Your immune system helps your body fight infections. People with primary immunodeficiency (PI) have an immune system that does not work correctly. This means that people with PI are more likely to get and become very sick from infections.

There are more than 400 types of PI that vary in severity, which affects how early they are detected. In some cases, a person with a mild form may not find out that they have PI until adulthood. In other cases, the disorder causes problems in infancy and is found soon after birth. All states include testing for one type of PI called severe combined immunodeficiency (SCID) as part of newborn screening. Treatments can help the immune system work better. Which treatment works best depends on the type of PI a person has.

There are more than 200 different forms of primary immune deficiency diseases (PIDDs). NIAID conducts research across all primary immune deficiency diseases, as well as the individual disease that make up this broad category. The following are the individual PIDDs NIAID is currently studying.

Autoimmune Lymphoproliferative Syndrome (ALPS)

Autoimmune lymphoproliferative syndrome (ALPS) is a rare immune disorder first described by NIH scientists in the mid-1990s that can cause numerous autoimmune problems, such as low levels of red blood cells, clot-forming platelets, and infection-fighting white blood cells. These problems can increase the risk of infection and hemorrhage.

APS-1 (APECED)

Autoimmune polyglandular syndrome type 1 (APS-1) causes a diverse range of symptoms, including autoimmunity against different types of organs and increased susceptibility to candidiasis, a fungal infection caused by Candida yeast. The disease also is called APECED.

BENTA Disease

BENTA disease is a rare genetic disorder of the immune system caused by mutations in the gene CARD11. The disease is characterized by high levels of certain immune cells starting in infancy, an enlarged spleen, enlarged lymph nodes, immunodeficiency, and an elevated risk of a type of cancer called lymphoma.

Caspase Eight Deficiency State (CEDS)

Caspase eight deficiency state, or CEDS, is a very rare genetic disorder of the immune system caused by mutations in the CASP8 gene. CEDS is characterized by an enlarged spleen and lymph nodes, recurrent sinus and lung infections, recurrent viral infections, and a low level of infection-fighting antibodies. NIH researchers first described this condition in two siblings in 2002.

CARD9 Deficiency and other Syndromes of Susceptibility to Candidiasis

CARD9 deficiency results in susceptibility to fungal infections like candidiasis, which is caused by the yeast fungus Candida. Typically, Candida and other fungi are present on the skin and do not cause severe problems in healthy people.

Chronic Granulomatous Disease (CGD)

CGD occurs when white blood cells called phagocytes are unable to kill certain bacteria and fungi, and mutations in one of five different genes may cause this disease. People with CGD have increased susceptibility to infections.

Common Variable Immunodeficiency (CVID)

CVID is caused by a variety of different genetic abnormalities that result in a defect in the capability of immune cells to produce normal amounts of antibodies. People with CVID experience frequent bacterial or viral infections of the upper airway, sinuses, and lungs.

Congenital Neutropenia Syndromes

Congenital neutropenia syndromes are a group of disorders present from birth that are characterized by low levels of neutrophils, a type of white blood cell necessary for fighting infections.

CTLA4 Deficiency

CTLA4 deficiency is a rare disorder that severely impairs the normal regulation of the immune system, resulting in conditions such as intestinal disease, respiratory infections, autoimmune problems, and enlarged lymph nodes, liver and spleen. NIAID scientists and their collaborators identified the disease in 2014.

DOCK8 Deficiency

DOCK8 immunodeficiency syndrome is a rare immune disorder named after the mutated gene responsible for the disease. The disorder causes dysfunction and decreased numbers of immune cells, as well as poor ability of immune cells to move across dense tissues like the skin. These abnormalities resulting from DOCK8 defects lead to recurrent viral infections of the skin and respiratory system.

GATA2 Deficiency

GATA2 deficiency is a rare disorder of the immune system with wide-ranging effects. First identified in 2011, the disorder is characterized by immunodeficiency, lung disease, problems of the vascular/lymphatic system, and myelodysplastic syndrome (a condition characterized by ineffective blood cell production). Early diagnosis is critical for optimal disease management, prevention of severe complications, treatment, and evaluation of at-risk relatives.

