Antibody deficiencies, also called immunoglobulin deficiency syndromes, are immune system disorders that are characterized by low or absent levels of immunoglobulin in the blood. Immunoglobulins (Ig) are antibodies that play an essential role in the body's immune system. They detect and bind to foreign substances (like bacteria, viruses, fungi, or allergens) that enter the body. This signals other immune cells to destroy the foreign substance. The antibodies are present in the bloodstream or bound to the outer surfaces of B-cells or plasma cells.
There are five classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM. Patients who have antibody deficiencies may have reduced or absent levels of one or more types of immunoglobulin. In most cases, the cause of antibody deficiency is unknown, although some disorders may be genetic (passed down from parent to child).
Immunoglobulin A (IgA) antibodies are primarily found in the nose, airway passages, digestive tract, ears, eyes, saliva, tears, and vagina. These antibodies protect body surfaces that are frequently exposed to foreign organisms and substances from outside of the body. The IgA antibodies make up about 10-15% of the antibodies found in the body.
IgG antibodies are the smallest but most abundant antibodies in the body, making up 75-80% of all the antibodies in the body. They are present in all body fluids. The IgG antibodies are considered the most important antibodies for fighting against bacterial and viral infections. They are the only antibodies that can cross the placenta. Therefore, the IgG antibodies of a pregnant woman help protect her fetus. IgG isotypes are associated with complement fixation (immune response in which an antigen-antibody combination deactivates a complement), opsonization (process by which antigens are altered so that they are more readily and more efficiently engulfed and destroyed by immune cells), fixation to macrophages, and membrane transport.
IgM antibodies are the largest type of antibody. They are found in the bloodstream and lymph fluid. The IgM antibodies are the first antibodies that are produced in response to an infection. They also stimulate other immune system cells to produce compounds that can destroy invading cells. IgM antibodies normally make up about 5-10% of all the antibodies in the body.
IgD antibodies are found in small amounts in the tissues that line the abdominal or chest cavity of the body. The function of IgD antibodies is not well understood. Researchers believe they play a role in allergic reactions to some substances, such as milk, medications, and poisons. IgD is present in very small amounts in normal human serum (clear fluid portion of blood).
IgE antibodies are found in the lungs, skin, and mucous membranes. They cause the body to react against foreign substances like pollen, fungus spores, and animal dander. IgE antibody levels are often high in people who have allergies. IgE is active against parasites and acts as a mediator when immediate hypersensitivity occurs. IgE is present in very small amounts in normal human serum
The most common antibody deficiencies include common variable immunodeficiency (CVID), hyperimmunoglobulin E syndrome (HIES), IgG subclass deficiencies, selective IgA deficiency, selective IgM deficiency, transient hypogammaglobulinemia of infancy (THI), and X-linked hypogammaglobulinemia. Some patients with antibody deficiencies experience no symptoms, while others may experience persistent and frequent infections, diarrhea, decreased qualify of life, and poor absorption of nutrients.
Currently there is no cure for antibody deficiencies. Treatment focuses on alleviating symptoms and resolving infections associated with the disorder. Patients typically receive antibiotics to treat infections and intravenous immunoglobulin (IVIG) to boost the body's immune system. Some antibiotics or vaccines may be recommended to prevent recurrent infections.
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types of the disease
Common Variable Immunodeficiency (CVID)
Overview: Common variable immunodeficiency (CVID), also called hypogammaglobulinemia or adult onset hypogammaglobulinemia, is a relatively common primary immune deficiency. Primary immune deficiencies are disorders that occur because part of the body's immune system does not function properly. These disorders are caused by intrinsic or genetic defects in the immune system. Therefore, individuals who have primary immune deficiencies are born with the disorder.
The disorder is characterized by a lack of antibody producing B-cells or plasma cells, low levels of most or all types of immunoglobulin, and recurrent bacterial infections.
While the exact incidence of CVID is unknown, researchers estimate that about one out of 50,000 individuals develop the disorder.
Although decreased serum levels of immunoglobulin G (IgG) and immunoglobulin A (IgA) are characteristic of the disorder, about 50% of CVID patients also have decreased immunoglobulin M (IgM) levels. In addition, about half of CVID patients experience some T-lymphocyte dysfunction.
