What Causes Primary Immunodeficiency? 7 Inherited Factors That May Raise the Risk

Primary immunodeficiency (PI), also called inborn errors of immunity (IEI), is a group of more than 550 genetic disorders that affect how the immune system works, making it harder for the body to fight infections.

In most cases, PI is caused by a genetic mutation (change) that you inherit from your parents, but it can also occur with no family history due to de novo (new) mutations. Also, having parents who are blood relatives (consanguinity) increases the risk of some types of PI.

Understanding the genetic causes of PI can help you make sense of your diagnosis and what it might mean for you and your family.

How Is Primary Immunodeficiency Inherited?

PI is caused by a genetic mutation (a permanent change in your DNA) that affects how the immune system functions. As mentioned above, these genetic changes may be passed down from the person’s biological parents or happen spontaneously in the person as de novo mutations.

Every person has 23 pairs of chromosomes, for a total of 46. This means they have two copies of most genes — one from each parent.

Whether you develop a genetic condition depends on:

• Which gene is affected
• How many copies are mutated
• Where the mutation is located

Mutations can be on a sex chromosome (X or Y) or on one of the other 22 pairs of chromosomes (autosomes).

There are three main ways that PI can be inherited, including:

• Autosomal recessive
• Autosomal dominant
• X-linked recessive inheritance

Some conditions are caused by several different mutations. That means that in some cases, one type of PI can be inherited in different ways.

Autosomal Recessive Inheritance

In autosomal recessive inheritance, you inherit two copies of the PI-causing genetic variant — one from each parent. Usually, the parents are unaffected because they have one copy of a functional gene.

Because of this, people with PI inherited this way often have no family history of PI. While autosomal recessive PIs are rare, they are more common in families or populations with consanguinity.

Autosomal Dominant Inheritance

In autosomal dominant inheritance, only one copy of a PI-causing gene is needed to cause the disease. This means that you can inherit PI from just one parent. Forms of PI with this type of inheritance are equally common in males and females, according to the Immune Deficiency Foundation.

In some cases, a gene can mutate spontaneously. When this happens, the person with PI may be the first in their family to have this condition. Although they didn’t inherit PI from their parents, they can pass the disease on to future children.

X-Linked Recessive Inheritance

In X-linked recessive inheritance, the gene that causes PI is on the X chromosome. Most males have one X and one Y chromosome, and most females have two X chromosomes. However, some people have different chromosome combinations due to genetic conditions or other biological differences.

Since males generally have only one X chromosome, they’ll be affected by the disorder if their X chromosome has PI-causing mutations. Females who have one X chromosome with the PI-causing gene usually don’t develop symptoms because the other unaffected X chromosome makes up for it. However, they can still pass the condition on to their children (this is known as being a carrier).

Inherited Factors That Cause PI

Different forms of PI used to be classified based on how they were inherited and what sort of symptoms they caused. But now, thanks to genetic testing, doctors can often find the exact PI-causing gene. We’ll explore some of the most common types of inherited genetic mutations linked to PI.

Antibodies are immune proteins made by B cells — a type of white blood cell that helps protect your body from infections. In some cases, a genetic mutation stops B cells from developing properly and being able to make antibodies.

One example of this is common variable immunodeficiency (CVID), a condition that makes it hard for the body to produce enough antibodies to fight infections. Often, no single genetic cause is found, but some people have certain genetic changes linked to CVID-like disease, which can be revealed through genetic testing.

Another example is X-linked agammaglobulinemia (XLA). In XLA, a mutation in the Bruton’s tyrosine kinase (BTK) gene prevents B-cell precursors from maturing into functional B cells that can make antibodies. As a result, people with XLA have very low levels of antibodies — or no antibodies at all — and are more likely to get severe infections.

The BTK mutation is passed down in an X-linked recessive inheritance pattern and is more common in males. Females with the same genetic mutation usually don’t have any symptoms, but they can be carriers and pass it down to their children.

There are several other gene variants that affect B-cell development and can lead to a similar condition.

T cells help fight infection. They destroy harmful germs and send signals to organize an immune response. Some types of PI are caused by mutations that interfere with T-cell development or function, resulting in T-cell deficiency.

For example, in DiGeorge syndrome, a portion of chromosome 22 is missing. Specifically, there’s a 22q11.2 deletion that can vary in size. The size of the deletion determines how severely the immune system is impacted.

People with DiGeorge syndrome have a missing or underdeveloped thymus. Problems with the thymus affect the body’s ability to make functional T cells.

Some types of PI involve mutations that disrupt the development of B cells and T cells.

For example, the most common gene mutation that causes severe combined immunodeficiency (SCID) is on the interleukin-2 receptor gamma (IL-2RG) gene. This gene provides instructions to make a protein called the common gamma chain.

Without a functioning gamma chain, T cells and natural killer (NK) cells can’t develop properly, and B cells can’t function. As a result, the immune system is severely impaired.

Since the IL-2RG gene is on the X chromosome, this type of SCID usually affects males because it is passed down in an X-linked inheritance pattern.

However, other types of SCID can be caused by genetic mutations on autosomes (nonsex chromosomes). These types are just as common in males and females. For example, a mutation in the gene that codes for the adenosine deaminase (ADA) protein (a protein that helps prevent toxic byproduct buildup) causes a buildup of harmful substances in B, T, and NK cells, causing them to die.

Although SCID can be caused by different genetic mutations, all forms result in a severe, life-threatening form of PI.

Phagocytes are immune cells that surround and kill germs, remove dead cells, and ingest foreign material. Certain genetic mutations can make phagocytes less effective.

For example, in chronic granulomatous disease (CGD), a genetic mutation makes neutrophils (a type of phagocyte) unable to make the chemicals they use to kill bacteria and fungi. Without these chemicals, infections can start more easily.

People can inherit CGD through an X-linked pattern or through autosomal recessive mutations.

The complement system is a group of proteins in the blood and tissue that help the immune system fight infection. Genetic changes that affect complement proteins can cause complement deficiencies.

As a result, people may have repeated infections and autoimmune disorders, like lupus. Complement deficiencies can be inherited, and they often run in families.

Immune regulation is the body’s way of balancing the immune system. It should be strong enough to fight infections, but controlled enough to avoid attacking your own healthy tissue.

In enteropathy X-linked (IPEX) syndrome, a genetic mutation affects the controls that normally pump the brakes on the immune system. As a result, the immune system can attack healthy tissues in the body, especially in the gut, skin, and hormone-producing organs. Because IPEX is due to a mutation on the X chromosome, males are more likely to be affected, while females can pass on the genetic mutation to their children.

Mutations that disrupt how immune cells communicate can affect how well the immune system works.

In Wiskott-Aldrich syndrome (WAS), a mutation in the WAS gene affects the signaling that tells white blood cells to attach to foreign invaders and thereby fight off infections. People with WAS may have normal levels of white blood cells, but they don’t work well. WAS is inherited in an X-linked pattern.

In hyper IgE syndrome, a mutation in the STAT3 gene disrupts the maturation of several types of immune cells. Without the STAT3 protein, other genes aren’t turned on and off as needed in the process of immune cells maturing. Hyper IgE syndrome is passed down in an autosomal dominant inheritance pattern.

Talk to Your Healthcare Team

If you or a loved one has been diagnosed with PI, talk with your healthcare team about the possible causes. They can guide you through genetic testing options to help identify the exact genes responsible for PI. A genetic counselor can then help you and your family understand what the results mean.

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