Glycosylation Disorders With Immunodeficiency

Glycosylation refers to the attachment of sugars to proteins, a normal process required for the healthy function of cells. Defects in glycosylation can disrupt the immune system, resulting in immunodeficiency and potentially causing extensive and severe symptoms.

Hyper-Immunoglobulin E Syndrome

People with autosomal dominant hyper-immunoglobulin E syndrome (HIES) have recurrent bacterial infections of the skin and lungs. Patients with HIES typically also have eczema, distinct facial features, and a tendency to experience bone fractures. The disease has several other names, including Job's syndrome, STAT3 deficiency, and Buckley syndrome.

Hyper-Immunoglobulin M (Hyper-IgM) Syndromes

Hyper-IgM syndromes are rare, inherited conditions in which the immune system fails to produce normal levels of the antibodies immunoglobulin A (IgA), IgG and IgE but can produce normal or elevated levels of IgM. Various gene defects that impair communication between T cells and antibody-producing B cells can lead to hyper-IgM syndromes. Hyper-IgM syndromes can cause severe respiratory infections in infancy and a higher risk of rare infections throughout life. Treatment includes regular intravenous or subcutaneous antibody replacement therapy, anti-fungal prophylactics, and in some cases, bone marrow transplant from a healthy donor.

Interferon Gamma, Interleukin 12, Interleukin 23 Deficiencies

Interferon gamma, interleukin 12, and interleukin 23 deficiencies are rare, inherited immune disorders in which the body fails to produce one or more of these signaling molecules, which allow infection-fighting immune cells to communicate. Deficiencies in these molecules lead to increased susceptibility to infections caused by bacteria and viruses. Many people with these deficiencies develop granulomas, or inflammatory lesions that form in tissues and organs because of recurring infections. While many of these deficiencies begin to cause symptoms in infancy or childhood, some cases are seen later in life. Treatment includes antibiotic therapy to prevent infections and, in some cases, bone marrow transplant from a healthy donor.

Leukocyte Adhesion Deficiency (LAD)

Leukocyte adhesion deficiency (LAD) is a rare, inherited immune disorder in which immune cells called phagocytes are unable to move to the site of an infection to fight off invading pathogens. People with LAD experience recurrent, life-threatening infections and poor wound healing. LAD is caused by a mutation in the gene ITGB2, which provides instructions for the phagocyte surface molecule CD18. Treatments for LAD include antibiotics to prevent and treat infection and, in some cases, bone marrow transplants from a healthy donor.

LRBA Deficiency

LRBA deficiency is a rare genetic disorder of the immune system caused by mutations in the LRBA gene. This disease impairs normal immune system functionality and results in autoimmunity, recurrent infections, and increased risk of lymphoma. Sometimes the excess lymphocytes enter and accumulate in organs where lymphocytes typically are not present in large numbers such as the gut, lungs and brain, which can cause a variety of symptoms.

PI3 Kinase Disease

PI3 Kinase disease is caused by genetic mutations that overactivate an important immune system signaling pathway. This causes a chain reaction of problems, disrupting the normal development of infection-fighting B and T cells. People with the disease have a weakened immune system and experience frequent bacterial and viral infections.

PLCG2-associated Antibody Deficiency and Immune Dysregulation (PLAID)

PLAID and PLAID-like diseases are rare immune disorders with overlapping features, and an allergic response to cold, called cold urticaria, is the most distinct symptom.

Severe Combined Immunodeficiency (SCID)

SCID is a group of rare, life-threatening disorders caused by mutations in different genes involved in the development and function of infection-fighting T and B cells. Infants with SCID appear healthy at birth but are highly susceptible to severe infections.

STAT3 Gain-of-Function Disease

STAT3 gain-of-function disease is a rare genetic disorder of the immune system caused by a malfunction in the STAT3 gene that leads overactive STAT3 proteins. Symptoms of this disease begin early in life and include swelling of the lymph nodes, low blood cell counts and autoimmunity that can affect multiple organs and tissues. People with STAT3 gain-of-function disease may experience recurrent infections, eczema and growth problems.

