Immunoglobulin deficiency syndromes

Definition

Immunoglobulin deficiency syndromes are a group of disorders that involve defects of any component of the immune system or a defect of another system that affects the immune system, leading to an increased incidence or severity of infection. In these disorders, specific diseasefighting antibodies (immunoglobulins such as IgG, IgA, and IgM) are either missing or are present in reduced levels. Children who have immunodeficiency syndromes may be subject to infection, diseases, disorders, or allergic reactions to a greater extent than individuals with fully functioning immune systems.

Description

Immunodeficiency is a defect of any component of the immune system or a defect of another system that affects the immune system leading to an increased incidence or severity of infection. Immunoglobulin deficiencies refer to missing or reduced levels of immunoglobulin (IgG, IgA, IgM) associated with an inability to make adequate specific antibody. These antibodies are specific proteins (immunoglobulins) produced by the immune system to respond to bacteria, viruses, fungi, parasites, or toxins that invade the body. Each class of antibody binds to corresponding molecules (antigens) on the cell surfaces of certain foreign organisms or substances, attempting to protect the body against reactions or illness. When the immune system is challenged by invading organisms, the antibodies may each play a protective role:

• Immunoglobulin G (IgG) is the most abundant class of immunoglobulins, directed toward viruses, bacterial organisms, and toxins. It is found in most tissues and in plasma, the clear portion of blood.
• Immunoglobulin M (IgM) is the first antibody produced in an immune response to any invading organism or toxic substance.
• Immunoglobulin A (IgA) is activated early in response to invasion by bacteria and viruses. It is found in saliva, tears, and all other mucus secretions.
• As of the early 2000s, IgD activity is not well understood.
• Immunoglobulin E (IgE) is found in respiratory secretions and is directed toward invasion of the body by parasites and in allergic reactions such as hay fever, atopic dermatitis , and allergic asthma .

Immunoglobulins are made by white blood cells known as B cells (B lymphocytes). Any disease that harms the development or function of B cells will, therefore, affect the production of immunoglobulin antibodies. T cells, another type of white blood cell, may also be involved in immunodeficiency disorders. About 70 percent of immunoglobulin deficiencies involve B lymphocytes and 20–30 percent involve T lymphocytes. Another 10 percent may involve both B and T lymphocytes.

Many of the infections that occur in children with immunoglobulin deficiency syndromes are caused by bacterial organisms or microbes. Certain of these invasive organisms form capsules when they enter the body, a mechanism used to confuse the immune system. In a healthy body with an adequately functioning immune system, immunoglobulin antibodies bind to the capsule and overcome the bacteria's defenses. Streptococci, meningococci, and Haemophilus influenzae , organisms that cause diseases such as otitis media , sinusitis , pneumonia , meningitis , osteomyelitis, septic arthritis, and sepsis, all make capsules. Children with immunoglobulin deficiencies are also prone to viral infections, including echovirus, enterovirus, and hepatitis B . They may also develop infection after receiving live (attenuated) polio vaccine . This is one of the reasons that live polio vaccine is no longer used routinely in the United States.

There are two types of immunodeficiency diseases: primary and secondary. Immunoglobulin deficiency syndromes are primary immunodeficiency diseases. They account for 50 percent of all primary immunodeficiencies and are the largest group of immunodeficiency disorders. Some are well defined and some are not fully understood. Secondary disorders occur in normally healthy people who are suffering from an underlying disease that weakens the immune system. Successful treatment of the disease usually reverses the immunodeficiency.

Examples of well defined immunoglobulin deficiency disorders include the following:

