatment has not shown significant benefit for the treatment of LAD.
Intravenous antibiotics: Intravenous antibiotics like clindamycin (Cleocin©), vancomycin (Vancocin©), clindamycin (Cleocin©), or Erythromycin (EES, Erythrocin© or Ery-Tab©) are usually administered when the patient suffers from a severe infection.
Fucose replacement therapy: Fucose replacement has been administered orally or intravenously in LAD II patients. However, it has shown variable effectiveness in improving phagocytic functions.
There is currently insufficient evidence available on the integrative therapies for leukocyte adhesion deficiency (LAD).
Since LAD is a genetic disorder, there is currently no known method of prevention. However, individuals can be tested to determine whether they are carriers of the disease.
This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).
- Immune Deficiency Foundation. www.primaryimmune.org. Accessed March 27, 2007.
- Leukocyte Adhesion Deficiency Web Site. www.ladinfo.org. Accessed March 27, 2007.
- National Organization for Rare Disorders. www.rarediseases.org. Accessed March 27, 2007.
- Natural Standard: The Authority on Integrative Medicine. www.naturalstandard.com. Copyright © 2007. Accessed March 27, 2007.
- Primary Immunodeficiency Resource Center. Leukocyte Adhesion Deficiency. http://npi.jmfworld.org. Accessed March 27, 2007.
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