Warts, Hypogammaglobulinemia, Infections, and Myelokathexis Syndrome (WHIMS)

People with WHIM syndrome have low levels of infection-fighting white blood cells, especially neutrophils, in their bloodstreams​. This deficiency predisposes them to frequent infections and persistent warts.

Wiskott-Aldrich Syndrome (WAS)

Wiskott-Aldrich syndrome (WAS) is a rare genetic disorder of the immune system that primarily affects boys. WAS is an X-linked recessive disease caused by mutations in the WAS gene, which provides instructions for production of Wiskott-Aldrich Syndrome Protein. It is characterized by abnormal immune function and a reduced ability to form blood clots. This can result in prolonged episodes of bleeding, recurrent bacterial and fungal infections, and increased risk of cancers and autoimmune diseases.

X-Linked Agammaglobulinemia (XLA)

XLA is caused by an inability to produce B cells or immunoglobulins (antibodies), which are made by B cells. People with XLA develop frequent infections of the ears, throat, lungs, and sinuses.

X-Linked Lymphoproliferative Disease (XLP)

XLP primarily affects boys and is characterized by a life-long vulnerability to Epstein-Barr virus (EBV), a common type of herpesvirus. Boys with XLP are healthy until they are exposed to EBV. Then, they can become seriously ill and experience swollen lymph nodes, an enlarged liver and spleen, hepatitis, and lymphoma, a type of cancer.

XMEN Disease

XMEN disease is a rare genetic disorder of the immune system. XMEN stands for “X-linked immuno-deficiency with magnesium defect, Epstein-Barr virus (EBV) infection, and neoplasia.” It is characterized by low levels of infection-fighting CD4+ cells, chronic EBV infection, and EBV-related lymphoproliferative disease, in which excessive numbers of immune cells are produced. Investigators at the National Institutes of Health first described XMEN disease in 2011.

Congenital neutropenia syndromes are a group of rare disorders present from birth that are characterized by low levels of neutrophils, a type of white blood cell necessary for fighting infections. NIAID supports basic scientific research on the immune system and the nature and development of neutrophils, which may lead to insights for addressing congenital neutropenia syndromes. Congenital neutropenia syndromes are primary immune deficiency diseases (PIDD).

Congenital neutropenia syndromes may also be called congenital agranulocytosis, severe congenital neutropenia, severe infantile genetic neutropenia, infantile genetic agranulocytosis, or Kostmann disease.

Researchers have identified numerous genetic mutations that cause congenital neutropenia syndromes. Generally, mutations that result in congenital neutropenia affect the development, lifespan, or function of neutrophils.

Congenital neutropenia syndromes are inherited through autosomal recessive, autosomal dominant, and X-linked inheritance patterns. The genes linked to these syndromes include the following:

• ELANE
• HAX1
• G6PC3
• GFI1
• CSF3R
• X-linked WAS
• CXCR4
• VPS45A
• JAGN1

In some people, however, the disease-causing mutation of their congenital neutropenia syndrome is unknown.

People with congenital neutropenia experience bacterial infections early in life. These may cause inflammation of the umbilical cord stump, abscesses (or boils) on the skin, oral infections, and pneumonia.

Congenital neutropenia also increases one’s risk for developing myelodysplastic syndromes (MDS), blood disorders that are distinguished by low levels of various blood cells. MDS may progress to a type of blood-cell cancer called acute myeloid leukemia.

Bone marrow and blood tests can measure the levels of various white blood cells to test for deficiencies. A person suspected of having congenital neutropenia also may undergo genetic testing for one of the genetic mutations known to cause the syndromes.

Standard therapy for congenital neutropenia includes injections of granulocyte colony-stimulating factor (G-CSF), an immune-cell-growth molecule that can help restore the function of the immune system. People on G-CSF therapy may have a lower incidence and severity of infections, improving their quality of life, but effects vary. For some individuals, a bone-marrow transplant may be recommended to replace defective immune cells with healthy ones from a donor.

Glycosylation refers to the attachment of sugars to proteins, a normal process required for the healthy function of cells. Defects in glycosylation can impair the growth or function of cells and tissues in the body. In some cases, these impairments disrupt the immune system, resulting in immunodeficiency.

