X-linked agammaglobulinemia (X-LA) was first described in 1952 by Dr. Ogden Bruton. This disease, sometimes called agumaglobulinemia of Bruton or congenital agammaglobulinemia, was one of the first immunodeficiency diseases found. X-LA is a hereditary disease in which the patient’s body is unable to produce antibodies, proteins that make up the gamma-globulin or immunoglobulin fraction of the blood plasma. Antibodies are an integral part of the body’s defense mechanism against certain microorganisms (eg, bacteria and viruses). Antibodies are necessary for recovery from infections. They also protect against re-infection with certain infections. There are antibodies specifically designed to bind to a particular microorganism – it’s like matching a key to a lock. When microorganisms such as bacteria enter the mucous membranes or into the body, antibodies specific for the microorganism adhere to its surface. Attaching an antibody to the surface of a microorganism can have one or more effects useful to a person. For example, some microorganisms must attach to the cells of the body in order to cause infection, and antibodies do not allow micro-organisms to “stick” to cells. Antibodies attached to the surface of certain microorganisms also activate other body defenses (for example, a group of blood proteins called serum complement) that can directly destroy bacteria or viruses. Finally, bacteria coated with antibodies are much easier to swallow and destroyed by white blood cells (phagocytes) than bacteria that are not coated with antibodies. All these mechanisms do not allow microorganisms to penetrate into the tissues of the body, where they can cause severe infections.
The main defect in X-LA is the patient’s inability to produce antibodies. Antibodies are proteins produced by special cells, called plasma cells. The development of plasma cells takes place in a certain order, starting with stem cells located in the bone marrow. From the stem cells, immature lymphocytes are formed, called pro-B lymphocytes. Pro-B-lymphocytes are the precursors of pre-B lymphocytes, from which B-lymphocytes are formed in turn. Each B-lymphocyte carries on its surface a sample of immunoglobulin, which this cell can produce. This surface cellular immunoglobulin can bind to foreign substances called antigens. When a B-lymphocyte contacts its specific antigen, for example, pneumococcus or tetanus toxoid, it ripens into a plasma cell that secretes antibodies. Each B-cell produces an antibody (immunoglobulin), slightly different from the products of other cells, which allows the body to respond to millions of different foreign substances. Most X-LA patients have precursors of B-lymphocytes, but very few of them then become B-lymphocytes. As a result, with X-LA, the main defect is the inability of B lymphocyte precursors to mature to the B-lymphocyte state. Patients with X-LA have mutations in the gene necessary for the normal development of B-lymphocytes. This gene, discovered in 1993, is called BTK (the Bruton tyrosine kinase gene) in honor of the discoverer of this disorder – Colonel, Ogden Bruton, MD. As the name of this disorder shows, the BTK gene is located on the X chromosome.
Patients with X-linked agammaglobulinemia (X-LA) are susceptible to infections due to lack of antibodies. These infections often develop on the surface or near the surface of the mucous membranes, for example, in the middle ear, paranasal sinuses and lungs, but in some cases, the infection can affect circulating blood or internal organs. As a result of this, infections of the paranasal sinuses (sinusitis), eye (conjunctivitis), ears (otitis), nose (rhinitis), intrapulmonary respiratory tract (bronchitis) or the lungs themselves (pneumonia) develop in patients with X-LA. There may also be an infection of the gastrointestinal tract, in particular, caused by the Giardia intestinal Giardia. Intestinal lamblia can cause abdominal pain, diarrhea, growth retardation or loss of blood proteins, for example, gamma globulin. Some patients with X-LA are also prone to skin infections. In the absence of antibodies, any of these infections can enter the bloodstream and spread to other organs deep into the body, for example, on bones, joints, or the brain. In patients with X-LA infections are usually caused by microorganisms that are very quickly destroyed or inactivated by antibodies in healthy people. The causative agents of such infections are most often pneumococcus, streptococcus, staphylococcus or Haemophilus influenzae. Some special types of viruses can also cause severe infections in these patients. In a physical examination, in most patients with X-LA, very small tonsils and lymph nodes (cervical glands) are found. This is due to the fact that the tonsils and lymph nodes mainly consist of B-lymphocytes. In the absence of B-lymphocytes, these tissues decrease.
