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 March 2003
Primary Immune DeficiencyContentsWhat is Primary Immune Deficiency?Selective IgA Deficiency Common Variable Immunodeficiency (CVI) X-Linked Agammaglobulinemia (XLA) Severe Combined Immunodeficiency (SCID) Chronic Granulomatous Disease (CGD) Hyper-IgM Syndrome Interferon-Gamma Receptor (IFNGR) Deficiency Hyper-IgE (HIE) Syndrome Leukocyte Adhesion Deficiency (LAD Glossary More Information WHAT IS PRIMARY IMMUNE DEFICIENCY?When 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 the cells of their immune systems. Between 25,000 and 50,000 people suffer from the most serious forms of PI diseases in the United States, but experts believe that many more have milder disease that is not yet diagnosed.1 Each type of immune system cell has its own special function and must work together with other types 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 the 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. Having any of them makes it easier to get infections and other medical conditions. More boys than girls have PI, and first symptoms often begin in infancy or later in childhood. Primary care doctors who suspect a patient has a problem with the immune system will run screening tests. If those tests indicate the person's immune system is not functioning normally, the doctor will consult with a special kind of doctor called a clinical immunologist. The immunologist can run special blood tests to find out the exact type of PI disease and how best to treat it. Other experts the doctor may consult include pulmonologists, rheumatologists, gastroenterologists, and hematologists. In this pamphlet, we discuss only a few PI diseases. Selective IgA DefficiencyApproximately one out of every 600 people have selective IgA deficiency. Among those with this PI, 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 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 know the exact cause or causes for these immature B cells. Sometimes clusters of cases occur in families. People with IgA-deficiency are more likely than the general population to be related to someone with combined variable immunodeficiency, another form of immune deficiency. Researchers are trying to find the genes that cause IgA deficiency on the involved chromosomes. What are the symptoms of IgA deficiency?Many people with IgA-deficiency are healthy, with no more than the usual number of infections. Those who do have symptoms typically have recurring ear, sinus, or lung infections that may not respond to regular treatment with 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 usually are normal. IgA-deficient people also have normal levels of immune system cells, including T cells and phagocytes, and complement proteins. Doctors diagnose IgA deficiency by doing tests to measure the amount of total Ig in the blood as well as the type of Ig 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. How is IgA deficiency treated?There is no specific treatment for selective IgA deficiency. Doctors treat bacterial infections with antibiotics. They give patients with giardiasis (an infection caused by a common intestinal parasite) metronidazole or quinacrine hydrochloride. COMMON VARIABLE IMMUNODEFICIENCY (CVI)CVI is relatively common. Infants sometimes have symptoms of CVI. In most cases, however, symptoms do not show up until the teen years or early adulthood. CVI is also called What causes CVI? No one knows the cause. Experts cannot trace a clear pattern showing that this PI is inherited. What are the signs and symptoms of CVI? Most people with CVI have Along with other autoimmune problems, some develop autoantibodies that attack their own blood cells. People with CVI also have an increased risk of developing some cancers. How is CVI diagnosed? To diagnose CVI, doctors look for How is CVI treated? CVI patients receive intravenous immunoglobulin (IVIG) every 3 to 4 weeks to restore normal antibody levels. Bacterial infections are treated with antibiotics. Physical therapy and daily postural drainage may help clear clogged lungs. X-Linked Agammaglobulinemia (XLA)
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 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 What are the symptoms of SCID? Babies typically have symptoms within the first three months of life. They usually get many serious or life-threatening infections, especially pneumonia, meningitis, and sepsis (blood infection). Common infections like chickenpox, measles, or cold sores can overwhelm their immune systems. These infants 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 how well the immune system is functioning. Because ongoing infections can interfere with test results, the doctor may have to repeat tests several times. Patients usually have a very low number of white blood cells, as well as few or no B and T cells. The few cells they have often do not function properly. Also, SCID patients have very low levels of IgG, IgA, and IgM antibodies. How is SCID treated? Transplanting bone marrow from a healthy brother or sister 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 can help. Until the transplant takes effect (in one to three years), the patient will be given intravenous immunoglobulin (IVIG) to get the antibody levels back to normal. Doctors have treated SCID patients who have ADA deficiency successfully with enzyme replacement therapy called PEG-ADA. Researchers are investigating gene therapy to correct both forms of SCID. 