X-linked severe combined immunodeficiency

Definition

Immunodeficiency disorders are characterized by an immune system that is lacking, impaired, or defective. As a result, patients with immunodeficiency disorders have increased susceptibility to infection and neoplasia (cancer development). They have more frequent infections that are generally more severe and last longer than those experienced by persons with healthy, functioning immune systems. Patients with immunodeficiency disorders also are susceptible to infection with organisms that do not normally infect healthy people.

Description

The immune system is the body's primary defense against infections. Any defect in the immune system decreases the body's ability to combat infections. Patients with immunodeficiency disorders may suffer more frequent infections, heal more slowly, and have a higher incidence of some cancers.

The normal immune system involves a complex interaction of cells and molecules that can recognize and attack 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 the immune protection present at birth. Adaptive immunity develops throughout life and has two components, humoral immunity and cellular immunity.

The innate immune system consists of the skin (which serves 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 attacks bacteria. The elements of 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 a foreign organism, tumor cell, or foreign chemical as an invader, and to develop a response to attempt to eliminate it.

The humoral response of adaptive immunity involves a type of cell called B lymphocytes that manufacture proteins called antibodies (also called immunoglobulins). Antibodies attach themselves to the foreign substance allowing phagocytes to begin engulfing and destroying the invading 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 the T lymphocyte. There are helper T lymphocytes and killer T lymphocytes. Helper T lymphocytes play a role in recognizing invading organisms and help killer T lymphocytes to multiply. As the name suggests, killer T lymphocytes destroy the target cell or organism.

Defects can occur in any component of the immune system. They can also occur in several components simultaneously, and are then referred to as combined immunodeficiency. Defects can be congenital or acquired.

Congenital immunodeficiency disorders

Congenital immunodeficiency is present at the time of birth and is the result of genetic defects. Though more than 70 different types of congenital immunodeficiency disorders have been identified, they are rare. They may be caused by defects in either B lymphocytes or T lymphocytes, or both, and can also occur in the innate immune system.

B lymphocyte deficiency

If there is an abnormality in either the development or function of B lymphocytes, then the ability to make antibodies is impaired. Impaired antibody production results in increased susceptibility 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 produce antibodies. Patients 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 disorder if the defectiveégene is present. Females may have the defective gene; however, since they have two X chromosomes, only one will have the defective gene and the other will have a normal gene to counter the defective gene. Women may pass the defective gene to their male offspring.

Another type of B lymphocyte deficiency involves a group of disorders called selective immunoglobulin deficiency syndromes. There are five different types of immunoglobulins-IgA, IgG, IgM, IgD, and IgE. The most common type of immunoglobulin deficiency is selective IgA deficiency. 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. Patients with this disorder tend to develop severe bacterial infections.

Common variable immunodeficiency is another type of B lymphocyte deficiency. In this disorder production of one or more of the immunoglobulin types is decreased and the antibody response to infections is impaired. This disorder generally develops between the ages of 10 and 20 years. Symptoms vary among affected patients, however, most suffer frequent infections and some also experience anemia and rheumatoid arthritis. Many patients with common variable immunodeficiency develop cancer.

T lymphocyte deficiencies

Severe defects in the ability of T lymphocytes to mature results in impaired immune responses to infection with viruses, fungi, and certain types of bacteria. These infections are often severe and can be fatal. DiGeorge syndrome is a T lymphocyte deficiency that begins during fetal development, although it is not inherited. Children with DiGeorge syndrome either have no thymus or have an underdeveloped thymus. Since the thymus directs the production of T lymphocytes, people with this immunodeficiency have very low numbers of T lymphocytes. They are susceptible to recurrent infections and usually have physical abnormalities as well, which may include low-set ears, a small receding jawbone, and widely spaced eyes. In some cases no treatment is required for DiGeorge syndrome because T lymphocyte production spontaneously improves. Either an underdeveloped thymus begins to produce more T lymphocytes or organ sites other than the thymus compensate by producing more T lymphocytes.

Combined immunodeficiencies

Some types of immunodeficiency disorders affect both B lymphocytes and T lymphocytes. For example, severe combined immunodeficiency disease (SCID) is caused by defective development or function of both of these 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 thrush (a fungal infection of the mouth), diarrhea, failure to thrive, and other serious infections. Treatment requires bone marrow transplant and, if left untreated, children with SCID generally die from infections before the age of two years.

Disorders of innate immunity

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). It is not, however, 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 such as chickenpox, cytomegalovirus, German measles, measles, tuberculosis, infectious mononucleosis (Epstein-Barr virus), chronic hepatitis, lupus, and bacterial and fungal infections.

Sometimes, acquired immunodeficiency is a side effect or consequence of drugs used to treat another condition. For example, organ transplant patients are given drugs to suppress the immune system so the body will not reject the transplanted organ. Some chemotherapy drugs, given to combat cancer, have the side effect of killing immune system cells. The risk of infection increases significantly while these drugs are being taken and usually returns to normal one the patient is off the drugs.

Causes and symptoms

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

Patients with an immunodeficiency disorder tend to become infected by organisms that do not usually cause disease in healthy people and they suffer repeated infections that resolve slowly and cause symptoms that persist for long periods of time. Patients with chronic infections tend to be pale and thin and may have skin rashes. Their lymph nodes tend to be larger than normal and their liver and spleen may also be enlarged. Broken blood vessels, especially near the surface of the skin, may be apparent and they may develop alopecia (hair loss) and/or conjunctivitis (inflammation of the lining of the eye).