The diagnosis of X-LA should be borne in mind when examining any boy with recurrent or severe bacterial infections, especially with a small amount or absence of tonsils and lymph nodes. The first study for screening should be the determination of serum immunoglobulins. In most cases with X-LA, a significant decrease or absence of immunoglobulins (IgG, IgM and IgA) is found. However, there are exceptions: some patients retain certain amounts of IgM or IgG. In addition, newborns normally produce only small amounts of immunoglobulins during the first months of life, and it is sometimes difficult to distinguish a newborn from a normal delay in producing immunoglobulins from a newborn with a true immune deficiency. If the level of serum immunoglobulins is low or the doctor has a serious suspicion that the patient is suffering from X-LA, the number of B cells in the peripheral blood should be determined. A low percentage (almost absence) of B-cells in the blood is the most characteristic and reliable laboratory sign of X-LA. If the brother of a newborn boy, or a cousin or sibling of a mother, suffers X-LA, this newborn has an X-LA risk, and his family and doctors should immediately determine the percentage of B cells in the blood to begin treatment before the child becomes ill. The diagnosis of X-CA can be confirmed by the lack of BTK protein in monocytes or platelets, or by the detection of BTK mutation in DNA. Almost every family has its own special mutation BTK, but members of the same family usually have the same mutation.
X-linked agammaglobulinemia (X-LA) is a genetic disease that can be inherited and be familial. It is inherited as a recessive trait linked to the X chromosome. It is important to know the type of inheritance, so that family members understand better why the child is sick, what the risk of illness in the next children is, and what it means for other family members. After identifying the gene that causes X-LA, it became possible to examine the patient’s sisters with X-LA and other female members of the family, for example, the mother’s sisters of the child’s mother, to determine if they are carriers of the disease. In X-LA carriers, the disease does not appear, but they can transmit it to their sons with a probability of 50%. In some cases, it is also possible to identify X-LA in a fetus before birth. Now these genetic studies are carried out only in several laboratories.
At present, there are no methods for curing patients with X-linked agammaglobulinemia (X-LA). A defective gene can not be corrected or replaced, and maturation of the precursors of B-lymphocytes in B-lymphocytes and plasma cells can not be stimulated.
However, patients with X-LA can be administered some absent antibodies. These antibodies are available as immunoglobulins (or gamma globulins) and can be injected directly into the blood (intravenously) or under the skin. Immunoglobulin preparations contain antibodies, replacing antibodies, which the patient’s X-LA can not produce independently. They contain antibodies to a wide range of microorganisms. Immunoglobulins are particularly effective in preventing the spread of infection in the blood and deep internal organs or tissues. Some patients are helped by the daily intake of antibiotics inside to protect themselves from infection, or to treat chronic sinusitis or bronchitis. Patients with X-LA should not be vaccinated on the basis of live viruses, for example, live polio vaccine, as well as measles, mumps and rubella (KSK) vaccine. There is a small possibility that live vaccines (especially oral polio vaccine) can be used in patients with agammagobulinemia to become a source of diseases for which they are designed.
Most patients with X-linked agammaglobulinemia (X-LA), regularly receiving immunoglobulins, are able to lead a relatively normal life. They do not need isolation or restriction of activity. It should be encouraged to actively engage in team sports. Occasionally, infections may require special attention, but children with X-CS can participate in all school and extracurricular activities, and when they reach adulthood they can work productively and have a family. It is necessary to adjust the child to a fully active lifestyle and encourage it!
The article is kindly provided by the worldwide organization IPOPI – working to improve the lives of people with primary immunodeficiency.
Copyright 2007 is owned by the Immune Deficiency Foundation, USA. “A guide to primary immunodeficiency diseases for patients and their families”, from which this material was taken under license, was developed by the Immune Deficiency Foundation with the support of Baxter Healthcare Corporation.
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