No clear pattern of inheritance has been observed. In most cases, there is no family history of immunodeficiency. However, when more than one family member is diagnosed with CVID, researchers believe it is the result of autosomal recessive inheritance.
Initially, the disorder was called acquired agammaglobulinemia. This name generally applied to patients who developed the immunodeficiency when they were 20-50 years old. However, today the use of the term is discouraged in order to avoid confusion with the acquired immune deficiency syndrome (AIDS). Instead, CVID that develops later in life is now referred to as adult-onset hypogammaglobulinemia.
In general, the expected survival rate for male and female patients is 92% and 94%, respectively. Factors associated with fatality include low levels of IgG, poor T-cell responses to antigens, and a low percentage of B cells. Deaths related to CVID are usually the result of lymphoma. Other potential causes of death include right-sided heart failure secondary to chronic lung infection, liver failure, and malnutrition (resulting from gastrointestinal tract disease).
The first signs of the deficiency are recurrent bacterial infections, which may occur as early as infancy or as late as the fourth decade of life. Common symptoms include recurrent infections of the ears, bronchi, sinuses, and lungs. Bronchiectasis (widening and scarring of the bronchial tubes) infections of the bronchi are severe. Patients with bronchiectasis may have a regular morning cough that produces yellow or green sputum. Many CVID patients have an enlarged spleen and lymph nodes. Other patients may develop painful inflammation of the knees, ankle, elbows, or wrist joints. Gastrointestinal symptoms may include abdominal pain, bloating, nausea, vomiting, diarrhea, or weight loss. Some patients develop autoantibodies, which are antibodies that mistakenly attack the body's tissues. Autoantibodies can destroy one or more types of body tissues, cause abnormal organ growth, or impair organ function. Autoantibodies commonly affect blood components (like red blood cells, connective tissues, and blood vessels), endocrine glands (like the thyroid or pancreas), as well as muscles, joints, and the skin.
Diagnosis: A nephelometry blood test may be performed to diagnose CVID. The disorder is diagnosed after significantly decreased IgG and IgA levels are observed in the patient's blood. Some patients may also have decreased IgM levels. During the procedure, a sample of blood is taken from the patient. Anti-immunoglobulins are added to the blood sample. A medical instrument then measures the movement of particles in a substance that is caused by the interaction between immunoglobulins and anti-immunoglobulins. The test quickly and accurately measures the amount of IgM, IgG, and IgA in the patient's blood. Healthy individuals have 100-400 milligrams of IgA per deciliter of blood, 560-1,800 milligrams of IgG per deciliter of blood, and 45-250 milligrams of IgM per deciliter blood.
Treatment: While there is currently no cure for CVID, various treatments may help relieve symptoms and resolve infections associated with the disease. Intravenous immune globulin (IVIG) therapy is used most often to treat CVID patients.
Immune globulin may be administered intravenously (injected into the vein) or subcutaneously (injected below the skin). Solutions of 3-12% intravenous immunoglobulin (IVIG) have been used on a regular basis to maintain a trough level of 400-500 milligrams/deciliter in adults. A dose of 400-600 milligrams/deciliter every two to four weeks is usually required. In patients with structural lung damage, a trough level of 700-800 milligrams/deciliter is generally required.
The most common side effects of IVIG include backache, nausea, vomiting, chills, low-grade fever, myalgias (general feeling of discomfort), and fatigue. Adverse effects usually occur within 30 minutes of the infusion and typically last for several hours. Slowing the rate of infusion or interrupting the infusion for a few minutes can help prevent side effects. Adverse effects can be treated with antipyretics, diphenhydramine, or corticosteroids. Although anaphylactic reactions to immunoglobulin concentrates are rare, patients who have IgA deficiency have an increased risk for these effects. Long-term intravenous access is not recommended because it can increase the risk of infection.
Patients with chronic sinusitis or lung disease may need long term treatment with broad spectrum antibiotics such as ampicillin (Principen®), tetracycline (Helidac Therapy®, Sumycin®, or Sumycin® Syrup), cephalexin (Biocef®, Keflex®, Keftab®, Panixine®, or Zartan®), trimethoprim/sulfmethoxazole (Bactrim® or Septra®), or ciprofloxacin (Cipro®).