NIAID scientists research genetic causes for glycosylation disorders with immunodeficiency, a set of rare diseases, and investigate the role that glycosylation plays in bacterial and viral infection. This research can benefit people affected by these disorders and build upon scientific knowledge of pathogens.

Glycosylation disorders with immunodeficiency are primary immune deficiency diseases (PIDDs).

Interestingly, glycosylation defects also may protect people against microbes that rely on glycosylation for growth and infection. In 2014, NIH researchers identified two cases in which defective glycosylation protected people against specific viral infections.

Researchers have not yet discovered the cause of many forms of glycosylation disorders with immunodeficiency. However, in 2014, NIH scientists discovered a new immunodeficiency caused by glycosylation defects. People with this disorder have mutations in the PGM3 gene, resulting in defective sugar metabolism that leads to problems with glycosylation, especially in immune cells. These findings suggest that glycosylation defects may also be involved in common immune disorders such as allergy or autoimmunity.

Glycosylation can impact how cells communicate, respond to their environment, grow, and function. Because glycosylation regulates a wide range of activities in cells throughout the body, defects in glycosylation can cause extensive and severe symptoms. People with PGM3 gene mutations that cause some cases of glycosylation disorders may experience the following symptoms:

• Susceptibility to bacterial and viral infections
• Allergies, including food allergy
• Asthma
• Eczema
• Autoimmunity
• Developmental delays, including motor and cognitive impairments

If a clinician suspects a patient may have a glycosylation defect, protein samples may be analyzed to measure sugars and look for deficiencies or abnormalities.

People who have glycosylation disorders with immunodeficiency may receive therapies commonly used to treat infections, allergies, and skin problems. For people with PGM3 defects, NIH researchers are evaluating ways to boost the production of the missing sugars by supplementing with other types of sugar. Based on insights gleaned from the study of glycosylation disorders, investigators at NIH are also exploring the use of glycosylation inhibitors to prevent and control viral infections.

Many different syndromes are known to lead to high levels of an antibody called immunoglobulin E, or IgE. Many more such syndromes likely remain unknown. Collectively, these conditions are called hyper-IgE syndromes, or HIES. Other conditions, such as severe eczema, can lead to extremely high IgE levels that are not caused by a syndrome at all.

To determine whether a person with a high level of IgE has a known syndrome causing it, physicians assess the individual’s other symptoms and search for the causative genetic mutation. Each set of mutations causes a specific syndrome, including autosomal-dominant CARD11 deficiency, DOCK8 deficiency, IL6R deficiency, IL6ST deficiency,PGM3 deficiency, STAT3 dominant-negative disease and many others.

Autosomal-Dominant CARD11 Deficiency

In 2017, NIH researchers showed that autosomal dominant mutations in a gene called CARD11 could lead to a loss of function of the CARD11 protein, impairing it from helping activate white blood cells normally. People with autosomal-dominant CARD11 deficiency can develop severe allergic disease, including eczema and food allergies; viral and bacterial infections of the skin; respiratory tract infections; and autoimmunity.

DOCK8 Deficiency

DOCK8 deficiency is an autosomal recessive syndrome associated with high IgE and is named for the mutated gene responsible for the disease. People with this syndrome have lower-than-normal numbers of immune cells, which have a diminished capacity to move through dense tissues like the skin. These abnormalities lead to recurrent viral infections of the skin and respiratory system. People with DOCK8 deficiency also typically have severe allergies, asthma, and an elevated risk for some types of cancer. Read more about this syndrome.

IL-6 Receptor Deficiency

IL-6 receptor (IL6R) deficiency is an autosomal recessive syndrome caused by the absence of the IL-6 receptor, a critical molecule located on the surface of cells and involved in inflammatory responses. The absence of this receptor leads to severe skin infections and rashes, respiratory tract infections, and high levels of IgE. NIAID investigators identified IL6R deficiency in 2019. Their ongoing research may help improve scientists’ understanding of drugs that inhibit the IL-6 receptor, which are often used to treat inflammatory diseases.

