Autoimmune Lymphoproliferative Syndrome (ALPS)

Autoimmune Lymphoproliferative Syndrome (ALPS) is an inherited disorder of the immune system that affects both children and adults. In ALPS, unusually large numbers of white blood cells, called lymphocytes, accumulate in the lymph nodes, liver, and spleen, which can lead to enlargement of these organs and to a variety of conditions such as anemia and excessive nose bleeds.

NIH first began to study ALPS in 1990, when researchers saw a child who had immune-system symptoms that did not fit any previously known disorders. In 1995, NIH named this newly identified condition ALPS, and as of 2005, NIH had evaluated and diagnosed ALPS in more than 200 patients. These patients come from all over the country and are of many different ethnic backgrounds.

NIH Findings

• ALPS is a disorder that develops in early childhood.
• ALPS is not cancer, and it is not contagious.
• There is a wide spectrum of illness in ALPS. For some, it is very mild; for others, it is more severe.
• Once a person has ALPS, he or she does not become sicker and sicker over time. In fact, the problems seem to lessen as children get to be teenagers and young adults.
• Most people with ALPS have episodes of autoimmune problems (conditions in which the immune system attacks cells in the body). These can happen at any age, but they appear worse in childhood.

Clinical Features

Not all people with ALPS will have all of its symptoms; some people have only a few. Signs of ALPS that are seen most often include the following:

• Enlarged spleen
• Enlarged lymph nodes, especially in the neck and underarms
• Enlarged liver
• Skin rashes
• Frequent nose bleeds
• Anemia (low blood counts)
• Increase in certain types of white blood cells (including double-negative T cells)
• Increased life-span of some white blood cells that are no longer needed
• Alteration in a gene

Autoimmune Problems

• Very low red-blood-cell counts (hemolytic anemia) that can make one weak
• Very low platelet counts (immune-mediated thrombocytopenia, or ITP) that cause bruises and nose bleeds and may pose a risk for hemorrhage (excessive bleeding); little spots called petechiae (pet-eek'-ia) may also show up on the skin when platelets are low
• Very low white-blood-cell counts (autoimmune neutropenia), creating a risk for bacterial infection

How ALPS Works

To understand ALPS, it helps to understand how the immune system responds to an infection. For example, when a person has the flu, cells in the nose and throat instruct the immune system to start making more lymphocytes, a major class of white blood cells comprising T cells and B cells. New troops of lymphocytes come to the nose and throat to seek out and destroy the cells infected with the flu virus. Once the virus is conquered, the lymphocytes get a message that their job is done and that they are no longer needed. At this point, it is normal for most of the fighter cells to disintegrate through a process called apoptosis.

While immune systems of people with ALPS are efficient in fighting germs and other agents, the problems begin after an infection is gone. In ALPS, apoptosis does not work as well as it should. In other words, the lymphocytes don't hear the message that the war is over. As a result, excess T cells and B cells gather in the lymph nodes, liver, and spleen.

Fas Gene

One reason the blood cells don’t get the message to disintegrate is the mutation of a gene called Fas. Under normal circumstances, the Fas gene produces Fas protein, which controls the life span of certain cells, including lymphocytes. The mutated Fas gene, however, produces abnormal Fas protein, which is unable to give the cells the message that it is time to die. Although most ALPS patients have one normal and one mutated copy of the Fas gene, the abnormal protein is able to interfere with the function of the normal one.

It is not completely understood how an abnormal Fas protein leads to ALPS, but it clearly does. However, Fas mutations do not explain all cases of ALPS. Approximately 17 percent of people with ALPS do not have a Fas mutation. Some of them have alterations in other proteins. In some ALPS patients, a genetic alteration has not yet been found. Also, there are many relatives of ALPS patients who have a Fas mutation and do not have ALPS. Scientists believe that other genes and environmental factors also play a role in determining which people get ALPS.

T Cells and B Cells

In general, the accumulation of extra T cells in people with ALPS does not cause a problem. Sometimes however, the proliferation of extra B cells can prompt the immune system to attack the body. B cells produce antibodies, which are custom-fit to stick to a specific germ. Instead of custom-designing antibodies against germs, the ALPS B cells make antibodies against platelets, which help the blood form clots; red blood cells, which help transport oxygen to body tissues; or other cells.

This causes autoimmune problems as the antibodies become stuck to the platelets and red blood cells, which then get stuck in the spleen. The spleen has to work extra hard to filter out the sticky cells and, as a result, begins to enlarge.

Ways to Manage ALPS

There is no cure for ALPS. However, most of its complications can be treated.

