Immunodeficiency

Definition

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

Description

The immune system is the body's main defense against 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 interferons. When phagocytes encounter an invading organism, they surround and engulf it in order 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 as of the early 2000s 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 sometimes also called immunoglobulins). The terms antibody and immunoglobulin are often used interchangeably, although immunoglobulin refers to the larger classification system for antibodies. There are five types or classes of immunoglobulin that antibodies fit into, and each has a slightly different role in response against bacteria and viruses. 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 the T lymphocyte. 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 (congenital) or acquired.

Congenital immunodeficiency disorders

Congenital immunodeficiency is present at the time of birth and is the result of genetic defects. These immunodeficiency disorders are also called primary immunodeficiencies. 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 also can occur in the innate immune system.

HUMORAL IMMUNITY DISORDERS The congenital immunodeficiency disorder, Bruton's agammaglobulinemia , also known as X-linked agammaglobulinemia, 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 sons.

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

A type of B lymphocyte deficiency involves a group of disorders called selective immunoglobulin deficiency syndromes . The five different types of immunoglobulins are called IgA, IgG, IgM, IgD, and IgE. The most common type of immunoglobulin deficiency is selective IgA deficiency, occurring in about one in every 500 white persons. 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 (CVID) 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 in people between the ages of ten and 20. The symptoms vary among affected people. Most people with this disorder have frequent infections, and some also experience auto-immune phenomena, such as autoimmune hemolytic anemia or rheumatoid arthritis. Persons with CVID develop cancer at a higher rate than the general population, particularly lymphomas.

T LYMPHOCYTE DEFICIENCIES Severe defects in the ability of T lymphocytes to mature result 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 genetic syndrome most frequently associated with a chromosomal deletion (22q11.2). This syndrome is often associated with T lymphocyte deficiencies. 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 low numbers of T lymphocytes. If the T cell count is very low the patients are susceptible to recurrent infections. The syndrome can be associated with other physical abnormalities. For example, these individuals may have distinctive facial features such as thin upper lip and flattened nasal bridge, and they may have low calcium from hypoparathyroidism or cardiac defects. If the entire syndrome is not present (as is the usual case), the syndrome is called incomplete DiGeorge, and if all elements are present and the thymus is absent, the syndrome is called complete. Children with complete DiGeorge are particularly susceptible to viral and fungal infections.

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.

COMBINED IMMUNODEFICIENCIES 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 usually is recognized during the first year of life. It tends to cause fungal infections, including severe thrush that does not respond to usual treatment; severe diarrhea; and serious bacterial infections. If the deficiency is not treated (usually by bone marrow transplant), a person with SCID usually dies from infection before the age of two years. The most common form of SCID is X-linked, i.e. the defect is on the X chromosome and, therefore, occurs only in boys. In the early 2000s new genetic defects leading to SCID are being identified each year.

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 ). HIV, however, 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 percent 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 (rubella ), measles, tuberculosis , infectious mononucleosis (Epstein-Barr virus), chronic hepatitis, lupus, and bacterial and fungal infections.

In some cases, 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 that 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.

Demographics

About 50,000 new cases of congenital immunodeficiencies are diagnosed in the United States each year. The frequency of severe combined immunodeficiency is estimated to be one out of every 50,000 to 500,000 births, and of combined variable immunodeficiency, one out of every 10,000 to 50,000 births. As of 2004 HIV is estimated to affect approximately 4.4 million children worldwide.

Causes and symptoms

Congenital immunodeficiency is caused by genetic defects that generally occur while the fetus is developing in the uterus. 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 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 do not 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 may be absent or larger than usual, and in some types of immune deficiency the spleen and liver may be enlarged. (The lymph nodes are small organs that house antibodies and lymphocytes.) This can result in black-and-blue marks in the skin. The person may lose hair from their head. Sometimes, a red inflammation of the lining of the eye (conjunctivitis ) is present. They may have a crusty appearance in and on the nose from chronic nasal dripping.

