Autoimmune Lymphoproliferative Syndrome (ALPS): NIAID
Article title: Autoimmune Lymphoproliferative Syndrome (ALPS): NIAID
Conditions: Autoimmune Lymphoproliferative Syndrome
Autoimmune Lymphoproliferative Syndrome (ALPS)
WHAT WE'VE FOUND OUT SO FAR AT THE NIH
A BRIEF INTRODUCTION TO IMMUNOLOGY
WHAT HAPPENS IN ALPS
MANAGEMENT OF ALPS
WAYS TO MANAGE ENLARGED SPLEENS IN ALPS
WAYS TO MANAGE AUTOIMMUNE PROBLEMS IN ALPS
DOES ALPS RUN IN FAMILIES?
A BRIEF INTRODUCTION TO GENETICS
THE FAS GENE
ARE MY CHILDREN AT RISK IF I HAVE A FAS GENE MUTATION?
SOME COMMON QUESTIONS AND PROBLEMS PEOPLE WITH ALPS FACE
THE ALPS TEAM AT THE NIH
PARTICIPATING IN OUR STUDY
Clinical Features of ALPS
In 1995, we gave this newly identified condition a name - ALPS. By August 1999, we diagnosed ALPS in 58 individuals from 35 families. These families come from all over the country and are of many different racial backgrounds.
We hope that this brochure will help answer some of your questions about ALPS. Share it with your family, physicians, members of your community, and your children's teachers so that they can understand ALPS better, too.
ALPS-WHAT IS IT?ALPS is a rare disease that affects both children and adults. ALPS stands for Autoimmune LymphoProliferative (lim-fo-pro-lif'-er-a-tive) Syndrome. Each of these three words helps describe the main features of this condition. The word autoimmune (self-immune) identifies ALPS as a disease of the immune system. The tools used to fight germs turn against our own cells and cause problems. The word lymphoproliferative describes the unusually large numbers of white blood cells (called lymphocytes (lim'-fo-sites)) stored in the lymph nodes and spleens of people with ALPS. The word syndrome refers to the many common symptoms shared by ALPS patients.
WHAT WE'VE FOUND OUT SO FAR AT THE NIHAt this time we are still learning about ALPS. Based on our experience, we believe the following to be true:
- ALPS is a disorder that develops in early childhood.
- ALPS is not cancer; it is not contagious; it is not AIDS.
- 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 improve as children get to be teenagers and young adults.
- Most people with ALPS have episodes of autoimmune problems. These can happen at any age, but they appear worse in childhood.
Common autoimmune problems in ALPS include:
- 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.
- Less often, other autoimmune problems can occur in almost any organ - skin, liver, kidney and nerves are examples.
A BRIEF INTRODUCTION TO IMMUNOLOGYYou may wonder what the connection is between the findings in ALPS and the immune system. To understand what happens in ALPS, we would like to review some basic information about the immune system. It is the immune system that defends our bodies against germs. There are many components of the immune system. Two major components are the spleen and white blood cells. The spleen is a fist-sized organ found to the left of your stomach. It has a special job of filtering the blood, by cleaning out dead blood cells that arenŐt needed any more. The blood contains many types of cells:
- red blood cells help transport oxygen to your tissues
- platelets help to form blood clots
- white blood cells are the soldiers in your immune system.
There are many kinds of T cells. Some of these direct our immune response to infections, and others kill infected cells. Each T cell is named for the markers found on its surface. There are over 100 different markers. For example, some T cells are called CD4 cells because they have the type 4 chemical marker coating their surfaces. Other T cells are named CD8 cells because they are coated by the type 8 marker. Almost all T cells of healthy people have either the type 4 or the type 8 marker. Those with neither type 4 nor type 8 markers are called double-negative T cells. People with ALPS often have increased numbers of double-negative T cells.
People with ALPS often have extra B cells, too. The B cells produce immunoglobulins (Ig's, also called antibodies). The antibodies are custom-fit to stick to specific germs. There are thousands of different antibodies in the body. Each is molded for a specific germ. Because ALPS patients have more B cells than normal, they produce more antibodies, including ones that cause autoimmune problems.
WHAT HAPPENS IN ALPSTo better understand how ALPS works, imagine that you have a respiratory infection, perhaps the flu. The cells in the nose and throat send out a message to the immune system to start making more lymphocytes to fight the flu. 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 they are no longer needed. At this point, it is normal for most of the fighter cells to disintegrate through a process called apoptosis (a-pop-to'-sis).
The immune systems of people with ALPS are efficient in fighting germs. The problem in ALPS happens after an infection is gone. In ALPS, apoptosis does not work as well as it should. In other words, the troops (lymphocytes) donŐt hear the message that the war is over. As a result, excess T and B cells gather in the lymph glands, liver and spleen. We can detect the extra cells in people with ALPS by looking for high numbers of double-negative T cells. In general, these extra T cells donŐt cause a problem.
