X-linked severe combined immunodeficiency

Definition

Immunodeficiency disorders are a group of disorders in which part of the immune system is missing or defective. Therefore, the body's ability to fight infections is impaired. As a result, the person with an immunodeficiency disorder will have frequent infections that are generally more severe and last longer than usual.

Description

The immune system is the body's main system to fight infections. Any defect in the immune system decreases a person's ability to fight infections. A person with an immunodeficiency disorder may get more frequent infections, heal more slowly, and have a higher incidence of some cancers.

The normal immune system involves a complex interaction of certain types of cells that can recognize and attack "foreign" invaders, such as bacteria, viruses, and fungi. It also plays a role in fighting cancer. The immune system has both innate and adaptive components. Innate immunity is made up of immune protections people are born with. Adaptive immunity develops throughout life. It adapts to fight off specific invading organisms. Adaptive immunity is divided into two components: humoral immunity and cellular immunity.

The innate immune system is made up of the skin (which acts as a barrier to prevent organisms from entering the body), white blood cells called phagocytes, a system of proteins called the complement system, and chemicals called interferon. When phagocytes encounter an invading organism, they surround and engulf it to destroy it. The complement system also attacks bacteria. The elements in the complement system create a hole in the outer layer of the target cell, which leads to the death of the cell.

The adaptive component of the immune system is extremely complex, and is still not entirely understood. Basically, it has the ability to recognize an organism or tumor cell as not being a normal part of the body, and to develop a response to attempt to eliminate it.

The humoral response of adaptive immunity involves a type of cell called B lymphocytes. B lymphocytes manufacture proteins called antibodies (which are also called immunoglobulins). Antibodies attach themselves to the invading foreign substance. This allows the phagocytes to begin engulfing and destroying the organism. The action of antibodies also activates the complement system. The humoral response is particularly useful for attacking bacteria.

The cellular response of adaptive immunity is useful for attacking viruses, some parasites, and possibly cancer cells. The main type of cell in the cellular response is T lymphocytes. There are helper T lymphocytes and killer T lymphocytes. The helper T lymphocytes play a role in recognizing invading organisms, and they also help killer T lymphocytes to multiply. As the name suggests, killer T lymphocytes act to destroy the target organism.

Defects can occur in any component of the immune system or in more than one component (combined immunodeficiency). Different immunodeficiency diseases involve different components of the immune system. The defects can be inherited and/or present at birth (congenital) or acquired.

Congenital immunodeficiency disorders

Congenital immunodeficiency is present at the time of birth, and is the result of genetic defects. Even though more than 70 different types of congenital immunodeficiency disorders have been identified, they rarely occur. Congenital immunodeficiencies may occur as a result of defects in B lymphocytes, T lymphocytes, or both. They can also occur in the innate immune system.

If there is an abnormality in either the development or function of B lymphocytes, the ability to make antibodies will be impaired. This allows the body to be susceptible to recurrent infections.

Bruton's agammaglobulinemia, also known as X-linked agammaglobulinemia, is one of the most common congenital immunodeficiency disorders. The defect results in a decrease or absence of B lymphocytes, and therefore a decreased ability to make antibodies. People with this disorder are particularly susceptible to infections of the throat, skin, middle ear, and lungs. It is seen only in males because it is caused by a genetic defect on the X chromosome. Since males have only one X chromosome, they always have the defect if the gene is present. Females can have the defective gene, but since they have two X chromosomes, there will be a normal gene on the other X chromosome to counter it. Women may pass the defective gene on to their male children.

Another type of B lymphocyte deficiency involves a group of disorders called selective immunoglobulin deficiency syndomes. Immunoglobulin is another name for antibody, and there are five different types of immunoglobulins (called IgA, IgG, IgM, IgD, and IgE). The most common type of immunoglobulin deficiency is selective IgA deficiency. The amounts of the other antibody types are normal. Some patients with selective IgA deficiency experience no symptoms, while others have occasional lung infections and diarrhea. In another immunoglobulin disorder, IgG and IgA antibodies are deficient and there is increased IgM. People with this disorder tend to get severe bacterial infections.

Common variable immunodeficiency is another type of B lymphocyte deficiency. In this disorder, the production of one or more of the immunoglobulin types is decreased and the antibody response to infections is impaired. It generally develops around the age of 10-20. The symptoms vary among affected people. Most people with this disorder have frequent infections, and some will also experience anemia and rheumatoid arthritis. Many people with common variable immunodeficiency develop cancer.

Severe defects in the ability of T lymphocytes to mature results in impaired immune responses to infections with viruses, fungi, and certain types of bacteria. These infections are usually severe and can be fatal.

