Autoimmune lymphoproliferative syndrome

Overview

Autoimmune Lymphoproliferative Syndrome (ALPS) is a rare genetic disorder of the immune system characterized by a failure of lymphocyte apoptosis (programmed cell death), leading to the accumulation of abnormal lymphocytes. This results in chronic lymphadenopathy (swollen lymph nodes), splenomegaly (enlarged spleen), and autoimmune destruction of blood cells (cytopenias).

ALPS is typically diagnosed in childhood and is considered one of the first inherited human diseases of immune dysregulation. Though it shares features with autoimmune and lymphoproliferative disorders, ALPS is distinct in its underlying mechanism: defective apoptosis due to mutations in the FAS signaling pathway.

Causes

ALPS is caused by mutations in genes involved in the FAS-mediated apoptotic pathway, most commonly:

• FAS (TNFRSF6) gene – most common, inherited in an autosomal dominant pattern with incomplete penetrance

• FASL (FAS ligand) gene

• CASP10 gene – encodes caspase-10, essential for apoptosis

These genetic mutations impair the normal elimination of activated or autoreactive lymphocytes, leading to their accumulation and autoimmunity.

Symptoms

The clinical presentation of ALPS can vary but commonly includes:

Lymphoproliferation:

• Chronic, nonmalignant lymphadenopathy

• Splenomegaly (very common)

• Hepatomegaly (in some patients)

Autoimmunity (particularly cytopenias):

• Autoimmune hemolytic anemia (AIHA)

• Immune thrombocytopenic purpura (ITP)

• Autoimmune neutropenia

Other possible features:

• Fatigue, fever, or recurrent infections

• Increased risk of lymphoma

• Elevated double-negative T cells (CD4-/CD8- TCRαβ+ cells) in the blood

Diagnosis

Diagnosis of ALPS is based on clinical findings, laboratory markers, and genetic testing. The hallmark laboratory feature is elevated levels of double-negative T cells (DNTs).

Diagnostic criteria include:

• Chronic non-malignant lymphadenopathy and/or splenomegaly

• Elevated DNTs ≥1.5% of total lymphocytes

• Defective lymphocyte apoptosis on in vitro testing (optional)

• Positive germline or somatic mutation in FAS or related genes

• Supportive markers:

  • Elevated serum vitamin B₁₂

  • Elevated IL-10, soluble FAS ligand, or IL-18

  • Autoimmune cytopenias

Imaging (e.g., ultrasound or CT scan) may show enlarged lymph nodes or spleen but is not specific for ALPS.

Treatment

There is no cure for ALPS, but treatment focuses on managing autoimmune cytopenias, reducing lymphoproliferation, and monitoring for malignancy.

First-line therapies:

• Corticosteroids: For managing autoimmune hemolytic anemia and thrombocytopenia

• Mycophenolate mofetil (MMF): Often used as a steroid-sparing agent

• Sirolimus (rapamycin): Effective for both cytopenias and lymphoproliferation; increasingly used in ALPS management

Other management:

• IVIG (intravenous immunoglobulin) in cases of severe cytopenia

• Splenectomy is generally avoided due to infection risks

• Antibiotic prophylaxis and vaccination in cases of functional asplenia

Monitoring and Support:

• Regular blood counts and immune marker testing

• Surveillance for lymphoma with imaging and clinical exams

• Genetic counseling for affected families

Prognosis

With proper management, many individuals with ALPS can lead relatively normal lives. However, outcomes depend on the severity of autoimmune complications and the development of malignancy.

Prognostic points:

• Many patients respond well to immunosuppressive therapy

• Risk of lymphoma is significantly increased and requires lifelong surveillance

• Mortality is primarily associated with complications from cytopenias or cancer

Ongoing research and targeted therapies such as sirolimus have improved the long-term outlook for patients with ALPS.