Causes and Risk Factors of Common Variable Immunodeficiency

Common variable immunodeficiency (CVID) is a disorder that affects the immune system and makes it harder for the body to fight off infections. It is likely caused by both environmental and genetic factors. Because it is a heterogenous (diverse) disorder, there are different causes in each person.

For the vast majority of CVID cases, the exact cause remains unknown. However, genetic mutations explain about 10%–20% of cases. In genetic cases, there is usually a mutation in one or more of the genes that influence the immune system.

Learn more about the causes and risk factors of common variable immunodeficiency.

Common Causes

Everyone with CVID has lower than normal antibodies, which are proteins produced by the immune system that fight off infections.

However, the reason why these antibodies are low may differ from person to person. CVID has different causes in different people. Most people with CVID will never know what caused their condition.

There is much research still to be done on the causes of CVID, but researchers state that genetic, environmental, and epigenetic (gene-related) factors all contribute to this disorder.

Genetic

Research on the causes of CVID largely focuses on genetics. Over 20 different genes are now associated with CVID. It is likely that there are many more genetic mutations associated with CVID that just haven't been discovered yet.

Currently, under 20% of CVID cases have a known underlying genetic cause.

Environmental

Since genetics explains only a minority of CVID cases, experts in the field believe that environmental factors play a role in whether a person will develop CVID. However, there has not been much research to date on what exactly these environmental causes might be.

One study published in 2019 found that bacteria in the gut is altered and less diverse among people with CVID. The researchers theorized that this lack of bacterial diversity in the gut could be a driver for CVID. There is currently not enough research to make any conclusions, but this theory is being actively researched.

Epigenetic

Epigenetics is the study of the impact of environment and behavior on gene functioning and expression. Epigenetics may play a role in whether a person develops CVID.

This is also an actively researched area, as researchers theorize that epigenetics could be the link between genetic and environmental factors that cause CVID.

Genetics

Certain genetic mutations can lead to a person developing CVID. This is usually due to a mutation in genes that are involved in the production or functioning of B cells.

B cells are a type of white blood cell that produce antibodies. Without properly functioning B cells, a person may not produce adequate numbers of antibodies and will, therefore, be susceptible to infections.

There are many different genetic mutations that have been associated with CVID. Some of these are inherited and are even unique within individual families. In other cases, genetic mutation is sporadic, not present in previous generations, or unexplained entirely.

Genetic mutations associated with CVID have been observed in multiple ways, including:

• Monogenic: One single gene either directly causing or being associated with CVID
• Digenic: The presence and interaction of two genes either directly causing or being associated with CVID
• Oligogenic: Many different genes interacting in a complex manner and either directly causing or being associated with CVID

Not all genetic mutations directly cause CVID. Some genetic mutations associated with CVID have been found in healthy individuals who have normal levels of antibodies and no signs of CVID. It's believed that certain environmental factors, as yet unidentified, interact with these genetic mutations to cause CVID.

Genetic Mutations Associated with CVID

The following monogenic (single gene) mutations are associated with CVID:

• TNFRSF13B: This is the most common genetic mutation associated with CVID. Approximately 8% of people with CVID have mutations in this gene. However it can also be found in healthy individuals so is not considered a direct cause of CVID. This gene produces a protein that helps B cells mature. Mutation can lead to immature B cells and, therefore, not enough antibodies to fight off infections.
• NFKB1: This is the second most common genetic mutation associated with CVID. This mutation interferes progressively over time with the body's ability to produce B cells. One study found that mutations in this gene accounted for 4% of CVID diagnoses in its participants. This gene is autosomal dominant, meaning a person only needs one copy. However, as with TNFRSF13B, not everyone with this mutation will develop CVID.

Other genetic mutations associated with CVID include:

• NFKB2
• CLTA4
• PI3KCD
• IKZF1
• STAT3
• LRBA
• CD19
• CD81
• ICOS CD20
• CD21
• TNFRSF13C

Risk Factors

Family history of immunodeficiency is the only known risk factor for CVID. Some people with CVID may inherit causal genes from their parents, although the majority of cases develop these mutations randomly.

Inheritance occurs in one of the following two ways:

• Autosomal dominant inheritance: One copy of the mutated gene is passed on from parent to child and is enough to cause CVID.
• Autosomal recessive inheritance: Each parent carries and passes on one copy of the mutated gene. The parents usually will not show signs of CVID themselves.

TNFRSF13B gene mutations can be either autosomal dominant or recessive.

An equal number of men and women have CVID, meaning that sex is not a risk factor.

A Word From Verywell

Researchers are still trying to understand both the genetic and environmental causes of CVID. Unfortunately, most people with CVID may never know what caused their condition. As it's currently understood, CVID is a heterogenous disorder. People share the commonality of low antibodies and frequent infections, but they may differ in many other ways, including the precise genetic mutations that lead to their condition.