Hyperimmunoglobulin E Syndrome (HIES)
Overview: Hyperimmunoglobulin E syndrome (HIES), also called Job syndrome, is an inherited immunodeficiency that is characterized by recurrent bacterial infections, skin abscesses, and high levels of immunoglobulin E (IgE). Immunoglobulin (Ig) is an antibody that is secreted by immune system cells to detect antigens (foreign substances like bacteria and viruses that enter the body). Once the antibodies attach to the antigen, white blood cells destroy the antigen.
Even though HIES patients have high levels of IgE in their blood, they are vulnerable to infection and disease because other important immune cells do not function properly. HIES patients are born with abnormal T-cells (type of white blood cells) that are unable to produce enough interferon-gamma, which stimulates white blood cells called macrophages to engulf foreign invaders. Consequently, the immune system's response to antigens is delayed.
Studies suggest that HIES is a genetic disorder that can be inherited as either an autosomal dominant (AD-HIES) or autosomal recessive (AR-HIES) trait. However, the specific gene involved remains unidentified.
HIES is an extremely rare disease, with only 250 cases ever reported internationally. Most individuals are not diagnosed until childhood, or sometimes adulthood.
The oldest reported HIES patient was 60 years old. Most patients die by age 20-30 from severe pulmonary (lung) infections and diseases like aspergillosis.
Symptoms: Common symptoms of HIES include persistent skin abscesses and infections, recurrent pus in the sinuses, eczema (type of skin rash), itchy skin, and painless skin abscesses (infections). Patients often suffer from recurrent infections such as fungal infections of the mouth and nails, bronchitis, pneumonia, ear infections, sinus infections, bone infections, and gingivitis (gum disease). Some patients may also suffer from skeletal and dental abnormalities such as scoliosis (curved spine), fractured bones (that often go unrecognized because they cause little or no pain), bone and teeth defects, and late shedding and fractures of baby teeth.
Diagnosis: HIES can be diagnosed after elevated levels of IgE are observed in the blood of patients who suffer from the characteristic symptoms. An enzyme-linked immunosorbent assay (ELISA) test is used to measure the level of antibodies in the blood. Patients are diagnosed with HIES if they have an IgE level greater than two standard deviations higher than normal, and they suffer from characteristic symptoms.
Treatment: There is currently no cure for HIES. Treatment focuses on resolving the infections commonly associated with the disorder. Antibacterial agents like nafcillin (Nafcil®, Unipen® or Nallpen®), oxacillin (Bactocill® or Prostaphlin®), and ampicillin (Marcillin®, Omnipen®, Polycillin®, Principen®, or Totacillin®) have been used to treat bacterial infections. Antifungals like fluconazole (Diflucan®) and Ketoconazole (Nizoral®) have been used to treat fungal infections. Intravenous immunoglobulin therapy (IVIG) may help to build up the immune system temporarily when patients have severe infections. Intravenous immunoglobulin (IVIG) is made of antibodies extracted from pooled blood donations from hundreds to thousands of donors. The immunoglobulin is typically injected into the patient's vein for about two to four hours a day for two to seven days. The patient usually receives another single dose every 10-21 days or every three to four weeks, depending on the severity of the condition.
IgG subclass deficiencies
Overview: Selective immunoglobulin G (IgG) subclass deficiencies are a group of inherited disorders that occur when subclasses of IgG are not produced. There are four subclasses of the IgG class of antibodies:
IgG1, IgG2, IgG3, and IgG4.
In healthy individuals, the antibody-producing B-cell can switch from one IgG subclass to another. Patients with IgG subclass deficiencies are born with defective B-cells that are do not mature properly, and they are unable to produce different IgG subclasses. This causes an imbalance of the IgG subclasses, with one or more subclasses being deficient. The overall level of IgG may be normal, but individual subclass levels may be higher or lower than normal.
Symptoms: Many patients experience no symptoms, while others may suffer from recurrent ear infections, sinusitis (sinus infections), bronchitis, and pneumonia. In rare cases, patients have experienced recurrent episodes of meningitis (infection of the membranes that cover the spinal cord and brain) or bacterial infections of the bloodstream.