• X-linked agammaglobulinemia is an inherited disease stemming from a defect on the X chromosome, consequently affecting more males than females. Defect results in absence or reduced numbers of B cells that do not mature and perform normal function. Mature B cells are capable of making antibodies and developing memory, a feature in which the B cell will rapidly recognize and respond to an infectious agent the next time it is encountered. All classes of immunoglobulin antibodies are decreased in agammaglobulinemia.
• Immunoglobulin heavy chain deletion, a form of agammaglobulinemia, is a genetic disorder in which part of the antibody molecule is absent. This condition results in the loss of several antibody classes and subclasses, including most IgG antibodies and all IgA and IgE antibodies. The disease occurs because part of the gene for the heavy chain has been lost.
• X-linked hypogammaglobulinemia can occur in combination with growth hormone (GH) deficiency, producing short stature and delayed puberty , primarily in boys but also occurring in girls.
• Transient hypogammaglobulinemia of infancy is a temporary disease of unknown cause. It is believed to be caused by a defect in the development of T helper cells (cells that recognize foreign antigens and activate T and B cells in an immune response). As the child ages, the number and condition of T helper cells improves, and this situation corrects itself. Hypogammaglobulinemia is characterized by low levels of gammaglobulin antibodies in the blood. During the disease period, children may have decreased levels of IgG and IgA antibodies. In some infants with this disorder, laboratory tests are able to show that the antibodies present do not react properly with infectious bacteria.
• IgG subclass deficiency is a disorder associated with a poor ability to respond and make antibody against polysaccharide antigens, primarily pneumococcus.
• Selective IgA deficiency is an inherited disease characterized by a failure of B cells to switch from making IgM to IgA antibodies. The amount of IgA produced is limited in either serum or the mucosal linings of organs. This condition may result in more infections of mucosal surfaces, such as the nose, throat, lungs, and intestines. However, most persons with this abnormality are asymptomatic.
• IgM deficiency is characterized by the absence or low level of total IgM antibodies, the body's first defense against infection. This condition results in slow response to infective organisms and slow response to treatment.
• IgG deficiency with hyper-IgM is a disorder that results when B-cells fail to switch from making IgM to IgG. This condition produces an increase in the amount of IgM antibodies present and a decrease in the amount of IgG and IgA antibodies. This disorder is the result of a genetic mutation.
• Severe combined immunodeficiency (SVID) is not precisely an immunoglobulin deficiency, but a combined deficiency resulting from a T-cell disorder. The T-cell dysfunction can either be X-linked, affecting more males than females and characterized by the absence of T lymphocytes, or it can occur through autosomal inheritance (not sex linked), resulting in an absence of both T and B lymphocytes and a deficient thymus gland, the lymphoid organ that produces T-cell lymphocytes.
• Common variable immunodeficiency (CVID) is a primary immunodeficiency with onset of symptoms typically occurring in the second or third decade of life. It is never diagnosed before two years of age and is diagnosed only after drug toxicity and other primary immune deficiencies have been ruled out. IgG and IgA and/or IgM will be measured at about two standard deviations below normal. The individual will typically not make antibodies against protein or polysaccharide antigens and will not make IgM antibodies against incompatible blood group antigens (hemagluttinins). T-cell dysfunction is the variable in this disorder. Children who have this disorder are subject to recurring infections and may not respond appropriately to immunization.

Demographics

Primary immunoglobulin deficiency syndromes occur only rarely. Those that are X-linked occur more in males than females; other immunoglobulin deficiencies occur equally in both sexes. Detection of the syndromes usually occurs in childhood. Numbers of new cases of specific syndromes are difficult to estimate because many deficiencies go undiagnosed. Among the syndromes for which incidence rates are available are IgA deficiency (one in 500–700), agammaglobulinemia (one in 50,000–100,000), severe combined immunodeficiency or SCID (one in 100,000–500,000), and common variable immunodeficiency or CVID (one in 50,000–200,000).

Causes and symptoms

Primary immunoglobulin deficiencies are primarily the result of congenital defects that affect the development and function of B lymphocytes (B cells), the white cells that fight infection and disease. Defects can occur at two main points in the development of B-cells. First, B cells can fail to develop into antibody-producing cells. X-linked agammaglobulinemia is an example of this disease. Secondly, B cells can fail to make a particular type of antibody or fail to switch classes during maturation. Initially, when B cells start making antibodies for the first time, they make IgM. As they mature and develop memory, they switch to one of the other immunoglobulin classes. Failure to switch or failure to make a subclass can lead to immunoglobulin deficiency diseases. Defects in the thymus gland that manufactures T lymphocytes or defects in the T lymphocytes themselves can also result in reduced production of immunoglobulins.

Symptoms are frequent and so are persistent infections, particularly of the respiratory system. Frequent digestive disturbances and diarrhea may lead to malab-sorption of essential nutrients and failure to thrive . Children with primary immunoglobulin deficiency syndromes will exhibit some of the following characteristics:

• signs of infection in the first days or weeks of life
• a slow response to treatment
• infection suppressed by appropriate treatment but not cured
• common bacterial or viral organisms causing increasingly acute recurring infections
• uncommon bacterial or viral organisms causing infection
• multiple simultaneous infections at more than one site
• delays in growth and development
• development of unexpected complications such as anemias and chronic diseases

When to call the doctor

Parents should seek medical care from a pediatrician or family practitioner if their young child or teenager has frequent or persistent infections such as upper respiratory infections, or chronic cough , ear infections, sinusitis, asthma, or pneumonia. Sores that do not heal or recurring or long-lasting skin irritations may also be signs of reduced immune system functioning.

Diagnosis

An immunodeficiency disease is suspected when children become ill frequently, especially repeat illness caused by the same organisms. Diagnosis will begin with a detailed history of the child's illnesses (dates, duration, and infection site) and review of all prior medications and immunizations and results of diagnostic tests performed. Determining which immunoglobulins are present and which are absent or present in reduced amounts is critical for diagnosis. Diagnostic testing may include routine blood tests such as a complete blood count (CBC) and differential (peripheral blood smear) to evaluate overall health and determine the type and number of red cells, white cells, and platelets present in the blood. Tests or cultures may be performed to determine the type of bacteria or virus causing recurring infections. B lymphocytes and T lymphocytes may be quantified. When immunodeficiency is suspected, levels of the classes of immunoglobulins are measured in blood serum by using a clinical laboratory procedure called electrophoresis. This procedure both quantifies the amount of each antibody present and identifies the various classes and subclasses of antibodies. Deficiencies may be noted in one class or subclass or in combinations of antibodies. Genetic testing may be done to help identify the type of immunodeficiency disease.