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 are females. Their immune systems are not effective against certain bacteria and fungi, including E. coli and Staphylococcus aureus (staph), as well as less common germs like Pseudomonas, Serratia, and Aspergillus. 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 necessary to produce oxygen byproducts, such as hydrogen peroxide and superoxide, which kill bacteria and fungi. What are the symptoms of CGD? Doctors may suspect CGD in babies between three months and two years of age who have had Children with CGD, however, may not develop symptoms until as late as adolescence. Repeated infections can cause tumor-like masses or "granulomas" to develop in the skin, lungs, lymph nodes, liver, or bones. Granulomas can block the gastrointestinal or urinary tracts. They 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 How is CGD treated? Early diagnosis of CGD is critically important. The goal is to prevent infections and their aftermath. Key issues to remember: Some people have been treated successfully with bone marrow transplantation, and this may be an option if a suitable donor can be found. Researchers are investigating gene therapy. NIAID scientists helped pinpoint the genes responsible for CGD. They also developed the approved CGD treatment that uses gamma interferon. Health care workers or others can treat patients at home with injections three times a week. This treatment reduces the number of serious infections by up to 72 percent. Hyper-IgM SyndromeHyper-IgM is a rare immunodeficiency disease in which the immune system fails to produce IgA and IgG antibodies. 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 making IgA and IgG. Most cases of hyper-IgM syndrome are linked to the X chromosome. Because boys carry only one X chromosome, unlike girls whose second X chromosome helps to protect against the disease, more boys than girls have IgM syndrome. 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-Hodgkin's 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. Patients also may have neutropenia, a low number of white blood cells. The doctor may ask whether the family recalls other relatives who had immune system problems in infancy. How is hyper-IgM syndrome treated? Patients receive injections of intravenous immunoglobulin (IVIG) every three or four weeks. For neutropenia, patients can take G-CSF, a protein that stimulates the body to produce more granulocytes. Their doctor may also prescribe antibiotics to prevent the lung disease, Pneumocystis carinii pneumonia. In a mouse model of this PI, scientists have restored the animal's ability to make antibodies and improved their survival by giving them artificial CD40 ligand, a molecule that allows T cells to communicate with B cells. A study to determine whether this treatment will be effective in humans is underway. Interferon-Gamma Receptor (IFNGR) DeficiencyThis very rare inherited disorder causes individuals to be more susceptible to mycobacteria that cause tuberculosis, as well as other types of mycobacteria, and infections caused by salmonella bacteria. Patients have either partial or complete IFNGR deficiency. What causes IFNGR deficiency? IFNGR deficiency is caused by an inherited mutation in a gene. The affected gene is found on cells called granulocytes. These granulocytes have protein receptors on their surfaces that reject interferon gamma, a chemical needed to fight off tuberculosis and other infections caused by mycobacteria as well as salmonella infections. What are the symptoms of IFNGR deficiency? Mycobacteria cause the most serious problems for people with IFNGR deficiency. Infections may involve the lungs, lymph nodes, blood and bone marrow. People with complete IFNGR deficiency have more serious infections than those with partial IFNGR deficiency. The disease occurs early in infancy in those with complete IFNGR deficiency. Those with partial deficiency are more likely to develop illness later in childhood. How is IFNGR deficiency diagnosed? A doctor suspects IFNGR deficiency in a patient with a history of severe or repeated mycobacterial infections. Sophisticated laboratory tests measure the amount of interferon gamma in the blood and show the patient's white blood cells respond poorly, or not at all, to interferon gamma. Depending on whether the patient has complete or partial IFNGR deficiency, the blood will have either very high or very low levels of interferon gamma. Genetic testing can determine whether the patient has one of four mutations that cause either partial or complete IFNGR deficiency. How is IFNGR deficiency treated? Patients with complete INFGR deficiency have a poorer outlook than those with partial INFGR deficiency. They need aggressive and long-term treatment with antibiotics. Patients with partial INFGR deficiency have milder disease that is easier to treat with antibiotics. Bone