Autoimmune Lymphoproliferative Syndrome (ALPS) is a rare, inherited disorder characterized by a failure in the programmed cell death mechanism (apoptosis) of certain white blood cells called lymphocytes. When these immune cells fail to die off, they accumulate in the body’s tissues, leading to a chronic buildup of excess lymphocytes. This overabundance results in the enlargement of organs and triggers autoimmune complications.
Genetic Basis and Cellular Malfunction
The underlying cause of ALPS is a defect in the cellular machinery that governs apoptosis, the body’s natural process for eliminating old or damaged cells.
In a healthy immune system, apoptosis acts as an “off switch” to contract the population of T and B lymphocytes once an infection has been cleared, maintaining immune balance. This specialized form of cell death is often triggered by the Fas receptor pathway, which tells the lymphocyte it is time to self-destruct.
The majority of ALPS cases are linked to mutations in the FAS gene, which provides instructions for making the Fas receptor protein on the surface of lymphocytes. When the FAS gene is mutated, the receptor is non-functional, preventing the cell from receiving the “death signal.” This genetic flaw makes lymphocytes resistant to apoptosis, allowing them to survive and accumulate (lymphoproliferation).
Mutations in other genes involved in the apoptotic pathway, such as FASLG or CASP10, can also cause ALPS-like disorders. This failure to regulate lymphocyte numbers drives both the physical enlargement of lymphoid organs and subsequent autoimmune issues.
Defining Clinical Signs and Associated Conditions
The uncontrolled survival of lymphocytes leads directly to the most recognizable physical signs of ALPS: chronic enlargement of the spleen (splenomegaly) and lymph nodes (lymphadenopathy). Splenomegaly affects over 80% of patients as the organ becomes engorged with accumulating lymphocytes. The chronic enlargement of the spleen can sometimes lead to the destruction of healthy blood cells, a process called splenic sequestration.
Lymphadenopathy, the persistent swelling of lymph nodes in areas like the neck, armpits, and groin, is present in over 90% of individuals. These enlarged nodes are non-malignant. Cell accumulation can also occasionally cause the liver to enlarge (hepatomegaly).
The second major manifestation is autoimmunity, where misregulated immune cells attack the body’s healthy tissues. The most frequent targets are blood cells, leading to cytopenias. These include autoimmune hemolytic anemia (destruction of red blood cells, causing fatigue) and autoimmune thrombocytopenia (destruction of platelets, causing easy bruising).
The simultaneous occurrence of both is known as Evans syndrome, which is frequently seen in ALPS. Less common autoimmune attacks can target other organs, potentially causing issues like autoimmune hepatitis in the liver or glomerulonephritis in the kidneys. These autoimmune complications often require immediate medical management.
Confirming the Diagnosis
Diagnosing ALPS requires clinical findings and specific laboratory markers. A definitive diagnosis relies on two required criteria: chronic lymphadenopathy or splenomegaly lasting more than six months, and the presence of Double-Negative T cells (DNTs) in the blood. DNTs are T lymphocytes that express the T-cell receptor but lack the surface markers CD4 and CD8.
In ALPS, DNTs accumulate to levels greater than 1.5% of total lymphocytes, indicating apoptosis failure in this population. The presence of elevated DNTs, combined with physical symptoms, strongly suggests the diagnosis.
Accessory criteria support the diagnosis, including elevated biological markers like soluble Fas ligand (sFASL) and Vitamin B12. Patients often show elevated levels of serum or plasma Vitamin B12, which can exceed 1500 ng/L. Genetic testing for a mutation in the FAS gene or related apoptotic genes (CASP10 or FASLG) provides the most direct confirmation. A definitive diagnosis is established when the required clinical and DNT criteria are met, along with a primary accessory criterion like a pathogenic gene mutation or proven defective lymphocyte apoptosis.
Treatment Strategies and Monitoring
Treatment for ALPS focuses on managing symptoms and complications, as there is no standard cure for the underlying genetic defect. The primary goal is to control autoimmune cytopenias and reduce the bulk of accumulating lymphocytes. Initial management of severe autoimmune episodes, such as profound anemia, often involves short courses of high-dose corticosteroids like prednisone.
Since long-term steroid use has significant side effects, chronic management transitions to steroid-sparing immunosuppressive medications. Drugs such as mycophenolate mofetil and sirolimus are frequently used to suppress the immune response and reduce circulating lymphocytes. Sirolimus is considered a highly effective option for chronic treatment.
A major concern is the increased risk of developing lymphoma, a cancer of the lymphatic system. Individuals with ALPS, particularly those with a germline FAS mutation, have a risk of developing Hodgkin lymphoma that is nearly 150 times greater than the general population. Lifelong monitoring is required, involving regular physical exams and imaging tests to watch for changes in the size of lymph nodes or the spleen. Hematopoietic stem cell transplantation is the only curative option, but it is typically reserved for the most severe cases unresponsive to immunosuppressive therapies.