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Autoimmune Lymphoproliferative Syndrome

Autoimmune LymphoProliferative Syndrome (ALPS) is a rare disease that affects both children and adults. It is characterized by a large number of white blood cells (called lymphocytes) stored in the lymph nodes and spleens, resulting from the malfunction of the immune system.

Symptoms

Some signs of ALPS are ones that people can feel or see, and some of them can be detected only by laboratory tests. Not all people with ALPS will have all of its possible symptoms. Some people have only a few. Some things that are seen most often in people with ALPS include:

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

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 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.

Causes

The immune system of people with ALPS is efficient in fighting germs. The problem in ALPS happens after an infection is gone. In ALPS, apoptosis (cell suicide) does not work as well as it should. In other words, the troops (lymphocytes) don't 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 don't 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.

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.

The Fas Gene

In over 83 percent of the ALPS patients, the Fas gene is mutated. 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. 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 percent 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.

Treatment

Ways to manage enlarged spleens in ALPS

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. 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.
  • There is less discomfort.
  • There is no longer a risk of spleen rupture, a very serious problem, should it occur.
Risks of Splenectomy
  • After splenectomy, people with ALPS are missing an organ which helps protect against infection.
  • The chances of getting certain bacterial infections increase, so people with ALPS must get some vaccines to avoid these infections.
  • After the spleen is removed, people with ALPS may need to take antibiotics for many years to help prevent specific bacterial infections.
Ways to manage autoimmune problems in ALPS

Steroids 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.

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.

 

Reference:

National Human Genome Research Institute, USA