Lung function impairment and bronchiectasis (widening and scaring of airways) have also been reported in some patients. Some patients develop autoimmunity. When this occurs, cells in the immune system mistake the body's own tissues for an invading substance.
Diagnosis: The standard diagnostic test for IgG subclass deficiency is an enzyme-linked immunosorbent assay (ELISA) or a radial immunodiffusion test. These tests measure the level of IgG subclasses in the blood. In healthy individuals, 60-70% of IgG antibodies in the bloodstream are IgG1, 20-30% are IgG2, five to eight percent are IgG3, and one to three percent are IgG4. Test results may vary from one laboratory to another. A healthcare provider should also evaluate the patient's response to vaccines. Patients who have IgG2 subclass deficiency often have poor responses to the Pneumococcal vaccine.
Treatment: Many patients outgrow their deficiency once they reach adulthood. For those patients who experience persistent deficiencies, antibiotics, intravenous immune globulin (IVIG) therapy, and immunizations may help prevent serious infections and the development of impaired lung function, hearing loss, or other injuries caused by infections. IVIG is made of antibodies extracted from pooled blood donations from hundreds to thousands of donors. IVIG has been shown in some studies to reduce the number of infections and courses of antibiotics in patients who have substantial IgG subclass deficiencies. Doses range from 200 to 400 milligrams/kilogram, given once every three or four weeks.
Selective IgA deficiency
Overview: Selective immunoglobulin A (IgA) deficiency is a primary immune deficiency that occurs when individuals are unable to produce antibodies called immunoglobulin A.
The B-cells of selective IgA patients are unable to switch from making immunoglobulin M (IgM) to IgA. Healthy individuals express IgM on their B-cells. Once the B-cells come into contact with a foreign substance in the body, they become plasma cells and are capable of producing other antibodies, including IgA.
The amount of IgA produced is either significantly reduced or absent. Healthy adults have serum IgA levels that range from 90-450mg/dl, while IgA deficient patients have serum levels of 7mg/dl or less.
The disorder is considered selective because all other antibodies (IgD, IgE, IgG, and IgM) are present at normal or increased levels. Other cells of the immune system, including the T-cells and phagocytic cells, are also produced at normal or increased levels. The T-cells and phagocytic cells are responsible for engulfing (destroying) the foreign substances that are bound to the antibodies.
Selective IgA deficiency appears to be an inherited disease that is passed down from parents to children. However, the exact genes involved remain unknown.
Symptoms: Most patients who have selective IgA deficiency experience no symptoms. Because the IgA antibodies protect body surfaces that are frequently exposed to foreign substances from outside of the body (like the nose, throat, lungs, and intestines), these patients may suffer from recurrent infections of these body parts. Ear infections, sinus infections, and pneumonia are the most common infections that occur in symptomatic patients. However, most infections are generally mild.
Allergies, which range from mild to severe, are also common among patients.
Diagnosis: A diagnosis of selective IgA deficiency can be made after low or absent levels of IgA are observed in a patient. Healthy adults typically have IgA levels of 100-400 milligrams/deciliter in the blood. The IgA will either be absent or below 7 milligrams/deciliter in patients who have selective IgA deficiency. Immunoglobulin G (IgG) and immunoglobulin M (IgM) will be present in normal levels.
Treatment: There is currently no cure for selective IgA deficiency. While many patients do not require any medical treatment, some may need antibiotics to treat infections commonly associated with the disorder. Commonly prescribed antibiotics for ear infections include amoxicillin (Trimox® or Biomox®) and Cefuroxime (Ceftin®, Kefurox®, or Zinacef®). Commonly prescribed antibiotics for sinus infections include amoxicillin (Amoxil®, Polymox®, or Trimox®) and trimethoprim/sulfamethoxazole, also called TMP/SMX (Bactrim®, Cotrim®, or Septra). Commonly prescribed antibiotics for pneumonia include azithromycin (Zithromax®), clarithromycin (Biaxin®), erythromycin (Erythrocin® or Ery-Tab®), and amoxicillin and clavulanate (Augmentin®).