DiGeorge syndrome is a T lymphocyte deficiency that starts during fetal development, but it isn't inherited. Children with DiGeorge syndrome either do not have a thymus or have an underdeveloped thymus. Since the thymus is a major organ that directs the production of T-lymphocytes, these patients have very low numbers of T-lymphocytes. They are susceptible to recurrent infections, and usually have physical abnormalities as well. For example, they may have low-set ears, a small receding jawbone, and wide-spaced eyes.

In some cases, no treatment is required for DiGeorge syndrome because T lymphocyte production improves. Either an underdeveloped thymus begins to produce more T lymphocytes or organ sites other than the thymus compensate by producing more T lymphocytes.

Some types of immunodeficiency disorders affect both B lymphocytes and T lymphocytes. For example, severe combined immunodeficiency disease (SCID) is caused by the defective development or function of these two types of lymphocytes. It results in impaired humoral and cellular immune responses. SCID is usually recognized during the first year of life. It tends to cause a fungal infection of the mouth (thrush), diarrhea, failure to thrive, and serious infections. If not treated with a bone marrow transplant, a person with SCID will generally die from infections before age two.

Disorders of innate immunity affect phagocytes or the complement system. These disorders also result in recurrent infections.

Acquired immunodeficiency disorders

Acquired immunodeficiency is more common than congenital immunodeficiency. It is the result of an infectious process or other disease. For example, the human immunodeficiency virus (HIV) is the virus that causes acquired immunodeficiency syndrome (AIDS). However, this is not the most common cause of acquired immunodeficiency.

Acquired immunodeficiency often occurs as a complication of other conditions and diseases. For example, the most common causes of acquired immunodeficiency are malnutrition, some types of cancer, and infections. People who weigh less than 70% of the average weight of persons of the same age and gender are considered to be malnourished. Examples of types of infections that can lead to immunodeficiency are chickenpox, cytomegalovirus, German measles, measles, tuberculosis, infectious mononucleosis (Epstein-Barr virus), chronic hepatitis, lupus, and bacterial and fungal infections.

Sometimes, acquired immunodeficiency is brought on by drugs used to treat another condition. For example, patients who have an organ transplant are given drugs to suppress the immune system so the body will not reject the organ. Also, some chemotherapy drugs, which are given to treat cancer, have the side effect of killing cells of the immune system. During the period of time that these drugs are being taken, the risk of infection increases. It usually returns to normal after the person stops taking the drugs.

Causes & symptoms

Congenital immunodeficiency is caused by genetic defects, and they generally occur while the fetus is developing in the womb. These defects affect the development and/or function of one or more of the components of the immune system. Acquired immunodeficiency is the result of a disease process, and it occurs later in life. The causes, as described above, can be diseases, infections, or the side effects of drugs given to treat other conditions.

People with an immunodeficiency disorder tend to become infected by organisms that don't usually cause disease in healthy persons. The major symptoms of most immunodeficiency disorders are repeated infections that heal slowly. These chronic infections cause symptoms that persist for long periods of time. People with chronic infection tend to be pale and thin. They may have skin rashes. Their lymph nodes tend to be larger than normal and their liver and spleen may also be enlarged. The lymph nodes are small organs that house antibodies and lymphocytes. Broken blood vessels, especially near the surface of the skin, may be seen. This can result in black-and-blue marks in the skin. The person may loose hair from their head. Sometimes, a red inflammation of the lining of the eye (conjunctivitis) is present. They may have crusty appearance in and on the nose from chronic nasal dripping.

Diagnosis

Usually, the first sign that a person might have an immunodeficiency disorder is that they don't improve rapidly when given antibiotics to treat an infection. Strong indicators that an immunodeficiency disorder may be present is when rare diseases occur or the patient gets ill from organisms that don't normally cause diseases, especially if the patient gets repeatedly infected. If this happens in very young children it is an indication that a genetic defect may be causing an immunodeficiency disorder. When this situation occurs in older children or young adults, their medical history will be reviewed to determine if childhood diseases may have caused an immunodeficiency disorder. Other possibilities will then be considered, such as recently acquired infections--for example, HIV, hepatitis, tuberculosis, etc.

Laboratory tests are used to determine the exact nature of the immunodeficiency. Most tests are performed on blood samples. Blood contains antibodies, lymphocytes, phagocytes, and complement components; all of the major immune components that might cause immunodeficiency. A blood cell count will determine if the number of phagocytic cells or lymphocytes is below normal. Lower than normal counts of either of these two cell types correlates with immunodeficiencies. The blood cells are also checked for their appearance. Sometimes a person may have normal cell counts, but the cells are structurally defective. If the lymphocyte cell count is low, further testing is usually done to determine whether any particular type of lymphocyte is lower than normal. A lymphocyte proliferation test is done to determine if the lymphocytes can respond to stimuli. The failure to respond to stimulants correlates with immunodeficiency. Antibody levels can be measured by a process called electrophoresis. Complement levels can be determined by immunodiagnostic tests.