Treatment

Immunoglobulin deficiency diseases cannot be cured, but treatment that replaces or boosts specific immunoglobulins can help support immune function in affected children. Immune serum, obtained from donated blood that contains adequate levels of IgG antibodies, may sometimes be transfused as a source of antibodies to boost the immune response, even though it may not contain all antibodies needed and may lack antibodies specific for some of the recurring infections. The preferred treatment is to give specific immunoglobulins intravenously (immunoglobulin intravenous therapy or IVIG) or subcutaneously. No replacement therapy is available for treating IgA deficiencies.

Treatment will also focus on controlling infections in immunodeficient children. Immunization against frequent infection can be achieved in some children by administering polysaccaride-protein conjugate vaccines shown to improve immune response in certain types of infection. Antibiotics are used routinely at the first sign of an infection to help eliminate infectious organisms. Antifungal drug therapy may be administered to treat fungus infections. Few drugs are effective against viral diseases, and each viral illness will be evaluated and treated differently, depending on the virus and the overall health of the child. Bone marrow transplantation may correct immunodefiency in some cases.

Alternative treatment

Several nutritional supplements are reported to help build the immune system. These include garlic (contains the essential trace element germanium), essential fatty acids (found in flax seed oil, evening primrose oil, and fish oils), sea vegetables such as kelp, acidophilus to supply natural bacteria in the digestive tract, and vitamins A and C, both powerful antioxidants that improve immune function and increase resistance to infection. Zinc is another nutrient essential to immune system functioning. Green drinks made with young barley are believed to cleanse the blood and supply chlorophyll and nutrients for tissue repair. Alcohol, certain prescription and over-the-counter drugs, and coffee and other caffeine drinks should be avoided. Stress is known to produce biochemicals that reduce white blood cell functioning, making it important to get sufficient sleep and reduce stress to help keep the immune system functioning. Therapeutic massage, yoga , and other types of stress reduction programs are available in most communities.

Nutritional concerns

Immune system function requires having certain essential nutrients and avoiding things that depress immunity. A diet that improves immune system functioning includes nutrients obtained as much as possible from whole foods such as fresh fruits and vegetables, whole grain breads and cereals, and brown rice and whole grain pasta for essential vitamins, minerals , and fiber. Such a diet also limits or eliminates refined foods.

Fish, fowl, and lean meats can be consumed in moderation. Sweets should be reduced or avoided.

Prognosis

Regular medical observation, treatment of symptoms, and appropriate immune system boosting usually produces a good result in children with immunodeficiencies. Prognosis is related to the immune system's ability to produce the specific antibodies that are missing or present in reduced amounts. Individuals with immunodeficiency syndromes may have a normal life span although a variety of complications can occur, including autoimmune, gastrointestinal, granulomatous, and malignant conditions as a result of progressive immune deficiency disorders and/or repeat infections.

Prevention

Immunodeficiency cannot be prevented; however, challenges to the immune system can be reduced and infections avoided in immunodeficient individuals. Immunoglobulin deficiencies require impeccable health maintenance and care, paying particular attention to good hygiene, balanced nutrition , sufficient rest, regular check ups and immunizations, and optimal dental care, as well as avoiding crowds and contact with other children or relatives with bacterial or virus infections.

Nutritional concerns

A healthy immune system can be maintained by providing essential nutrients through a good diet and regular supplementation. Parents can help assure that their children and teens have three nutritious, low-fat, high-fiber, whole-food meals a day (limiting or eliminating altogether refined or prepared foods and fast foods) and healthy snacks in between, such as nuts, fresh fruit, popcorn, raw veggies, and whole grain crackers with nut butters (if no allergies to peanuts or other nuts), naturally sweetened jellies, and low-fat cheeses. Vitamin supplements should include vitamins A, C, and E, valuable parts of the body's defense system that help to increase production of healthy white blood cells and to fight infection.

Parental concerns

Parents with immunoglobulin deficient children and teenagers will likely be concerned that their children are in frequent contact with schoolmates and friends, the common route to infection. When infection occurs frequently, it is important to remember that the pediatrician or family practitioner will have specific criteria and diagnostic tests for evaluating the child, identifying the immunodeficiency, and determining appropriate therapy. Meanwhile, parents can help keep their children away from crowds and avoid contact with other children or relatives with bacterial or virus infections.

Resources

BOOKS

Beers, Mark H., ed. Merck Manual of Medical Information, Second Home Edition. Whitehouse Station, NJ: Merck Research Laboratories, 2003.

Sompayrac, Lauren. How the Immune System Works. Oxford, UK: Blackwell, 2003.

ORGANIZATIONS

Centers for Disease Control and Prevention. 1600 Clifton Road, Atlanta, GA 30333. Web site: http://www.cdc.gov.

WEB SITES

Chin, Terry. "IgA and IgG Subclass Deficiency." eMedicine. Available online at http://www.emedicine.com/ped/topic190.htm (accessed January 14, 2005).

Makhoul, Issam. "Pure B-Cell Disorders." eMedicine. Available online at http://www.emedicine.com/med/topic216.htm (accessed January 14, 2005).

L. Lee Culvert Jacqueline L. Longe