marrow transplantation has cured a small number of patients. NIAID scientists are developing methods to add a corrective gene to bone marrow cells that will become granulocytes. They are also working to improve the multi-drug treatment that is the mainstay for IFNGR-deficient patients. Patients with complete IFNGR deficiency may especially benefit from treatment that includes immune boosters or "cytokines," including IL-2, IL-12, interferon gamma, and GM-CSF. Hyper-IgE (HIE) SyndromeThis rare condition is also called Job syndrome. Health care experts have reported only 200 cases of HIE. People with HIE have very high levels of the IgE antibody. HIE causes recurring bacterial infections and other complications. What causes HIE? HIE is caused by an inherited abnormality in a gene. In about half of the cases, the flawed gene is linked to chromosome 4. In most known cases, it is autosomal dominant. This means that to be born with this disease, a person needs to inherit the affected gene from only one parent. Scientists suspect that the affected gene (or genes) may prevent T cells from properly regulating the immune response to germs. What are the symptoms of HIE? People with HIE have repeated bacterial infections of the skin, sinuses, and lungs. These infections are often caused by Staphylococcus aureus (staph). HIE patients may also have scoliosis (curvature of the spine), weak bones and recurrent bone fractures, strokes or other brain problems, severe itching and inflamed skin. They may fail to lose baby teeth. How is HIE diagnosed? Doctors will suspect HIE in a person who has a red, itchy skin rash and recurring staph infections of the skin, sinuses, lungs, or joints. Patients with HIE often have distinctive facial characteristics Blood tests show normal levels of IgG, IgA, and IgM, but very high levels of IgE and a high number of white blood cells called eosinophils. Tests also show poor immune response to immunizations. How is HIE treated? There is no specific treatment for HIE. Patients receive lifelong antibiotics to fight the recurring infections. People with HIE who lack other types of antibodies may find intravenous Ig injections (IVIG) helpful. NIAID scientists are evaluating HIE patients and their relatives to better understand the medical problems associated with this disease to identify and treat complications. By disrupting different genes in the mouse, they hope to produce the syndrome in this animal so they will have a useful model for research. Finding the gene or genes involved in HIE will be critically important to developing better therapies for HIE, especially gene therapy. Leukocyte Adhesion Deficiency (LAD)LAD is a rare PI disease, found in one out of every million people. This disease causes recurrent, life-threatening infections. Phagocytes cannot find their way to the site of infection to fight off invading germs. LAD is autosomal recessive disease, meaning that to be born with this disease, both parents must have the affected gene. What causes LAD? LAD is caused by a lack of beta 2 integrin, also called CD18, molecules. These molecules are normally found on the outer surface of phagocytes. Without them, the phagocytes cannot attach to blood vessel walls and enter infected tissues where they help fight infection. Mutations in the gene that instructs, or codes for, the production of CD18 cause LAD. What are the symptoms of LAD? Children with LAD cannot fight off infection properly. They may have There are at least two forms of LAD How is LAD diagnosed? Blood tests to diagnose patients with LAD show a very high number of white blood cells and very low levels of CD18, a protein. Doctors may suspect LAD if an infant's umbilical cord does not fall off and heal properly after birth. They also will suspect the disease in children who develop severe infections caused by bacteria and fungi, and whose wounds are slow to heal. How is LAD treated? Doctors treat patients with bacterial infections early and aggressively with antibiotics. Some patients have been treated successfully with bone marrow transplants. Interferon gamma increases CD18 and improves the ability of white blood cells to move about. NIAID researchers are using interferon gamma in people with LAD type 1 to see if it can help reduce the number and severity of their recurrent infections. Researchers are also investigating gene therapy as a potential cure for LAD. Glossaryantibody - a protein molecule (also called an immunoglobulin) produced by B cells in response to an antigen. When an antibody attaches to an antigen, it destroys the antigen. antigen - the portion of a foreign substance or germ that can cause the immune system to become active against it. antibiotics - Medicines used to treat some bacterial diseases. autoantibody - an antibody that reacts against the body's own tissue autoimmune disease - a disease that results when the immune system mistakenly attacks the body's own tissues. Rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes are examples of autoimmune diseases. B cells(also called B lymphocytes) - white blood cells that come from bone marrow and develop into plasma cells, mature B cells capable of producing antibody. bronchi - airways