Intravenous immunoglobulin (IVIG) therapy, which is often used to treat other primary immunodeficiencies, should not be used to treat selective IgA deficiency because some patients may develop antibodies to IgA. Once antibodies are created, severe reactions, including anaphylaxis (life-threatening allergic reaction), may occur if the patient receives IVIG.
Selective IgM deficiency (SIgMD)
Overview: Selective Immunoglobulin M deficiency (SIgMD) is an immune disorder that occurs when patients have low levels of immunoglobulin M (IgM). Healthy individuals typically have 45-250 milligrams/deciliter of IgM in their blood. Patients with SIgMD typically have concentrations of IgM patients that are lower than 40 milligrams/deciliter.
Some patients may be born with SIgMD, while others may develop the disorder as a result of another medical condition, such as cancer, an autoimmune disease, or a gastrointestinal problem. Patients who are receiving immunosupressants may also develop SIgMD.
Some patients may experience no symptoms, while others may have serious infections. Infants and small children are more likely to develop severe infections that may be life threatening because their immune systems are not fully developed. In older children and adults, SIgMD is usually discovered during the investigation of other conditions, such as autoimmune disease or cancer.
SIgMD is a rare disorder. Researchers estimate that less than 0.03% of the general population and about 1% of hospitalized patients have the disorder.
Symptoms: Patients may be asymptomatic, while others may experience prolonged or life-threatening infections, especially during infancy. Recurrent infections, including, sinusitis and pneumonia, are caused by bacteria. Patients may also experience atopic or chronic dermatitis, allergic rhinitis (hay fever), wheezing, and/or diarrhea.
Diagnosis: A nephelometry blood test may be performed to diagnose SIgMD. The disorder is diagnosed after significantly decreased IgM are observed in the patient's blood. During the procedure, a sample of blood is taken from the patient. Anti-immunoglobulins are added to the blood sample. A medical instrument then measures the movement of particles in a substance that is caused by the interaction between immunoglobulins and anti-immunoglobulins. The test quickly and accurately measures the amount of IgM in the patient's blood.
Treatment: There is currently no cure for SIgMD that is inherited. SIgMD that is caused by another medical condition may resolve once the underlying condition is treated. Treatment focuses on resolving infections associated with the disorder. Commonly prescribed antibiotics include amoxicillin (Trimox® or Biomox®), cefuroxime (Ceftin®, Kefurox®, or Zinacef®), amoxicillin (Amoxil®, Polymox®, or Trimox®), trimethoprim/sulfamethoxazole, also called TMP/SMX (Bactrim®, Cotrim®, or Septra), azithromycin (Zithromax®), clarithromycin (Biaxin®), erythromycin (Erythrocin® or Ery-Tab®), and amoxicillin and clavulanate (Augmentin®).
Transient hypogammaglobulinemia of infancy (THI)
Overview: Transient hypogammaglobulinemia of infancy (THI) is a temporary immunodeficiency that occurs when patients have low levels of immunoglobulin G (IgG), the most common antibody in the bloodstream. Immunoglobulins are antibodies that help the body fight against disease and infection. Additional types of antibodies, including immunoglobulin A (IgA), may also be low in children with THI.
In healthy babies, antibody levels in the blood reach a natural low point when they are between three and four months of age. This happens because babies are no longer receiving IgG from their mothers, and they are unable to produce their own yet. Once healthy babies reach six months of age, their antibodies are produced at a normal rate.
In children who have THI, the levels of IgG and IgA levels remain low after six months of age because not enough immunoglobulin is produced. Babies who are born prematurely are at an even greater risk of developing THI because they had less time to build up antibody supplies before birth. There appears to be no correlation between breastfeeding and THI.
Researchers estimate that THI affects about 1 out of 10,000 children. However, this number may be higher because some children experience few or no symptoms, and they might not be diagnosed.
Symptoms of THI vary. Some children may experience few or no symptoms while others may experience recurrent infections. In general, children who have THI suffer from milder infections that are caused by more typical bacteria and viruses than children with more severe immune deficiencies. Common symptoms of THI include recurrent ear infections or non-infectious inflammation of the middle ear, recurrent bronchitis, frequent sinusitis (infection or inflammation of the sinuses), bacterial infection (like pneumonia), infections of the skin, and meningitis (infection of the membranes that cover the spinal cord and brain).