IL6ST Deficiency

IL6ST deficiency is an autosomal recessive syndrome caused by mutations in the IL6ST gene that lead to infections, high IgE levels, and bone and joint abnormalities similar to those seen in STAT3 dominant-negative disease. The syndrome is also characterized by neurodevelopmental abnormalities. NIAID researchers helped identify this disorder in 2017 and continue to study it.

PGM3 Deficiency

PGM3 deficiency is caused by autosomal recessive mutations in the gene that codes for PGM3, a protein responsible for glycosylation, which is a critical process that adds sugar molecules to proteins throughout the body. PGM3 deficiency can lead to recurrent bacterial and viral infections, autoimmunity, inflammation, severe allergic disease, developmental delays, and skeletal abnormalities. NIH researchers identified the cause of PGM3 deficiency in 2014 and continue to study the disease.

STAT3 Dominant-Negative Disease

STAT3 dominant-negative disease (STAT3DN)—also known as autosomal dominant hyper-IgE syndrome (AD-HIES) or Job’s Syndrome—results from mutations in the gene that encodes a signaling protein called STAT3. This protein is involved in many different activities of the body, explaining why STAT3DN affects not only the immune system but also facial appearance, bones, lungs, skin, and arteries. NIAID investigators identified the role of STAT3 in this disease in 2007. Read more about this syndrome.

PIDDs are caused by genetic abnormalities that prevent the body from developing normal immune responses.

All of the body’s cells contain instructions on how to do their jobs. These instructions are packaged into 23 pairs of chromosomes—22 pairs of numbered chromosomes, called autosomes, and one pair of sex chromosomes (XX for girls and XY for boys). One chromosome in each pair is inherited from the person’s mother and the other from the father. Each chromosome contains many genes, which are made up of DNA, the carrier of genetic information. Errors, or mutations, in genes can cause diseases such as PIDDs.

Genetic mutations sometimes appear randomly. For example, de novo, or “new,” mutations occur as a result of a mutation in the egg or sperm of one of the parents or in the fertilized egg itself. In these cases, the affected person does not have a family history of disease.

Most often, genetic mutations run in families. Several types of inherited mutations can cause PIDDs.

Autosomal Dominant

To develop an autosomal dominant disease, a person needs an abnormal gene from only one parent, even if the matching gene from the other parent is normal. A parent with an autosomal dominant disease has a 50 percent chance of having a child with the condition. The chance of one child inheriting the mutation is independent of whether his or her siblings have the mutation. In other words, if the first two children in a family have the mutation, the third child still has a 50 percent chance of inheriting it.

In the example, a man with an autosomal dominant disorder has two affected children and two unaffected children.

Autosomal Recessive

Two copies of an abnormal gene—one from each parent—must be present for an autosomal recessive disease to develop. Typically, both parents of an affected child carry one abnormal gene and are unaffected by the disease because the normal gene on the other chromosome continues to function. In this case, each child has a 25 percent, or one in four, chance of being affected by the disease. Each child also has a 50 percent chance of inheriting one copy of the mutated gene. People who inherit one abnormal gene copy will not develop the disease, but they can pass the mutation on to their children.

In the example, two unaffected parents each carry one copy of a gene mutation for an autosomal recessive disorder. They have one affected child and three unaffected children, two of which carry one copy of the gene mutation.

X-Linked Recessive

X-linked recessive diseases are caused by genes located on the X chromosome. Boys have only one copy of X-linked genes because they have one X chromosome. If a boy inherits a disease-causing mutation in a gene located on the X chromosome, he will develop the disease.

Girls usually do not develop X-linked recessive diseases because they have two X chromosomes and would need to inherit two abnormal copies of the gene—one from each parent—to be affected by the disease. Even if a girl carries the mutated gene on one X chromosome, the normal gene on the other X chromosome continues to function and she remains unaffected by the disease. Women who inherit one abnormal gene copy can pass the mutated gene on to their children.

In the example, an unaffected woman carries one copy of a gene mutation for an X-linked recessive disorder. She has an affected son, an unaffected daughter who carries one copy of the mutation, and two unaffected children who do not have the mutation.

