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Autoimmune Lymphoproliferative Syndrome
Introduction
Autoimmune lymphoproliferative syndrome (ALPS) was first described in 1967 when Canale and Smith reported on five children with massive lymphadenopathy and splenomegaly mimicking lymphoma. In 1992 Sneller et al. similarly described two patients with a progressive lymphoproliferative disorder associated with autoimmunity and whose blood and lymph nodes demonstrated an increase in an atypical population of CD41992 − and CD8 − T cells (double-negative T cells, DNTs). We now know an elevation of DNTs in the peripheral blood results from a primary defect in Fas-mediated T-cell apoptosis and is a requirement to diagnose ALPS. Although the role of DNTs in ALPS is not completely understood, recent evidence suggests a hyperactive mammalian target of rapamycin (mTOR) pathway within T-cell subsets may be responsible, and sirolimus, an mTOR inhibitor, shows significant promise in the treatment of symptomatic patients with ALPS. Because of significant morbidity associated with ALPS and its association with lymphoma, clinicians should have a heightened suspicion of this disease in appropriate clinical circumstances. With modern treatments, patients with ALPS can expect to have a near-normal life span.
Pathophysiology
ALPS is a primary immunodeficiency defined by a defect in the Fas-mediated external apoptosis pathway, which plays a pivotal role in lymphocyte homeostasis. During the process of downregulating the body’s normal immune response, activated B and T lymphocytes increase the expression of the cell-surface protein Fas (also termed CD95/APO1). During this process, activated T lymphocytes increase expression of Fas ligand. Fas and Fas-ligand interact through the Fas-activating death domain, triggering the recruitment and intracellular cascade of procaspases 8 and 10, whose downstream effects initiate DNA degradation, proteolysis, and cellular apoptosis. As such, Fas maintains lymphocyte homeostasis and peripheral immune tolerance, and therefore, defects in this external pathway of apoptosis can result in aberrant lymphoproliferation, autoimmunity, and cancer.
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