Primary Immune Deficiency, NIAID Fact Sheet: NIAID
Article title: Primary Immune Deficiency, NIAID Fact Sheet: NIAID
Conditions: Primary Immune Deficiency, Selective IgA Deficiency, Common Variable Immunodeficiency, X-Linked Agammaglobulinemia, SCID, Chronic Granulomatous Disease, Hyper-IgM Syndrome
Primary Immune Deficiency
OverviewWhen people are born with a faulty immune system, they are said to have a primary immune deficiency or immunodeficiency. Unlike people with AIDS, caused by the human immunodeficiency virus or HIV, people with primary immunodeficiency (PI) diseases have inherited abnormal changes in cells of their immune system.
The various types of immune cells each have their own specialized function and must work together to fight disease effectively. Because there are many different types of cells that make up the immune system, an error in any one of them can disrupt our immune defenses. Depending on which cell and the type of error that occurs, more than 80 different forms of PI diseases are possible. Some are severe, while others cause few or no symptoms. All of them make people more susceptible to infections and other medical conditions. More boys than girls have PI, and patients’ first symptoms often begin in infancy or later in childhood.
Primary care physicians who suspect a patient has a problem with their immune system will run screening tests. If those tests indicate the person has an abnormally-functioning immune system, the physician will consult with a clinical immunologist who can run specialized blood tests to determine the exact type of PI disease and how best to treat it. Other experts who may need to be consulted include pulmonologists, rheumatologists, gastroenterologists, and hematologists.
We discuss only a few of the PI diseases below. You will find sources of additional information at the end of this fact sheet.
Selective IgA DeficiencyApproximately one out of 600 individuals have selective IgA deficiency. Among those with this disease, people of European ancestry greatly outnumber those of other ethnic groups. People with this deficiency lack immunoglobulin A (IgA), a type of antibody that protects against infections of the mucous membranes lining the mouth, airways and digestive tract.
What are symptoms of IgA deficiency?
Many IgA-deficient patients are healthy, with no more than the usual number of infections. Those patients who do have symptoms typically have recurring ear, sinus, or lung infections that may not respond to standard courses of antibiotics. People with IgA-deficiency are likely to have other problems, including allergies, asthma, chronic diarrhea, and autoimmune diseases.
How is IgA deficiency diagnosed?
People with IgA deficiency have low levels of IgA antibodies in their blood. In contrast, their levels of IgM and IgG immunoglobulins usually are normal. IgA-deficient people also have normal levels of other immune system cells, including T cells, phagocytes, and complement proteins.
Doctors diagnose IgA deficiency by doing tests to measure the amount of total immunoglobulin in the blood as well as the type of immunoglobulin known as IgG2. Other tests determine how well a person is producing antibodies against specific germs following immunization with a common vaccine, such as a tetanus shot.
What causes IgA deficiency?
IgA deficiency is caused by faulty white blood cells called B cells or B lymphocytes. While patients have normal numbers of B cells, these cells do not mature into normal IgA-producing cells. Scientists do not yet know the exact cause or causes for these immature B cells. Sometimes clusters of cases occur in families, and IgA-deficient patients are more likely than the general population to be related to someone with combined variable immunodeficiency, another form of immunodeficiency discussed below. Research is underway to determine the location of the suspected genes on the involved chromosomes.
How is IgA deficiency treated?
There is no specific treatment for selective IgA deficiency. Doctors treat bacterial infections with antibiotics, and patients with giardiasis (an infection caused by a common intestinal parasite receive metronidazole or quinacrine hydrochloride.
Common Variable Immunodeficiency (CVI)CVI is also called hypogammaglobulinemia, adult-onset agammaglobulinemia, late-onset hypogammaglobulinemia, and acquired agammaglobulinemia. CVI is relatively common. Infants sometimes have symptoms of CVI, though in most cases symptoms do not show up until the second or third decade of life.
What are the symptoms of CVI?
Most patients with CVI get frequent bacterial infections of the ears, sinuses, bronchi, and lungs. Patients may develop painful swollen joints in the knee, ankle, elbow, or wrist. CVI patients frequently complain of symptoms involving the digestive tract. They also commonly have an enlarged spleen and swollen glands or lymph nodes. Along with other autoimmune problems, some patients develop autoantibodies that attack their own blood cells. CVI patients have an increased risk of developing some cancers.
What causes CVI?
