CTLA-4 haploinsufficiency (CTLA-4 insufficiency)

CTLA-4 haploinsufficiency is a disorder of immune regulation. It is also called CTLA-4 insufficiency, CTLA4 deficiency or CHAI, short for CTLA-4 haploinsufficiency with autoimmune infiltration. Scientists at the U.S. National Institutes of Health and their collaborators first described it in 2014.

CTLA-4 is a protein on the surface of T cells that works like a brake, keeping immune cells in check. Regulatory T cells, the white blood cells that tell the rest of the immune system to stand down, rely on it. “Haploinsufficiency” means that one working copy of a gene is not enough. With only one working copy, there is too little CTLA-4, and the immune system can run out of control.

The result can be two problems at once. The immune system may not fight germs well, and it may attack the body’s own tissues. Immune cells can also build up in organs where they do not belong.

CTLA-4 haploinsufficiency is caused by a change in one copy of the CTLA4 gene. It is inherited in an autosomal dominant way, so a parent who carries the change has a 50% chance of passing it to each child. The change can also appear for the first time in a child. In a worldwide study of 133 carriers, the change had arisen new in 7 affected people.

Not everyone who carries the change becomes ill. In the same study, at least 67% of carriers were affected. Some relatives have only mild signs, such as thyroid disease or vitiligo, while others become seriously ill, and illness can start as late as age 50. That is why relatives who carry the change are followed over time, even when they feel well.

Symptoms often start in childhood or the teen years. In the worldwide study, the median age at onset was 11, and three in four affected people had symptoms before age 18. Some people are not diagnosed until adulthood. The first problems can bring someone to almost any kind of specialist.

Common problems include low antibody levels, repeated ear, sinus and lung infections, and swollen lymph nodes and spleen. Autoimmune low blood counts, such as low platelets or red cells, are frequent and can be severe. Many people have long-lasting diarrhea from gut inflammation. Immune cells can also build up in the lungs, brain, bone marrow and kidneys.

The risk of some cancers is higher, especially lymphoma, a cancer of immune cells. Infections with Epstein-Barr virus (EBV) and cytomegalovirus (CMV) are watched closely, because they have been linked to some of these cancers.

Doctors think of it in a child or adult with repeated sinus and lung infections plus autoimmune problems, especially low blood counts. Other clues are long-lasting diarrhea, weight loss, a large spleen, swollen lymph nodes and immune cells crowding into organs. People are often first checked for inflammatory bowel disease, common variable immunodeficiency (CVID) or autoimmune lymphoproliferative syndrome (ALPS). Experts advise considering CTLA-4 haploinsufficiency in those cases.

First tests include a complete blood count, antibody levels and flow cytometry, a test that counts the types of white blood cells. Many people have low IgG and IgA and low numbers of T cells, B cells and natural killer (NK) cells. Scans or biopsies can check organs for immune cell build-up.

A genetic test confirms the diagnosis by finding a change in one copy of the CTLA4 gene. Specialized lab tests can then check how much CTLA-4 the T cells make and how well it works, to show whether the change matters. These tests are also abnormal in LRBA deficiency, so they are not used on their own.

Care is matched to the organs involved. Immunoglobulin (Ig) replacement, which is antibodies taken from donated plasma, works well to prevent infections. Some people also take antibiotics to prevent infections.

To calm the immune attack, care teams use abatacept, a lab-made form of CTLA-4 that stands in for the weak brake. They also use sirolimus, rituximab and steroids. An international study followed 173 carriers in 2014–2020. These medicines eased the disease, especially low blood counts and immune cell build-up in the gut, lungs and brain. But they gave only partial control and had to be continued. Removing the spleen brought lasting relief to only 4 of 16 people with low blood counts.

In the United States, abatacept is approved for some kinds of arthritis and to help prevent graft-versus-host disease after a transplant. It is not approved for CTLA-4 haploinsufficiency, so this use is off-label. The first prospective trial of abatacept in this group gave 20 adults with CTLA-4 insufficiency or LRBA deficiency a weekly shot for a year. Published in 2026, it found abatacept generally safe. It eased swollen lymph nodes and immune activation, but low blood counts and kidney problems were not well controlled.

A donor stem cell transplant (allogeneic transplant) replaces the immune system and offers a possible cure. In a worldwide study, the main reasons for transplant were low blood counts or gut disease that did not respond to treatment, and Hodgkin lymphoma.

Once infections, inflammation and autoimmunity are managed, many people are able to lead fairly normal lives. They do not need to be isolated or limited in their daily activities. Because the disease varies and can affect many organs, people are often followed by several specialists.

A positive gene test in a family raises hard questions. Care teams usually keep checking relatives who carry the change but feel well, because illness can start later in life. The Immune Deficiency Foundation says every family member found to carry the change should be counseled about their risks.

People who have a transplant range from young children to adults. In the European study, the median age at transplant was 14, and the oldest patient was 56. A transplant means conditioning treatment, a hospital stay and months of checks for infection and graft-versus-host disease, when donor immune cells attack the body.

A transplant needs blood-forming cells from a donor with a close tissue (HLA) match. For this condition, unrelated volunteers have been the main route. In the largest European study, of 40 transplants, 30 used a matched unrelated donor, 5 used a partly matched unrelated donor and 5 used a matched family donor.

Choosing a family donor takes extra care. A relative can carry the family’s CTLA4 change without any symptoms, and illness can start later in life. European transplant guidelines say family donors should be checked for the family’s gene change, especially in conditions that can start late.

Because most transplants in that study used unrelated donors, registry volunteers matter. Joining a registry cannot promise a match for any one person, but more volunteers of every background widen the choices.

When a transplant from a donor is planned, the team usually tests brothers and sisters first. Each full sibling has about a one in four chance of being a full match.

Most patients do not have a matched relative. In the words of NMDP, the U.S. registry, “75% of patients don’t have a fully matched donor in their own family.” The team then searches registries of volunteer donors around the world and banks of donated cord blood. In some transplants, a half-matched parent, child or sibling can also be the donor.

Matching depends on inherited tissue markers called HLA, so a patient is most likely to match someone who shares their ancestry. Every person who joins makes the search a little more likely to succeed, especially for patients from groups that are underrepresented on registries.

Outlook varies widely. Some carriers never become ill, and many people do well once their infections and autoimmune problems are controlled. Others become seriously ill. In a worldwide study, 15 of 90 affected people had died, at a median age of 23, from causes that included severe infections, lymphoma and other complications.

For people who have a transplant, disease activity beforehand matters most. In a European study of 40 transplants, people with lower disease activity before transplant were more likely to survive and to stay free of disease. At last follow-up, 28 of the 30 survivors were in remission. Almost all deaths were caused by the transplant, and survival improved over time.