Sometimes in ALPS, the B cells make a mistake. Instead of making antibodies to be custom-designed against germs, the B cells make antibodies against platelets, red blood cells, or other cells. This causes autoimmune problems. 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. This is another reason why the spleen gets so big.
MANAGEMENT OF ALPSThere is no cure for ALPS. However, we can treat and prevent most of its complications. Management of ALPS involves:
- Diagnosis. You probably know from experience that this may take months or years until you find a doctor who recognizes the features of ALPS.
- Counseling and education. The more you know about ALPS and how to recognize its symptoms and signs, the better you will be able to manage it.
- Knowing what's treatable. Unfortunately, we have not found ways to permanently make the swelling of lymph nodes go down or to fix the problem with apoptosis (see WHAT HAPPENS IN ALPS).
- Therapies. Complications of ALPS, including the many different autoimmune problems, can be treated successfully. ALPS can be managed through close communication with doctors as symptoms and signs arise.
WAYS TO MANAGE ENLARGED SPLEENS IN ALPSVirtually all people with ALPS have an oversized spleen. Usually, it is not necessary to remove the spleen unless there are severe problems like anemia. However, removing a spleen carries both risks and benefits, which doctors and patients must carefully consider before deciding what to do.
BENEFITS OF SPLENECTOMY
- It will be easier to regulate and control blood counts.
- You will feel less discomfort.
- There is no longer a risk of spleen rupture, a very serious problem, should it occur.
WAYS TO MANAGE AUTOIMMUNE PROBLEMS IN ALPSSteroids are the first line of treatment for autoimmune episodes, like hemolytic anemia and ITP. 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 Imuran and cyclosporin, 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.
POSSIBLE LONG-TERM SIDE EFFECTS OF STEROIDS
- Thinning of bones
- Poor wound healing
- Difficulty in fighting infection
- Cataracts of the eyes
- Mood swings
- Weight gain
- The body starts to rely on the steroids and the amount has to be slowly reduced.
- Blood Transfusions are useful to replace red blood cells when anemia is severe.
- Vaccines are important to help prevent infections. The fewer infections you have, the less often you will need to "call in the troops." In addition to all the childhood vaccinations, it is important to get a yearly flu shot and boosters as needed. People with allergies to eggs should discuss this with their doctor prior to receiving a flu shot.
- Gene Therapy is unfortunately not likely to work for ALPS.
DOES ALPS RUN IN FAMILIES?Children can inherit ALPS from one of their parents. The process of apoptosis is controlled by several genes. Most people with ALPS have an altered gene that plays a major role in apoptosis. The altered gene may be passed from one generation to the next. Before discussing what this gene does, we need to describe some basic information about genes and how they work.
A BRIEF INTRODUCTION TO GENETICSGenes, which are made of DNA, are located on chromosomes in the cells of our body. We have two copies of each gene, except for the genes on the sex chromosomes. Genes act as the blueprint for the development and operation of our bodies. Each gene contains the instructions for making one of the building blocks of a cell. We each have around 100,000 genes that determine who we are, what we look like, and how our bodies work. By chance, every person has approximately 10-12 genes that donŐt work as well as they should or donŐt work at all. These genes are mutated. That is, the DNA is slightly different in mutated genes. Not all changes, or mutations, are harmful. Sometimes these changes cause no problems at all, but sometimes they cause human disease. Sometimes it takes alterations in several genes to cause problems. Other times the genetic mutation interacts with the environment to cause health problems.
THE FAS GENEWe have found genetic changes or mutations that seem to be factors in the development of ALPS. In over 83% of the ALPS patients, we have found an alteration in a gene that encodes a cell component, or protein, called Fas. This alteration causes the gene to produce abnormal Fas protein. We do not completely understand how abnormal Fas protein leads to ALPS, but it clearly does. We still need to identify other genetic and non-genetic factors that contribute to the development of ALPS.
The Fas protein is one of several proteins that are important for apoptosis, the normal process through which cells die. Fas controls the life span of certain cells, particularly the lymphocytes. Like people, cells have a normal life span in which they grow, do their job, and then die. The mutated Fas protein does not work well, and can't give the cells the message that it is time to die. Although most ALPS patients have one normal and one altered copy of the Fas gene, the altered protein is able to interfere with the function of the normal one.
However, Fas mutations do not explain all cases of ALPS. About 17% of people with ALPS do not have a Fas mutation. In some of them there are alterations in other proteins known as Fas-ligand and Caspase-10. 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. We believe that other genes and environmental factors also play a role determining which people get ALPS.
ARE MY CHILDREN AT RISK IF I HAVE A FAS GENE MUTATION?There are many people who have no signs of ALPS, yet have a Fas mutation. Individuals with a Fas mutation have a 50/50 chance of passing the Fas mutation on to their children. That means that each child has a 50% chance of inheriting the unaffected gene and a 50% chance of inheriting the altered gene. This chance is the same for each child. In other words, if you have 5 children and they have each inherited the Fas mutation, the sixth child still has the same 50/50 risk of inheriting the Fas mutation. Of the children who inherit the Fas mutation, approximately half of them will develop some features of ALPS. This figure is based on the 98 people we have studied so far at NIH who have a Fas gene mutation. Of these 98 people with the Fas gene mutation, 48 have enough symptoms to be diagnosed with ALPS and additional persons have some features of ALPS. Children who have inherited the unaltered Fas gene have almost no chance of developing ALPS.
