Autoimmune Lymphoproliferative Syndrome (ALPS) is a rare, inherited disorder of the immune system characterized by the failure of certain immune cells to undergo programmed cell death. This defect prevents the body from regulating the number of lymphocytes, a type of white blood cell. Since these cells do not die off as they should, they accumulate in various organs, leading to a complex set of symptoms that typically begin in childhood.
Defining Autoimmune Lymphoproliferative Syndrome
The core issue in ALPS is a defect in lymphocyte apoptosis, the programmed cell death necessary to remove immune cells. In healthy individuals, this “self-destruct” mechanism, known as the Fas pathway, ensures the immune system returns to a resting state. When this pathway is defective, immune cells survive too long, leading to a massive buildup called lymphoproliferation.
This uncontrolled cell accumulation results in the enlargement of lymph nodes and internal organs. The hallmark cellular finding in ALPS is the abnormal expansion of Double-Negative T-cells (DNTs). These are mature T lymphocytes that lack the CD4 and CD8 surface markers normally present on helper and cytotoxic T-cells. While DNTs typically represent less than two percent of total T-cells in healthy people, in ALPS patients, this population expands significantly, often exceeding 2.5% of the total T-cell count.
Genetic Basis of ALPS
The primary cause of ALPS is a genetic mutation that disrupts the Fas signaling pathway, which initiates apoptosis. Most cases are linked to mutations in the FAS gene, which provides instructions for making the Fas receptor protein on the surface of lymphocytes. This receptor normally binds to its ligand (FasL) to trigger the death cascade, but a defective receptor prevents this signal from being received or processed.
Mutations in the FAS gene usually follow an autosomal dominant inheritance pattern, meaning a person only needs one copy of the mutated gene to be affected. These are classified as Type 1A ALPS and account for approximately 65% of all cases. The condition can also arise from a somatic mutation, where the genetic change occurs after conception and is only present in a portion of the body’s cells, often just the lymphocytes.
Less common forms of the disorder include Type 1B ALPS, which is caused by a mutation in the FASLG gene, the gene for the Fas ligand. Other rare variants involve mutations in genes for downstream signaling molecules, such as CASP10. The severity of ALPS can vary widely, a phenomenon known as incomplete penetrance, where not everyone who inherits the gene will develop symptoms.
Key Physical Manifestations
The overaccumulation of lymphocytes in ALPS leads to a set of distinct physical signs, most commonly appearing in early childhood. The most noticeable manifestation is chronic, non-malignant lymphadenopathy, the persistent swelling of lymph nodes. These enlarged lymph nodes may fluctuate in size but generally remain prominent for more than six months.
Internal organs are also affected by this cellular overgrowth, leading to splenomegaly (enlarged spleen) and hepatomegaly (enlarged liver). The spleen often becomes severely enlarged, and an enlarged liver is observed in approximately 30 to 40% of patients. Although these enlargements are non-cancerous, they can cause discomfort and contribute to other health issues.
A significant complication of ALPS is the development of autoimmunity, where the dysregulated immune system mistakenly attacks healthy cells. This often presents as cytopenias, or low blood cell counts, which pose the most serious immediate health risks. Examples include hemolytic anemia (low red blood cells), thrombocytopenia (low platelets), and neutropenia (low neutrophils). Individuals with ALPS also face an increased lifetime risk of developing B-cell lymphoma, estimated to be about 20% by age 40.
Diagnosis and Management Approaches
Diagnosing ALPS requires a combination of clinical observations and specific laboratory tests, as its symptoms can overlap with other conditions like lymphoma. A persistent, unexplained lymphoproliferation lasting over six months, coupled with chronic autoimmune cytopenias, is a strong indicator. Laboratory diagnosis relies on identifying the hallmark expansion of Double-Negative T-cells.
Further confirmation involves specialized blood tests to measure specific biomarkers that are often elevated in ALPS patients. These include high serum levels of Vitamin B12, Interleukin-10 (IL-10), and soluble Fas ligand (sFasL). Genetic testing confirms the diagnosis by sequencing the FAS gene and other associated genes to identify the specific mutation responsible for the defective apoptosis.
Management of ALPS focuses on controlling the autoimmune components and reducing the excess lymphocyte burden. Corticosteroids are often the initial treatment for acute autoimmune cytopenias due to their broad immunosuppressive effects. For chronic or recurring cytopenias, or to avoid the long-term side effects of steroids, steroid-sparing immunosuppressive drugs are used.
Medications like sirolimus and mycophenolate mofetil are effective in managing the autoimmune destruction of blood cells and reducing the size of the enlarged organs. Surgical removal of the spleen is generally avoided and only considered as a last resort for life-threatening, treatment-resistant cases. Patients require continuous monitoring for the development of lymphoma, which involves regular physical exams and sometimes imaging.