CVI has no clear pattern of inheritance. The cause is unknown.
How is CVI diagnosed?
Blood tests to measure the amount of immunoglobulins in the blood of CVI patients show below-normal levels of IgG and IgA. Patients may have zero to slightly low levels of IgG antibodies, while IgM levels are low to normal. Blood tests also will determine how well B cells produce antibodies following a common immunization like a measles or tetanus shot. Other tests show doctors how well the T cells are working. Doctors will test patients with digestive symptoms for gastrointestinal infections.
How is CVI treated?
CVI patients receive immunoglobulin injections, or IVIG, every 3-4 weeks to restore normal antibody levels. Infections are treated with antibiotics. Physical therapy and daily postural drainage may help clear clogged lungs.
X-Linked Agammaglobulinemia (XLA)XLA is sometimes called Bruton type, X-linked infantile, or congenital agammaglobulinemia. One out of 100,000 people have XLA. Defects on the X chromosome cause XLA. Only boys get XLA. That is because girls have two sets of X chromosomes, and the normal copy compensates for the faulty gene.
What are the symptoms of XLA?
Infants with XLA develop frequent pus-producing infections of the inner ear, lungs, and sinuses. Serious infections can develop in the bloodstream and internal organs. Patients tend to cope sufficiently well with most viral infections, but are very susceptible to hepatitis, polio, and ECHO viruses. They may fail to grow to normal height or to gain weight. Their tonsils and adenoids are often missing.
How is XLA diagnosed?
Patients with XLA have extremely low levels of mature B cells. Blood tests also show overall immunoglobulin levels to be low, and antibodies to specific germs (as seen after immunizations, for instance) are missing.
What causes XLA?
Alternations in a gene found on the X chromosome cause XLA. This gene normally produces a protein called btk, which is required for B-cell development.
.How is XLA treated?
XLA patients need lifelong antibody replacement through monthly injections of gamma globulin (IVIG).
Severe Combined Immunodeficiency (SCID)Approximately one in every million people develop SCID, a group of inherited disorders. People with SCID have severe abnormalities in both B and T cell immunity.
What are the symptoms of SCID?
Babies typically have symptoms within the first three months of life. They usually get numerous, serious or life-threatening infections, especially pneumonia, meningitis, and sepsis. Common infections like chickenpox, measles, or cold sores can overwhelm the patient's immune system. Patients also commonly have chronic skin infections, candida (yeast) infections of the mouth and diaper area, chronic hepatitis, diarrhea, and blood disorders.
How is SCID diagnosed?
The doctor will order tests to measure immune function. Because ongoing infections can interfere with results, tests may have to be repeated several times.
Patients usually have a very low number of white blood cells or lymphocytes, as well as few or no B and T cells. Those few cells they do have often do not function properly. Also, SCID patients have very low levels of IgG, IgA, and IgM antibodies.
What causes SCID?
A number of genetic abnormalities can cause SCID. The two most common forms are linked to the X chromosome. Patients with abnormalities on this chromosome either 1) lack an enzyme called adenosine deaminase (ADA), or 2) lack the ability to produce IL-2 receptor gamma chain, a molecule that T cells need to communicate with B cells.
How is SCID treated?
Transplanting bone marrow from a healthy sibling whose tissue type closely matches the patient’s is the most effective treatment. If a matched sibling is not available, a donor as closely matched as possible is used. Until the transplant takes effect (in one to three years), intravenous immunoglobulin (IVIG) is given to normalize antibody levels. SCID patients with ADA deficiency have been treated successfully with enzyme replacement therapy called PEG-ADA. Gene therapy for correction of both forms of SCID is under investigation.
Chronic Granulomatous Disease (CGD)Only four or five of every million people develop CGD. Males are four times more likely to get this disease than females. The CGD patient's defense system is not effective against certain bacteria and fungi, including E. coli and Staphylococcus aureus, as well as less common germs like Pseudomonas, Serratia, and Aspergillus.
What are the symptoms of CGD?
Doctors may suspect CGD in male infants between three months and two years of age who have had fevers, skin rashes, persistent cough, boils, gum disease, swollen glands or lymph nodes, and enlarged liver and spleen. However, patients with CGD may not develop symptoms until as late as adolescence. Repeated infections can cause tumor-like masses or “granumlomas” to develop in the skin, lungs, lymph nodes, liver, or bones. Granulomas can cause blockage of the gastrointestinal or urinary tracts. The lesions tend to heal slowly and to drain for a long time after treatment.