When to call the doctor

In an undiagnosed child, parents should inquire about immune deficiency if there are frequent infections, prolonged infections, unusual infections, unusual complications of usual infections, or if there is a family history of immune deficiency. If a child is known to have an immunodeficiency disorder, a healthcare provider should be contacted if the child shows signs of having an infection, such as fever , vomiting , diarrhea, swelling of the lymph nodes, or unusual fatigue.

Diagnosis

Usually, the first sign that individuals may have an immunodeficiency disorder is that they do not improve rapidly when given antibiotics to treat an infection. An immunodeficiency disorder is likely to be present when rare diseases occur or the patient gets ill from organisms that do not normally cause diseases, especially if the patient gets repeatedly infected. When this happens in very young children, a genetic defect may be causing an immunodeficiency disorder. When this situation occurs in older children or young adults, their medical history may indicate that childhood diseases may have caused an immunodeficiency disorder. Other possibilities also exist, such as recently acquired infections (e.g. 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 determines if the number of phagocytic cells or lymphocytes is below normal. Lower than normal counts of either of these two cell types correlates with immunodeficiency. The blood cells also are 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. Complement levels can be determined by immunodiagnostic tests.

Treatment

There is no cure for congenital immunodeficiency disorders. Therapy is aimed at controlling infections (such as with antibiotics) and, for some disorders, replacing defective or absent components.

Patients with Bruton's agammaglobulinemia must be given periodic infusions of pooled immunoglobulin from multiple donors. The product is called intravenous immunoglobulin (IVIG). The infusions are given approximately once a month for life to compensate for the patients' inability to make these proteins.

Common variable immunodeficiency also is treated with periodic infusions of IVIG 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. In some severe cases, a bone marrow transplant or thymus transplant can be performed to correct the problem.

For most 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, such as a brother or sister) is removed. The bone marrow, a substance that is found in the cavity of bones, is the factory that produces blood cells, 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. One type of SCID called adenosine deaminase (ADA) deficiency is treated with infusion of the deficient enzyme on a regular basis, and another type of SCID due to an absence of an interleukin, a protein that is important in directing the immune response, is also treated by infusions of the missing protein.

Treatment of the HIV infection that causes AIDS consists of drugs called antiretrovirals. These drugs interrupt the virus replication cycle and, therefore, spare the T cells. Several of these drugs used in various combinations with one another can treat but not cure the disease. Decreasing the viral in the blood to very low levels allows the immune system to remain in tact. Other treatments for people with AIDS are aimed at the particular infections and conditions that arise as a result of the impaired immune system.

For people being treated for cancer, periodic relief from chemotherapy drugs can restore the function of the immune system. In some cases, IVIG is utilized to boost the immune system.

Alternative treatment

For some individuals, alternative treatments such as acupuncture therapy to ease infection-related symptoms or homeopathic medicines to boost immunity may be used in conjunction with traditional medicine as part of a patient's treatment plan.

Nutritional concerns

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.

Prognosis

The prognosis depends on the type of immunodeficiency disorder. People with Bruton's agammaglobulinemia who are given IVIG infusions 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 may not live beyond two years of age.

People with HIV/AIDS are living longer than in the past because of the antiretroviral drugs that became available in the mid-1990s. In the early 2000s HIV is still a potentially fatal illness, but medications have changed the face of the disease for those who have access to them. If medical treatment is timely and successful, T cells do not become depleted and opportunistic infections do not occur.

Prevention

Primary or congenital immunodeficiencies are genetic and are not preventable by avoidance of exposures or by dietary measures. However, someone with a congenital immunodeficiency disorder might want to consider getting genetic counseling before having children in order 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 (e.g. using a condom ) and by not using illegal intravenous drugs. These are the primary routes of transmitting the virus.

Nutritional concerns

In general, people with immunodeficiency disorders should maintain a healthy diet because malnutrition can aggravate immunodeficiencies. People can prevent malnutrition by getting adequate nutrition . They also should avoid being near others 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 also should avoid eating undercooked food because it might contain bacteria that could cause infection. While this food might not cause infection in others, it is a potential source of infectious organisms for someone with an immunodeficiency.

