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

Primary immunodeficiency (PI) is a group of more than 500 genetic disorders that affect how the immune system works. In most cases, PI is caused by a genetic mutation (change) that you inherit from your parents. These genetic mutations make it harder for the body to fight infections.

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The only known risk for PI is a family history of the disease. Understanding the genetic causes of PI can help you make sense of your diagnosis and what it might mean for you and your family’s health.

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. Most people who have these genetic changes inherit them from their biological parents.

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, and whether the mutation is 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 — autosomal recessive, autosomal dominant, and X-linked recessive inheritance. Some conditions are caused by several different genes. 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.

Types of PI with autosomal recessive inheritance are very rare. However, these conditions are more common in families where parents are closely related.

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.

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. Males have one X and one Y chromosome, while females have two X chromosomes. Since males only have one X chromosome, they’re more likely to be affected. Females who have one X chromosome with the PI-causing gene usually don’t develop symptoms, but 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.

1. Mutations That Affect Antibody Production

Antibodies are immune proteins made by B cells — a type of white blood cell that helps protect your body from infections. When a genetic mutation affects the production of antibodies, the immune system can’t work properly against bacteria and viruses.

In some cases, a genetic mutation stops B cells from developing properly. 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. However, the exact genetic cause of CVID is unknown.

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 gene is found on the X chromosome. This means that the BTK mutation is passed down in an X-linked recessive inheritance pattern and is more common in males. Although females with the same genetic mutation usually don’t have any symptoms, they can be carriers and pass it down to their children.

Not everyone with low or absent antibody levels has a BTK mutation. Several other gene variants that affect B cell development can lead to a similar condition.

2. Mutations That Affect T Cells

T cells help fight infection by destroying harmful germs and sending 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 large portion of chromosome 22 is missing, resulting in a missing or underdeveloped thymus. The thymus is part of the immune system where T cells mature. Without a functioning thymus, the body can’t make functional T cells to mount an effective immune response.

3. Mutations That Affect Both B and 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 (IL2RG) gene. This gene gives instructions for making a protein called the common gamma chain. This protein is a key part of several receptors that help immune cells grow and function. Without a functioning gamma chain, T cells and natural killer (NK) cells can’t develop properly, and B cells can’t function.

Since the IL2RG gene is on the X chromosome, this type of SCID is passed down in an X-linked inheritance pattern. It usually affects males, because they have only one X chromosome. Females have two X chromosomes, so one healthy copy can often protect them.

However, other types of SCID can be caused by genetic mutations on autosomes (nonsex chromosomes) and are just as common in males and females. For example, a mutation in the gene that codes for the adenosine deaminase (ADA) protein 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 form of PI.

4. Mutations That Disrupt Phagocytes

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.

5. Mutations in the Complement System

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. This results in increased recurrent infections and autoimmune disorders, like lupus. Complement deficiencies can be inherited, and they often run in families.

6. Genetic Defects That Impair Immune Regulation

Immune regulation is the body’s way of keeping the immune system strong enough to fight infections, but controlled enough to avoid attacking your own healthy tissue. In immune dysregulation, polyendocrinopathy, enteropathy X-linked (IPEX) syndrome, there’s a genetic mutation that 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.

7. Mutations Linked to Immune Cell Communication and Signaling

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 makes it harder for white blood cells to respond to the environment and mount an immune attack against foreign invaders. Although people with WAS may have normal white blood cell counts, the immune cells don’t work as 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. The STAT3 gene isn’t involved directly in the process of immune cells maturing. Instead, this gene regulates other genes responsible for this process. 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. Genetic counseling can help you and your family understand what the results mean for you and your family.

Talk With Others Who Understand

On myPIteam, people come together to learn more about life with primary immunodeficiency disorders.

Have you or a loved one been diagnosed with primary immunodeficiency? Have you had genetic testing for PI? Share your experience in the comments below.