HOW TO EXPLAIN ALPS TO YOUR KIDSIt may seem easier not to tell your children anything about ALPS, but children, like adults, often want to know "why?" and don't like to be left in the dark. The more children understand about ALPS, the fewer fears and misunderstandings they may have. The following is one way we have explained ALPS to a child. You may find these ideas helpful for your family.
|ALPS IS A PROBLEM WITH THE
Usually, the immune system attacks germs, as an army would attack its enemy. The soldiers are called lymphocytes. They go around the blood stream and find germs. After the soldiers kill the germs, their job is done and it is time for them to go away and die. In ALPS, the soldiers don’t hear the message to die. They stay and hang out in places like your spleen and the lymph nodes found under your cheeks, making them really big. Sometimes, the soldiers become confused and they attack members of their own side, such as the red blood cells and platelets in your body. Without enough red blood cells, you may feel tired. Without enough platelets, you may get nosebleeds, red spots on your skin and bruises. Sometimes you may need to take medicine or get a transfusion of new blood. Sometimes you have to be extra careful not to bump your belly because your spleen is fragile. Even though living with ALPS can be hard, all kids still go to school, and most adults work. All have responsibilities, contribute to their communities in many ways, have friends, and have fun.
SOME COMMON QUESTIONS AND PROBLEMS PEOPLE WITH ALPS FACEDo you have the mumps? No! People with mumps have a very different condition, even though both involve swelling of the sides of your face. Some people who ask questions are well-meaning, some are curious, and some are just plain rude. You don't have to answer if you don't want to. You can just ignore the question. A simple answer, such as "I was born this way" or "God made me this way" is often enough to satisfy curiosity. People tend to say different things depending on their mood. The important thing is to find an answer that feels comfortable to you.
Why is your face so round? If you are taking steroids, you may gain weight quickly. Some parents talk to teachers about the side effects of steroids in advance, so that the class knows what to expect. Try to remember that the swelling is temporary. It goes away once you stop taking the medicine.
Are you contagious? People often worry that ALPS is catching. It is important that people understand that ALPS is not infectious.
Stares from strangers: It's a fact of life that people will stare at people who look different. Often there are good days when stares don't seem to matter, and bad days when you feel like crawling under the bed. Parents of children with ALPS have to work extra hard to develop their child's self-confidence and sense of security. The important thing is to let them know that you love them no matter how they look. Children and adults with ALPS need to be reminded that they have many positive characteristics.
Spleens and sports: Sometimes 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. This can be hard for many to accept. We at the NIH encourage people with large spleens to wear spleen guards. A spleen guard is a piece of fiberglass that is molded to a person's stomach. It is easily wrapped around your stomach and held in place under your shirt. In general, the spleen guard is worn whenever someone is involved in an activity at high risk for stomach injury, such as contact sports. Other people choose different sports, such as swimming, track, or bicycling.
Relatives who do not have ALPS: Brothers and sisters 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. Relatives who have a Fas mutation but do not have ALPS may feel guilty that they are not sick. 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.
The positive side: 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.
THE ALPS TEAM AT THE NIHThe team at the NIH 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 us. We study their blood for specific laboratory findings related to ALPS. After reviewing the medical records and lab results, the team invites those who we think have ALPS to NIH for evaluation and follow-up. With the many referrals we have been getting recently, we are beginning to think that ALPS is more common than once thought.
WHAT'S THE PURPOSE OF OUR STUDY AT THE NIH?We are trying to better understand this rare disease, to find the cause and hopefully to find improved ways to treat ALPS. Of course, the ultimate hope is to find a cure.
WHY WE WANT TO INVOLVE OTHER MEMBERS OF YOUR FAMILY IN OUR STUDYWe know there is a genetic component to ALPS. However, the development of ALPS in families with mutations in apoptosis genes is not straightforward. For example, we want to know why some family members have an alteration in Fas and no sign of ALPS. Therefore, we would like to study this gene, and other genes, in your family. We have other research questions that may be helped by studying other members of your family. Therefore, we are inviting your family members to join our study by providing us with a small sample of their blood in order to help us answer our research questions.
PARTICIPATING IN OUR STUDYEach person who is interested in participating will have a chance to discuss study details with the investigators. We will ask each person to read and sign a consent form. All of the tests, evaluations and treatments at the NIH are free. Family members who participate will be helping us better understand ALPS.
Please call either,
Dr. Stephen Straus (301-496-5221) or
Janet Dale, RN, MPH (301-496-1699) or
Dr. Jennifer Puck (301-402-2194).
Stephen Straus, M.D. | Michael Sneller, M.D. | Janet Dale, RN, MPH
Jennifer Puck, M.D. | Michael Lenardo, M.D.
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