Parental concerns

If a child has been diagnosed with an immunodeficiency disorder, the parents may be instructed to refrain from having normal childhood vaccinations that contain live viruses, since even weakened versions of the virus may cause serious disease. In some cases, the immuno-deficient child needs to be encouraged to wear a mask when in public or around family members who are sick in order to reduce the risk of developing an infection.

KEY TERMS

Agammaglobulinemia —The lack of gamma globulins in the blood, associated with an increased susceptibility to infection.

B lymphocytes —Specialized blood cells that manufacture proteins called antibodies that attach themselves to invading foreign substances.

Chromosome —A microscopic thread-like structure found within each cell of the human body and consisting of a complex of proteins and DNA. Humans have 46 chromosomes arranged into 23 pairs. Chromosomes contain the genetic information necessary to direct the development and functioning of all cells and systems in the body. They pass on hereditary traits from parents to child (like eye color) and determine whether the child will be male or female.

T lymphocytes —Specialized blood cells that recognize invading organisms (helper T lymphocytes) and destroy them (killer T lymphocytes).

Resources

BOOKS

Doan, Thao. Concise Medical Immunology. Hagerstown, MD: Lippincott Williams & Wilkins, 2005.

Fireman, Philip. Atlas of Allergies and Clinical Immunology. St. Louis, MO: Mosby, 2005.

Mahon, Connie. Clinical Immunology. Paramus, NJ: Prentice Hall PTR, 2005.

Playfair, J. H., et al. Immunology at a Glance. Oxford, UK: Blackwell Publishing, 2005.

PERIODICALS

Bonilla, Francisco A., and Raif S. Geha. "Primary Immunodeficiency Disorders." Journal of Allergy and Clinical Immunology 112, no. 2 (February 1, 2003): S571–81.

Cooper, Megan A., Thomas L. Pommering, and Katalin Koranyi. "Primary Immunodeficiencies." American Family Physician (November 15, 2003): 2001.

Fischer, Alain. "Have We Seen the Last Variant of Severe Combined Immunodeficiency?" The New England Journal of Medicine (November 6, 2003): 1789.

ORGANIZATIONS

Children Affected by AIDS Foundation. 6033 W. Century Blvd., Suite 280, Los Angeles, CA 90045. Web site: <www.caaf4kids.org>.

Immune Deficiency Foundation. 40 W. Chesapeake Ave., Suite 308, Towson, MD 21204. Web site: <www.primaryimmune.org>.

WEB SITES

Frye, Richard E., and Delia M. Rivera-Hernandez. "Human Immunodeficiency Virus Infection." eMedicine, December 14, 2004. Available online at <www.emedicine.com/ped/topic1027.htm> (accessed January 7, 2005).

Makhoul, Hanan, et al. "Combined B-Cell and T-Cell Disorders." eMedicine, June 29, 2003. Available online at <www.emedicine.com/med/topic3538.htm> (accessed January 7, 2005).

Park, C. Lucy. "Common Variable Immunodeficiency." eMedicine. May 26, 2004. Available online at <www.emedicine.com/ped/topic444.htm> (accessed January 7, 2005).

Trigg, Michael. "Severe Combined Immunodeficiency Syndrome." Nemours Foundation, August 2002. Available online at <http://kidshealth.org/parent/medical/allergies/severe_immunodeficiency.html> (accessed January 7, 2005).

Wong, Henry, and Clarissa Yang. "Severe Combined Immunodeficiency." eMedicine, November 12, 2002. Available online at <www.emedicine.com/derm/topic879.htm> (accessed January 7, 2005).

John T. Lohr, PhD Teresa G. Odle Stephanie Dionne Sherk

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 method for fighting 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 interferons. 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. These immunodeficiency disorders are also called primary immunodeficiencies. Even though more than 70 different types of congenital immunodeficiency disorders have been identified, they rarely occur. About 50,000 new cases are diagnosed in the United States each year. Congenital immunodeficiencies may occur as a result of defects in B lymphocytes, T lymphocytes, or both. They also can occur in the innate immune system.