Splenectomy

Virtually all people with ALPS have an oversized spleen. Usually, it is not necessary to remove the spleen unless there are severe problems like anemia. Removing a spleen carries both risks and benefits, which doctors and patients must carefully consider before deciding what to do.

• Easier to regulate and control blood counts
• Less discomfort
• No risk of spleen rupture

• There is an increased likelihood of certain bacterial infections. Patients must get vaccinated to avoid infections. Some may need to take antibiotics for many years.

Steroids

Steroids are the first line of treatment for autoimmune episodes, like hemolytic anemia (very low red-blood-cell counts) and immune-mediated thrombocytopenia (very low platelet counts). One common steroid is prednisone. It is often given for a short time, but sometimes it is needed for longer periods.

When prednisone is not enough to treat the episode, other drugs, such as mycophenolate mofetil, rituximab, and vincristine, may also be prescribed. Steroids have saved lives and have dramatically reduced the complications in some people with ALPS. However, like all treatments, steroids have some disadvantages, so they should not be used too much or for too long.

• Thinning of bones
• Poor wound healing
• Difficulty fighting infection
• Diabetes
• Cataracts of the eyes
• Mood swings
• Weight gain
• Dependence

Other Treatments

Blood transfusions are useful to replace red blood cells when anemia is severe.

Vaccines are important to help prevent infections. In addition to all childhood vaccinations, it is important to get a yearly flu shot and boosters as needed. People with allergies to eggs should discuss the risks with their doctor prior to receiving a flu shot.

ALPS and Your Family

Risk to Children

Individuals with a Fas mutation have a 50/50 chance of passing the Fas mutation on to their children. This chance is the same for each child. Children who have inherited the unaltered Fas gene have almost no chance of developing ALPS.

Relatives Who Do Not Have ALPS

Siblings or other relatives who don't have ALPS are still affected by the condition. Some worry that their brother or sister will die. Some think they will develop ALPS because they look or act like their brother or sister. Some children struggle with how much of their parents' time is spent with their sick brother or sister. It is important for families to talk openly about ALPS so that any misconceptions can be explained and feelings can be expressed. Family counseling is often helpful.

Many families say that ALPS has brought them closer together. Family members learn that they can rely on each other for support. Children learn from their parents' open and honest communication, and the experience teaches them how to solve problems.

Common Questions and Problems People with ALPS Face

Why is your face so round?

People taking steroids may gain weight quickly. Some parents talk to teachers about the side effects of steroids in advance, so that classmates know what to expect. The swelling is temporary and goes away once the child stops taking the medicine.

Are you contagious?

People often worry that ALPS can spread to others, but ALPS is not infectious.

Stares from strangers

Parents of children with ALPS have to work extra hard to develop their children's self-confidence and sense of security. Children and adults with ALPS need to be reminded that they have many positive characteristics.

Spleens and sports

Some doctors recommend that people with enlarged spleens not play contact sports. When the spleen is large, it is fragile and there is a risk of rupture. NIH encourages use of a spleen guard, which is a piece of fiberglass that is molded to a person's stomach. It is easily wrapped around the stomach and held in place under a shirt.

In general, the spleen guard is worn during any activity with a high risk for stomach injury, such as contact sports. Some people wear spleen guards while swimming, running track, or bicycling.

The ALPS Team at NIH

The ALPS team is composed of doctors, scientists, nurses, genetic counselors, and several students and scientists in training. Physicians from around the country refer families suspected of having ALPS to NIH. The team reviews the medical records and blood samples of the families and invites those who are thought to have ALPS to NIH for evaluation and follow-up.

What's the Purpose of the NIH Studies?

Researchers are trying to better understand this rare disease, to find the cause, and to uncover new ways to treat it. Of course, the ultimate goal is to find a cure.

Why Are Family Members Involved?

There is a genetic component to ALPS, but the development of the disease in families with mutations in apoptosis genes is not straightforward. For example, researchers want to know why some family members have an alteration in the Fas gene and no sign of ALPS. Other research questions may also be answered by studying family members. Therefore, NIH invites family members to join its studies by providing a small blood sample.

How Do I Participate?

Those interested in participating will have a chance to discuss study details with NIH researchers. Each potential volunteer will be asked to read and sign a consent form.

All of the tests, evaluations, and treatments at NIH are free. Family members who participate will be helping us better understand and treat ALPS.

Ongoing Studies

For more information, or to volunteer for NIAID-funded clinical studies related to ALPS by going to ClinicalTrials.gov.