Foundations · Year 1 · from Foundations
Case 2: Autoimmune Lymphoproliferative Syndrome (Fas Deficiency)
Clinical Image
Source: Wikipedia - Autoimmune lymphoproliferative syndrome - CC BY-SA 3.0
Case Presentation
A 7-year-old boy is referred for evaluation of chronic lymphadenopathy and splenomegaly present since age 2. He has had multiple episodes of immune thrombocytopenia and autoimmune hemolytic anemia requiring steroids. Physical examination reveals massive splenomegaly and diffuse non-tender lymphadenopathy. Flow cytometry reveals an expanded population of double-negative T cells (CD3+CD4-CD8-), comprising 8% of lymphocytes (normally <1.5%). Genetic testing identifies a heterozygous mutation in FAS (TNFRSF6). The immunologist explains that Fas is a death receptor critical for eliminating activated and autoreactive lymphocytes. When FasL on one lymphocyte engages Fas on another, it triggers formation of the death-inducing signaling complex (DISC), activating caspase-8 and initiating apoptosis. Without functional Fas, lymphocytes that should be eliminated persist, accumulating as double-negative T cells and causing lymphoproliferation and autoimmunity. This is autoimmune lymphoproliferative syndrome (ALPS). Management includes treatment of autoimmune cytopenias, surveillance for lymphoma (elevated risk), and consideration of sirolimus which can reduce lymphoproliferation. He eventually requires splenectomy for refractory cytopenias.
Key Learning Points
- The extrinsic apoptotic pathway is triggered by death receptor engagement (Fas-FasL, TRAIL-DR4/5); this pathway is essential for immune homeostasis and eliminating autoreactive lymphocytes
- ALPS demonstrates the physiological importance of apoptosis: defective Fas signaling prevents normal lymphocyte death, causing accumulation of abnormal lymphocytes and autoimmunity
- The accumulation of double-negative T cells (CD3+CD4-CD8-) is a hallmark diagnostic feature and reflects cells that should have been eliminated after activation