Primary Immune Deficiency
What is Primary Immune Deficiency?
Selective IgA Deficiency
Common Variable Immunodeficiency (CVI)
X-Linked Agammaglobulinemia (XLA)
Severe Combined Immunodeficiency (SCID)
Chronic Granulomatous Disease (CGD)
Interferon-Gamma Receptor (IFNGR) Deficiency
Hyper-IgE (HIE) Syndrome
Leukocyte Adhesion Deficiency (LAD
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 Defficiency
Approximately 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
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
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
frequent bacterial infections of the ears, sinuses,
bronchi, and lungs
painful swollen joints in the knee, ankle, elbow, or wrist
problems involving the digestive tract
an enlarged spleen and swollen glands or lymph
Along with other autoimmune problems, some
develop autoantibodies that attack their own blood
cells. People with CVI also have an increased risk of developing
How is CVI diagnosed?
To diagnose CVI, doctors look for
below-normal levels of IgG and IgA
zero-to-slightly-low levels of IgG
low-to-normal IgM levels
whether B cells produce antibodies following a common
vaccination like a tetanus shot
how well the T cells are working
gastrointestinal infections if there are digestive symptoms
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)
One out of 100,000 people have XLA. Genetic alterations on
the X chromosome cause XLA. Boys get XLA if they inherit an X
chromosome that contains the alteration. Girls, on the other
hand, are protected by having two sets of X chromosomes
because one healthy chromosome can override the malfunctioning
XLA is also called
- Bruton type agammaglobulinemia
- X-linked infantile agammaglobulinemia
- congenital agammaglobulinemia
What causes XLA?
Mutations in a gene found on the X
chromosome cause XLA. This gene normally produces a protein
that B cells need to mature.
What are the signs and symptoms of
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. They tend to
cope well with most short-term viral infections, but are very
susceptible to chronic viral infections such as
hepatitis, polio, and ECHO viruses.
They may fail to grow to normal height or to gain weight.
Their tonsils and adenoids are often missing.
X-linked recessive diseases are caused by genes
located on the X chromosome. Although we have two copies
of most genes, men have only one X chromosome and only
one copy of genes on that X chromosome. If a man
inherits a diseases-causing gene mutation that is on the
X chromosome, he has no backup normal X gene, and he
will likely develop the disease.
A woman will not usually develop an X-linked
recessive disease because she has two X chromosomes, but
she can be a "carrier." She remains healthy because the
normal gene on one X chromosome continues to function,
even though she carries the mutated gene, and can pass
it on to her children. With each and every pregnancy,
there is an equal chance that the baby will be a boy
with the disease, a healthy girl who is a carrier, a
healthy boy, or a healthy girl who is not a carrier.
For some X-linked recessive immunodeficiency
diseases, carriers can be identified by laboratory
tests. With others, a woman is discovered to be a
carrier only after she gives birth to a child with the
Adapted from chart in "Primary
Immunodeficiency" NIH Pub. No. 99-4149, June
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. They don't develop antibodies to specific germs (as
seen after immunizations, for instance).
How is XLA treated
For the rest of their lives, people with XLA must have
their antibodies replaced through monthly injections of
intravenous immunoglobulin (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 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
lack an enzyme called adenosine deaminase (ADA) or
lack the ability to produce interleukin (IL)-2 receptor gamma
chain, a molecule that T cells need to communicate
with B cells.
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
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
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
Swollen glands or lymph nodes
Enlarged liver and spleen
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
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
elevated erythrocyte sedimentation rate or ESR (a sign of
chronic infection or inflammation) They usually have normal antibody
levels. To confirm a CGD diagnosis, specialized laboratories perform
various tests of phagocyte function.
How is CGD treated?
Early diagnosis of CGD is critically important. The goal is to
prevent infections and their aftermath. Key issues to remember:
High doses of antibiotics over a long period of time help treat
Oral antibiotics, such as trimethoprim combined with
sulfamethoxazole, taken continuously help prevent infections.
Abscesses often must be drained surgically.
Granulomas ultimately go away with long-term antibiotic therapy.
Steroids reduce gastrointestinal and genitourinary tract
Anemia may require whole-blood transfusions.
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 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
What are the symptoms of hyper-IgM
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
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) Deficiency
This 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
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
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
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
Hyper-IgE (HIE) Syndrome
This 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
Asymmetry or uneven facial features
Broad nasal bridge
Wide, fleshy nasal tip
Protruding lower jaw
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
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
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
Severe infections of the soft tissue
Eroding skin sores without pus
Severe infections of the gums with tooth loss
Infections of the gastrointestinal tract
Wounds that heal slowly and may leave scars
There are at
least two forms of LAD
A severe form, called LAD type 1, which commonly causes death in
early infancy from infections
A more moderate form in which children may survive into young
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.
antibody - 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
antibiotics - Medicines used to treat some
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
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
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
immunization - the process of inducing
protection (immunity) against the destructive forces of a
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
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
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.
- DHHS, NIH, NIAID, Division of Allergy, Immunology and
Transplantation, "Immunosuppression and Vaccination: Populations
at Risk." Slide based on estimates from the U.S. Centers for
Disease Control and Prevention, NIH, and the United Network for
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