How is CGD diagnosed?
The doctor will order lab tests to look for certain blood abnormalities including an increased number of white blood cells and low number of red blood cells (anemia). Patients also often have abnormal chest x-rays, excessively high level of immunoglobulins in the blood (hypergammaglobulinemia), and elevated erythrocyte sedimentation rate or ESR (a sign of chronic infection or or inflammation). They usually have normal antibody levels. To confirm a CGD diagnosis, specialized laboratories perform various tests of the function of phagocytes, a type of white blood cell. The phagocyte’s job is to kill bacteria and fungi.
What causes CGD?
Patients with CGD have poorly-functioning phagocytes caused by mutations in one of four different genes. The abnormal genes cannot make proteins required for the production of oxygen byproducts, such as hydrogen peroxide and superoxide, which kill bacteria and fungi.
How is CGD treated?
It is critically important to see a doctor and get diagnosed early. It is also important for doctors to aggressively treat infections with prolonged high doses of antibiotics. There is not yet a specific therapy for CGD. To prolong infection-free periods, physicians often prescribe continuous preventive oral antibiotics, such as trimethoprim combined with sulfamethoxazole. Abscesses often require surgical drainage. The granulomas ultimately resolve with long-term antibiotic therapy. Steroids reduce the gastrointestinal and genitourinary tract obstructions. Patients with anemia may require whole blood transfusions. Patients have been treated successfully with bone marrow transplantation, and this may be an option if a suitable donor can be found. Gene therapy is under investigation.
Researchers at the National Institute of Allergy and Infectious Diseases helped pinpoint the genes responsible for CGD. They also developed the approved CGD treatment that uses gamma interferon. This treatment reduces the number of serious infections by up to 72 percent. The treatment can be given at home by subcutaneous injections three times a week. .
Hyper-IgM SyndromeHyper-IgM is a rare immunodeficiency disease in which the immune system fails to produce IgA and IgG antibodies.
What are the symptoms of hyper-IgM syndrome?
Infants usually develop recurring upper and lower respiratory infections within the first year of life. Other signs of the disease include enlarged tonsils, liver, and spleen, chronic diarrhea, and an increased risk of unusual or “opportunistic” infections and non-Hodgkins lymphoma.
How is hyper-IgM syndrome diagnosed?
The doctor will order laboratory tests that show normal numbers of T and B cells, but high levels of IgM and very low IgG and IgA. He may question whether the family recalls other relatives who became sick in infancy. Patients may also have neutropenia, a low number of white blood cells.
What causes hyper IgM syndrome?
A flawed gene (or genes) in T cells is responsible for hyper IgM syndrome. The faulty T cells do not give B cells a signal they need to switch from making IgM to IgA and IgG. Most cases of hyper-IgM syndrome are linked to the X chromosome. Because males do not have a second, healthy, X-chromosome to offset the disease, boys far outnumber girls with this disease.
How is hyper-IgM syndrome treated?
Patients receive injections of intravenous immunogloblulin (IVIG) every three to four weeks. For neutropenia, patients can take granulocyte colony-stimulating factor (G-CSF). Their doctor may also prescribe antibiotics to prevent the respiratory infection, pneumocystis carinii pneumonia.
In a mouse model of this disease, scientists have restored the animal’s ability to make antibodies and improved their survival by administering man-made CD40 ligand, the molecule that allows T cells to communicate with B cells. A study to determine whether this treatment will be effective in humans is underway.
Where can I get more information about primary immune deficiency?National Institute of Child Health
and Human Development
Public Information and
31 Center Drive, Room 2A32
Bethesda, MD 20892-2425
American Academy of Allergy,
Asthma, and Immunology
611 E. Wells Street
Milwaukee, WI 53202
Immune Deficiency Foundation
40 W. Chesapeake Avenue, Suite 308
Towson, MD 21204
The Jeffrey Modell Foundation
747 Third Avenue
New York, NY 10017
1-800-JEFF-844 (24-hour hotline)
NIAID is a component of the National Institutes of Health (NIH). NIAID supports basic and applied research to prevent, diagnose, and treat infectious and immune-mediated illnesses, including HIV/AIDS and other sexually transmitted diseases, tuberculosis, malaria, autoimmune disorders, asthma and allergies. NIH is an agency of the U.S. Department of Health and Human Services.
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