HUMORAL IMMUNITY DISORDERS. Bruton's agammaglobulinemia, also known as X-linked agammaglobulinemia, a congenital immunodeficiency disorder. 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.

B LYMPHOCYTE DEFICIENCIES. 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.

A 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, occurring in about one in every 500 white persons. 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 also will experience anemia and rheumatoid arthritis. Many people 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 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 and is the result of a deletion in a particular chromosome. 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. People with DiGeorge syndrome are particularly susceptible to viral and fungal infections.

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.

COMBINED IMMUNODEFICIENCIES. 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 usually is 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. In 2003, a report showed a new form of severe SCID with severe mutation of T receptor cells.

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 ). 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.

In 2003, a new infection emerged that produces immunodeficiency. Severe acute respiratory syndrome (SARS) mysteriously appeared in a hospital in China. It eventually affected 8,000 people in Asia and Canada, killing 800 altogether. The virus is characterized by fever, lower respiratory tract symptoms, and abnormal chest x rays. However, it also produces immunodeficiency. No cases of the disease were reported from July 2003 through December 2003, but scientists feared it would reappear.

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 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 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 do not 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 also may 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 lose hair from their head. Sometimes, a red inflammation of the lining of the eye (conjunctivitis ) is present. They may have a 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 do not 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 do not 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 also are 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 usually is 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 antiretrovirals. 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 and conditions that arise as a result of the impaired immune system. SARS is a relatively new acquired disease. Treatment to date involves combination therapy with steroids and interferon and supplemental oxygen for breathing difficulties. In 2004, reports in the United States said that a drug called octagam 5%, an intravenous immunoglobulin, was used to treat primary immunodeficiency diseases. The drug has been used in Europe for the same purpose.

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.

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 also should 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 also should 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 antiretroviral drugs that became available in the mid 1990s. However, AIDS still is 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 immuno-deficiency 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 do not 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.

Resources

PERIODICALS

"2003 Begins With SARS, Ends With Flu." Medical Letter on the CDC & FDA January 11, 2004: 24.

Cooper, Megan A., Thomas L. Pommering, and Katalin Koranyi. "Primary Immunodeficiencies." American Family Physician November 15, 2003: 2001.

Fischer, Alain. "Have We Seen the Last Variant of Severe Combined Immunodeficiency?" The New England Journal of Medicine November 6, 2003: 1789.

Low, Donald E., and Allison McGreer. "SARS—One Year Later." The New England Journal of Medicine December 18, 2003: 2381.

"Octagam is Efficacious for Treating Primary Immuno deficiency Diseases." Medical Letter on the CDC & FDA July 11, 2004: 52.

"Preliminary Report Suggests Combination Therapy May Help Treat SARS." Drug Week January 9, 2004: 557.

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.

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 defectiveâgene 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 lowset 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

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.

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.

Resources

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: Merck Research Laboratories, 1997.

Roitt, Ivan M. Roitt's Essential Immunology. Oxford: Blackwell Science Ltd., 1997.

The Washington Manual of Medical Therapeutics, 30^th ed. Philadelphia: Lippincott Williams & Wilkins., 2001.

Barbara Wexler

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 defective gene 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.

Resources

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: Merck Research Laboratories, 2005.

Roitt, Ivan M. Roitt's Essential Immunology. Oxford: Blackwell Science Ltd., 1997.

The Washington Manual of Medical Therapeutics, 30th ed. Philadelphia: Lippincott Williams & Wilkins, 2001.

Immunodeficiency

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 present at birth. Adaptive immunity develops the immune system to fight off specific invading organisms throughout life. 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 interferons . 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 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 syndromes. 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 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.

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.

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.

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

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.

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.

See also AIDS, recent advances in research and treatment; Immunity, active, passive and delayed; Immunity, cell mediated; Immunity, humoral regulation; Immunodeficiency disease syndromes; Immunodeficiency diseases; Infection and resistance