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
Source: NIAID
March 2001
Primary Immune Deficiency
Overview
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 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 Deficiency
Approximately 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 Syndrome
Hyper-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 DevelopmentPublic Information and
Communications Branch
31 Center Drive, Room 2A32
Bethesda,
MD 20892-2425
301-496-5133
http://www.nichd.nih.gov/American
Academy of Allergy,
Asthma, and Immunology611 E.
Wells Street
Milwaukee, WI 53202
414-272-6071
http://www.aaaai.org/Immune
Deficiency Foundation40 W. Chesapeake Avenue, Suite
308
Towson, MD 21204
1-800-296-4433
http://www.primaryimmune.org/The
Jeffrey Modell Foundation747 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, tuberculosis, malaria, autoimmune disorders, asthma and
allergies. NIH is an agency of the U.S. Department of Health and
Human Services.
Prepared by:
Office of Communications
and Public Liaison
National Institute of Allergy and Infectious
Diseases
National Institutes of Health
Bethesda, MD 20892
Public Health Service
U.S. Department of Health and
Human Services
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