People with PI are more likely to have

• More frequent or repeated infections, such as
  • Ear infections
  • Sinus infections
  • Pneumonia
  • Bronchitis
  • Meningitis
  • Skin infections
  • Thrush (a fungal infection of the mouth or skin, also called candidiasis)
• Infections that last longer than in most people
• Infections that are hard to treat and do not respond to antibiotics or require IV antibiotics
• Infections that are more severe and require hospitalization, such as sepsis or abscesses (pus-filled infections) of internal organs
• Infections that most people don’t get (sometimes called opportunistic infections)
• Lack of weight gain or growth in an infant (failure to thrive)
• Digestive problems, such as chronic diarrhea

People with PI are more likely to have autoimmune disorders and certain blood disorders. Because your immune system protects your body against cancer, people with PI are more likely to have certain cancers. In some cases, PI is due to a genetic disorder that involves other health problems, such as 22q11.2 deletion syndrome (also called DiGeorge syndrome).

Talk to your doctor if you think that you or your child has signs of PI. Your doctor might refer you or your child to a clinical immunologist, a doctor who specializes in the immune system. You can use the American Academy of Allergy, Asthma, and Immunology’s Find an Allergist/Immunologist tool to find a doctor near you.

PI often has an underlying genetic cause and can run in families. Sharing your family history of PI with your doctor can be important for your and your children’s health or if you are pregnant or planning a pregnancy. If you or your child have been diagnosed with PI, be sure to share this information with your family members. Your doctor might refer you for genetic counseling and testing if you have been diagnosed with PI or have a family health history of PI.

Early diagnosis can help prevent or delay some of the health problems caused by PI. Left untreated, some types of PI can result in serious health problems, including organ damage, and even death. Even with treatment, most PI do not have a cure.

Taking steps to prevent infection is very important if you have PI. These steps include

• Washing your hands the right way
• Taking good care of your teeth
• Maintaining healthy habits, including being physically active, eating healthy, and getting enough sleep
• Avoiding exposure to people who are sick and crowds
• Asking your doctor which vaccinations are safe for you. In some cases, people with PI cannot have live vaccines such as rotavirus, chickenpox, oral polio, and measles, mumps, rubella. Newborn screening for SCID can find babies with this PI early, before they receive these vaccines.

Treatments vary, depending on the type of PI, and can include

• Antibiotics to prevent certain infections
• Treatments that help your immune system work better (including immunoglobulin replacement therapy and interferon-gamma therapy)
• Growth factors to help increase the number of white blood cells, which are part of the immune system
• Stem cell transplant to provide your body with working immune cells from another person (donor)
• Gene therapy to replace the gene that does not work correctly with one that does

We rely on our immune system to fight harmful bacteria or viruses—either on its own or with the help of antibiotics or antivirals—every day. Most of us recover quickly from infectious illnesses, and our immune system helps protect us from repeat infections in the future.

People with primary immune deficiency diseases (PIDDs), however, have defects in one or more parts of their immune system. They often cannot overcome infections, even with the aid of medicine.

Are you or your child at risk for a PIDD?

• Do you get multiple, serious infections that are difficult to treat within a year?
• Have you had bacterial infections that don’t get better, even after you’ve taken antibiotics?
• When you are sick, do you need to go to the hospital and/or receive intravenous antibiotics to get well?
• Do you have a family history of primary immune deficiency?

If you answered “yes” to any of these questions, you may be at risk for a PIDD. Consult with your doctor to get tested for an immune deficiency.

What to ask your doctor

• Based on my medical and family history, am I at risk for an immune deficiency?
• What tests will be performed to determine my diagnosis, and how long will it take to get the results back?
• What precautions should I take to reduce my risk of infection?
• Should I see a specialist?

To diagnose a potential immune deficiency, your doctor will need to take a blood sample and send it to a lab for an initial screening test. If that test shows that you may be at risk for a PIDD, you'll need additional testing.

What to bring to your doctor’s appointment

• A current list of medicines you have taken in the past and their effects
• Specific questions you want to have answered
• A journal to write down answers to your questions or to take notes