Activated PI3K delta syndrome

Activated PI3K delta syndrome (APDS) is a rare primary immunodeficiency disorder characterized by the mutation of the phosphoinositide 3-kinase delta (PI3Kδ) gene. This mutation leads to the abnormal activation of the PI3Kδ pathway, which plays a crucial role in the activation, development, and survival of B cells and T cells. The disorder manifests through a variety of clinical symptoms, including recurrent respiratory infections, lymphoproliferation, autoimmunity, and in some cases, susceptibility to certain cancers.

Etiology

APDS is caused by gain-of-function mutations in the PIK3CD gene, which encodes the p110δ catalytic subunit of PI3Kδ, or in the PIK3R1 gene, encoding the p85α regulatory subunit. These mutations lead to the constitutive activation of the PI3Kδ pathway, disrupting normal immune cell function.

Pathophysiology

The PI3Kδ pathway is pivotal in the signaling of several types of immune cells, including B cells and T cells. In APDS, the mutation-induced hyperactivity of this pathway results in the uncontrolled proliferation and survival of these cells, contributing to the clinical manifestations of the disease. The pathway's dysregulation also impairs the immune response to infections and disrupts immune tolerance, leading to autoimmunity.

Clinical Manifestations

Patients with APDS present a spectrum of clinical features, including:

• Recurrent respiratory infections: Due to the impaired immune response, individuals are more susceptible to bacterial, viral, and fungal infections.
• Lymphoproliferation: Enlargement of lymph nodes and spleen (splenomegaly) is common, resulting from the excessive proliferation of lymphocytes.
• Autoimmunity: The disease can cause the immune system to attack the body's own cells, leading to conditions such as autoimmune hemolytic anemia or immune thrombocytopenia.
• Increased cancer risk: There is an elevated risk of developing lymphoma and other cancers due to the uncontrolled proliferation of immune cells.

Diagnosis

Diagnosis of APDS is based on clinical presentation, immunological findings, and genetic testing. Immunological tests may reveal elevated levels of IgM and reduced levels of IgG and IgA. Genetic testing is essential for confirming the presence of mutations in the PIK3CD or PIK3R1 genes.

Treatment

Treatment strategies for APDS aim to manage symptoms, prevent infections, and address complications:

• Immunoglobulin replacement therapy: To prevent infections by providing the antibodies that the patient's body cannot produce sufficiently.
• Antibiotic prophylaxis: Long-term antibiotics may be used to prevent respiratory infections.
• Immunosuppressive therapy: Medications such as rapamycin can help control lymphoproliferation and autoimmunity by inhibiting mTOR, a downstream target of PI3Kδ.
• PI3Kδ inhibitors: Specific inhibitors targeting the PI3Kδ pathway are under investigation and have shown promise in managing the disease by directly addressing the underlying cause.

Prognosis

The prognosis of APDS varies depending on the severity of symptoms and the effectiveness of treatment. Early diagnosis and appropriate management can significantly improve the quality of life and reduce the risk of severe complications.

See Also

• Primary immunodeficiency
• Lymphoproliferative disorders
• Autoimmune diseases
• Genetic testing