Diagnosis: THI is usually suspected if a child experiences recurrent infections past the age of six months. A blood test can indicate low levels of antibodies in the bloodstream. However, this is a nonspecific diagnostic test because many other immune disorders cause low levels of antibodies. A definitive diagnosis can only be made once the condition has resolved on its own.
Treatment: THI will resolve on its own, without treatment. However, THI patients have an increased risk of developing infections and may need antibiotic treatment. Intravenous immune globulin (IVIG) therapy is controversial, but may be beneficial in some patients. IVIG is made of antibodies extracted from pooled blood donations from hundreds to thousands of donors. A qualified healthcare provider should closely monitor the patient's antibody levels several times a year to check for improvement, and to ensure that a more serious immunodeficiency disorder is not present.
Most children require antibiotics like amoxacillin (Amoxil®, Amoxil® Pediatric Drops, or Trimox® Pediatric Drops) or cefuroxime (Ceftin® or Zinacef®) to treat bacterial infections associated with THI.
There is still debate over whether IVIG therapy is helpful for THI patients because it delays the child's normal antibody formation. There is also the risk of allergic reaction to the therapy. Therefore, IVIG may be more beneficial in patients with severe infections who are not responding to antibiotics. Patients should consult their qualified healthcare providers to evaluate the risks and benefits.
Children with THI are given routine immunizations. In general, most children with THI respond normally to vaccines.
Overview: X-linked agammaglobulinemia is an inherited immunodeficiency that occurs when patients have low levels of all types of immunoglobulin (IgA, IgD, IgE, IgG and IgM) in the blood. Immunoglobulins are antibodies that help the body fight against disease and infection.
The disease is inherited as an X-linked recessive trait. This means the mutated gene that causes the disorder is located on the X chromosome. Since males only have one X chromosome, the disorder affects males almost exclusively. If a male inherits the mutated gene, he will develop the disease 100% of the time. Females, on the other hand, have two X chromosomes. Females need to inherit two mutated X chromosomes in order to develop the disease. If a female inherits the mutated gene, chances are the other gene will be healthy because the disease is not common. However, if the female inherits one mutated gene, she is a carrier for the disease and there is a 50% chance that she will pass the gene to each of her children.
The mutated gene prevents the B-cells from developing into mature cells. Mature B-cells play an important role in the immune response because they produce antibodies. Consequently, patients with agammaglobulinemia have decreased levels of all types of antibodies in their blood.
Symptoms: Symptoms of X-linked agammaglobulinemia may include frequent pus-producing infections, ear infections, lung infections, sinus infections, pneumonia, missing tonsils, missing adenoids, and delayed growth.
Diagnosis: A diagnosis of X-linked agammaglobulinemia can be made after low or absent levels of all antibodies are observed in the patient's blood. Patients typically have lower than 200mg/dL of IgG in the blood. IgA and IgM are almost undetectable.
Treatment: There is currently no cure for agammaglobulinemia. Treatment focuses on relieving symptoms and boosting the body's immune system to prevent future infections. Commonly prescribed antibiotics include amoxicillin (Trimox® or Biomox®), cefuroxime (Ceftin®, Kefurox®, or Zinacef®), amoxicillin (Amoxil®, Polymox®, or Trimox®), trimethoprim/sulfamethoxazole, also called TMP/SMX (Bactrim®, Cotrim®, or Septra), azithromycin (Zithromax®), clarithromycin (Biaxin®), erythromycin (Erythrocin® or Ery-Tab®), and amoxicillin and clavulanate (Augmentin®).
Intravenous immune globulin (IVIG) is often used to boost the body's immune system. IVIG is made of antibodies extracted from pooled blood donations from hundreds to thousands of donors. The immunoglobulin is typically injected into the patient's vein for about two to four hours a day for two to seven days. The patient usually receives another single dose every 10-21 days or every three to four weeks, depending on the severity of the condition. Treatment is typically administered every two to three weeks for life.