Treatment

There is no cure for immunodeficiency disorders. Therapy is aimed at controlling infections and, for some disorders, replacing defective or absent components.

Patients with Bruton's agammaglobulinemia must be given periodic injections of a substance called gamma globulin throughout their lives to make up for their decreased ability to make antibodies. The gamma globulin preparation contains antibodies against common invading bacteria. If left untreated, the disease is usually fatal.

Common variable immunodeficiency also is treated with periodic injections of gamma globulin throughout life. Additionally, antibiotics are given when necessary to treat infections.

Patients with selective IgA deficiency usually do not require any treatment. Antibiotics can be given for frequent infections.

In some cases, no treatment is required for DiGeorge syndrome because T lymphocyte production improves on its own. Either an underdeveloped thymus begins to produce more T lymphocytes or organ sites other than the thymus compensate by producing more T lymphocytes. In some severe cases, a bone marrow transplant or thymus transplant can be done to correct the problem.

For patients with SCID, bone marrow transplantation is necessary. In this procedure, healthy bone marrow from a donor who has a similar type of tissue (usually a relative, like a brother or sister) is removed. The bone marrow is a substance that resides in the cavity of bones. It is the factory that produces blood, including some of the white blood cells that make up the immune system. The bone marrow of the person receiving the transplant is destroyed, and is then replaced with marrow from the donor.

Treatment of the HIV infection that causes AIDS consists of drugs called antivirals. These drugs attempt to inhibit the process that the virus goes through to kill T lymphocytes. Several of these drugs used in various combinations with one another can prolong the period of time before the disease becomes apparent. However, this is not a cure. Other treatments for people with AIDS are aimed at the particular infections that arise as a result of the impaired immune system.

In most cases, immunodeficiency caused by malnutrition is reversible. The health of the immune system is directly linked to the nutritional health of the patient. Among the essential nutrients required by the immune system are proteins, vitamins, iron, and zinc.

For people being treated for cancer, periodic relief from chemotherapy drugs can restore the function of the immune system.

In general, people with immunodeficiency disorders should maintain a healthy diet. This is because malnutrition can aggravate immunodeficiencies. They should also avoid being near people who have colds or are sick because they can easily acquire new infections. For the same reason, they should practice good personal hygiene, especially dental care. People with immunodeficiency disorders should also avoid eating undercooked food because it might contain bacteria that could cause infection. This food would not cause infection in normal persons, but in someone with an immunodeficiency, food is a potential source of infectious organisms. People with immunodeficiency should be given antibiotics at the first indication of an infection.

Prognosis

The prognosis depends on the type of immunodeficiency disorder. People with Bruton's agammaglobulinemia who are given injections of gamma globulin generally live into their 30s or 40s. They often die from chronic infections, usually of the lung. People with selective IgA deficiency generally live normal lives. They may experience problems if given a blood transfusion, and therefore they should wear a Medic Alert bracelet or have some other way of alerting any physician who treats them that they have this disorder.

SCID is the most serious of the immunodeficiency disorders. If a bone marrow transplant is not successfully performed, the child usually will not live beyond two years old.

People with HIV/AIDS are living longer than in the past because of the antiviral drugs that became available in the mid 1990s. However, AIDS is still a fatal disease. People with AIDS usually die of opportunistic infections, which are infections that occur because the impaired immune system is unable to fight them.

Prevention

There is no way to prevent a congenital immunodeficiency disorder. However, someone with a congenital immunodeficiency disorder might want to consider getting genetic counseling before having children to find out if there is a chance they will pass the defect on to their children.

Some of the infections associated with acquired immunodeficiency can be prevented or treated before they cause problems. For example, there are effective treatments for tuberculosis and most bacterial and fungal infections. HIV infection can be prevented by practicing "safe sex" and not using illegal intravenous drugs. These are the primary routes of transmitting the virus. For people who don't know the HIV status of the person with whom they are having sex, safe sex involves using a condom.

Malnutrition can be prevented by getting adequate nutrition. Malnutrition tends to be more of a problem in developing countries.

Key Terms

Agammaglobulinemia

The lack of gamma globulins in the blood. Antibodies are the main gamma globulins of interest, so this term means a lack of antibodies.

Further Reading

For Your Information

Books

• Abbas, A.K., A. H. Lichtman, and J.S. Pober. Cellular and Molecular Immunology. Philadelphia: W.B. Saunders Company, 1997.
• Berkow, Robert, Editor in Chief. Merck Manual of Medical Information. Whitehouse Station, NJ: Merck Research Laboratories, 1997.
• Roitt, Ivan M. Roitt's Essential Immunology. Oxford: Blackwell Science Ltd., 1997.

Gale Encyclopedia of Medicine. Gale Research, 1999.