Diagnosis

One of the first signs that a patient may have an immunodeficiency disorder is failure to improve rapidly when given antibiotics to treat an infection. Another strong indicator is if a person becomes ill from organisms that do not normally cause diseases. When this occurs in very young children, it may indicate a genetic defect responsible for the immunodeficiency disorder. Among older children or young adults, their medical history helps determine if childhood diseases may have caused an immunodeficiency disorder. Other possibilities to consider are recently acquired infections such as HIV, hepatitis, or tuberculosis.

Laboratory tests are used to determine the exact nature of an immunodeficiency. Most tests are performed on blood samples. 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 cell types indicate the presence of immunodeficiency. The blood cells are also examined for their appearance. Some patients may have normal cell counts but their blood cells may be structurally defective. If the lymphocyte cell count is low, further testing is performed to determine whether any particular type of lymphocyte is lower than normal. A lymphocyte proliferation test determines if the lymphocytes can respond to stimuli. The failure to respond to stimulants correlates with immunodeficiency. Antibody levels may be measured by a process known as electrophoresis, while complement levels can be determined by immunodiagnostic tests.

Treatment

There is no cure for congenital or most acquired immunodeficiency disorders. Therapy is aimed at controlling infections and, for some disorders, replacing defective or absent cellular components. Patients with Bruton's agammaglobulinemia must be given periodic injections of gamma globulin throughout their lives to compensate for their decreased ability to produce antibodies. The gamma globulin preparation contains antibodies against common invading bacteria. 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 for the deficiency. Instead, antibiotics are given for infections.

In some cases, no treatment is required for DiGeorge syndrome because T lymphocyte production increases spontaneously. However, in some severe cases, bone marrow transplant or thymus transplant may be performed.

For patients with SCID, bone marrow transplantation is essential. In this procedure, healthy bone marrow is removed from a compatible donor (one with a similar tissue type, usually a brother or sister). The bone marrow of the patient receiving the transplant is destroyed and replaced with the bone marrow from the donor.

Treatment of the HIV infection that causes AIDS consists of drugs called antiretrovirals. Several of these drugs, used in various combinations, can prolong the period of time before the disease becomes symptomatic. However, these drugs do not produce a cure. Other treatments for patients 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 status of the patient. Among the essential nutrients required by the immune system are proteins, vitamins, iron, and zinc. Among cancer patients, periodic relief from chemotherapy drugs can restore the function of the immune system.

In general, patients with immunodeficiency disorders should be counseled to maintain a healthy diet. This is because malnutrition can aggravate immunodeficiencies. Patients should also be advised to avoid exposures to sick people because they can easily acquire new infections. For the same reason, patients should be instructed to practice good personal hygiene, especially dental care. Patients with immunodeficiency disorders should also avoid eating undercooked food because it might contain bacteria that could cause infection. Also, they should be given antibiotics at the first indication of an infection.

Prognosis

Prognosis for individuals with immunodeficiency disorders depends upon the type of disorder. Patients with Bruton's agammaglobulinemia who are given injections of gamma globulin generally live into their 30s or 40s and death is usually from chronic pulmonary infections. Patients with selective IgA deficiency generally live normal lives. They may experience allergic reactions to a blood transfusion, however, and should therefore wear a Medic Alert bracelet or have some other way to alert healthcare professionals about their disorder.

SCID is a serious immunodeficiency disorder. Without successful bone marrow transplant, a child with this disorder usually will not live beyond two years of age.

Although people with HIV/AIDS are living longer than in the past because of antiretroviral drugs, AIDS remains a fatal disease. AIDS patients usually die of opportunistic infections-viral and bacterial infections that occur because the impaired immune system is unable to fight them.

Health care team roles

Diagnosis and effective management of immunodeficiency disorders involves cooperation and collaboration between the patient and an interdisciplinary team of health care professionals. The patient's primary care physician or pediatrician, immunologist, nurses, laboratory technologists, respiratory therapists, pharmacists, pharmacy assistants, and health educators are involved in helping patients and families gain an understanding of how to prevent infections and effectively manage them when they occur or recur.

Patient education

Nurses and health educators help patients learn how to prevent infection. They teach patients how to identify early symptoms of infection that require prompt medical attention. Pharmacists and pharmacy assistants may offer additional instruction about antibiotic therapy and the importance of adhering to prescribed treatment.

Prevention

There is no way to prevent a congenital immunodeficiency disorder. Physicians and health care providers should recognize symptoms as early warning signs and implement appropriate treatment as soon as possible. People with congenital immunodeficiency disorders may want to consider genetic counseling before having children to determine if there is a chance they will pass the defect on to their children.

Some 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 by not using illegal intravenous drugs. These are the primary routes of transmitting the virus.

Malnutrition can be prevented by obtaining adequate nutrition. Although it does exist in the United States, malnutrition is considered a problem of greater magnitude 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.

Humoral immune response

Immune system response to antigens found in body fluids. This response is mediated by antibodies, which are secreted by B lymphocytes circulating in the blood.

Lymphocytes

White blood cells that fight infection and disease.