in the lungs cell - building block that makes up tissues, organs, systems, and bloodstream of the body. chromosome - physical structure in a cell that houses genes. Almost every human cell has 23 pairs of chromosomes (egg and sperm cells have half). complement - a series of blood proteins whose action "complements" the work of antibodies. Complement destroys bacteria, produces inflammation, and regulates immune reactions. gene - a unit of genetic material that is inherited from a parent. A gene carries the directions a cell uses to perform a specific function, like making proteins. Genes are made of DNA, the basic chemical unit of life. granulocyte - a cell filled with potent chemicals that destroy germs and reduce inflammation. hepatitis - a liver disease. IgA, immunoglobulin A - a type of antibody concentrated in mucous membranes and body fluids like tears, saliva, and secretions of the respiratory and gastrointestinal tract. IgG, immunoglobulin G - the major antibody found in the blood that can enter tissues. It coats germs, helping other cells to seek and destroy them. IgM, immunoglobulin M - an antibody that remains in the bloodstream where it can kill bacteria that enter the blood stream. immunoglobulins - a large family of proteins, also known as antibodies. There are five classes of immunoglobulins: IgA, IgM, IgG, IgD, and IgE. Only IgA, IgG, and IgM are further classified into specific subclasses, denoted by a numeric suffix (for example, IgG2). immune response - reactions of the immune system to foreign substances. immune system - complex network of specialized cells and organs that has evolved to defend the body against attacks by foreign invaders. immunity - protection from disease-causing microbes. immunization - the process of inducing protection (immunity) against the destructive forces of a disease-causing microbe. infection - a state in which microorganisms have invaded or multiplied in body tissues. inflammation - an immune system tool to stop the progression of disease-causing microbes, sometimes seen at the site of an injury like a cut. Signs of it include redness, swelling, and heat. lymph nodes - small bean-shaped organs of the immune system, distributed widely throughout the body. They are fortresses of B, T, and other immune cells. lymphocytes - small white blood cells (B and T cells) that are the major players in immune defense. neutrophils - an important white blood cell that is both a phagocyte and a granulocyte abundant in the blood. microbes - an important white blood cell that is both a phagocyte and a granulocyte abundant in the blood. molecule - The smallest physical unit made up of a chemical substance such as a protein or a fat. Molecules are the building blocks of a cell, and a gene determines how each molecule is produced. mucous membrane - The moist lining of certain body cavities such as the mouth. mutation - a change in a cell's DNA that may cause the cell to produce an abnormal protein. opportunistic infections - infections caused by microbes that usually do not cause disease in healthy individuals, but which can result in overwhelming and widespread infection in people with immune deficiency. phagocytes - large white blood cells that contribute to immune defense by engulfing microbes, such as bacteria and fungi, or other cells and foreign particles. T cells (T lymphocytes) - white blood cells that either orchestrate the immune response (regulatory T cells) or directly attack infected or malignant cells (cytotoxic T cells). tissue - a group of similar cells joined to perform the same function. tissue type - the type of histocompatibility antigens on a person's cells or tissues. If the histocompatibility antigens do not match well, there is a much greater chance that the recipient will reject the donated tissue. vaccine - substance that contains parts of antigens from an infectious microbe. By stimulating an immune response (but not disease), it protects the body against subsequent infection by that organism. More Information
National Institute of Allergy and Infectious Diseases National Institutes of Health Building 31, Room 7A50 31 Center Drive, MSC 2520 Bethesda, MD 20892-2520 http://www.niaid.nih.gov/ National Institute of Child Health and Human Development National Institutes of Health Public Information and Communications Branch 31 Center Drive, Room 2A32 Bethesda, MD 20892-2425 301-496-5133 http://www.nichd.nih.gov/ Medlineplus National Library of Medicine National Institutes of Health 8600 Rockville Pike Bethesda, MD 20894 301-496-6308 http://medlineplus.gov/ American Academy of Allergy, Asthma, and Immunology (AAAAI) 611 E. Wells Street Milwaukee, WI 53202 414-272-6071 http://www.aaaai.org/ Immune Deficiency Foundation 40 W. Chesapeake Avenue, Suite 308 Towson, MD 21204 1-800-296-4433 http://www.primaryimmune.org/ The Jeffrey Modell Foundation 747 Third Avenue 34th Floor New York, NY 10017 1-800-JEFF-844 (24-hour hotline) http://www.jmfworld.com/ 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, illness from potential agents of bioterrorism, tuberculosis, malaria, autoimmune disorders, asthma and allergies. NIH is an agency of the U.S. Department of Health and Human Services. | |||||