Autoimmune lymphoproliferative syndrome: more than a FAScinating disease

Abstract

Autoimmune lymphoproliferative syndrome (ALPS) is an inherited syndrome characterized by abnormal lymphocyte survival caused by failure of apoptotic mechanisms to maintain lymphocyte homeostasis. This failure leads to the clinical manifestations of non-infectious and non-malignant lymphadenopathy, splenomegaly, and autoimmune pathology, most commonly, autoimmune cytopenias. Since ALPS was first characterized in the early 1990s, insights in disease biology have improved both diagnosis and management of this syndrome. Sirolimus is the best-studied and most effective corticosteroid-sparing therapy for ALPS and should be considered first-line for patients in need of chronic treatment. This review highlights practical clinical considerations for the diagnosis and management of ALPS. Further studies could reveal new proteins and regulatory pathways that are critical for lymphocyte activation and apoptosis.

Keywords: Fas/FasL; MMF; Targeted therapy; autoimmune; cytopenias; double negative T cells; lymphoproliferative disease; sirolimus.

Figure 1.. Fas apoptotic pathway.

In an attempt to downregulate an immune response, activated B and T cells upregulate FAS while activated T cells will activate FAS ligand (FASL). These cells will interact and trigger a caspase cascade, leading to proteolysis, DNA degradation, and apoptosis. This FAS-mediated pathway is part of the extrinsic apoptotic pathway. In contrast, mitochondrial-induced apoptosis after cellular stress is part of the intrinsic apoptotic pathway.

Figure 2.. Proposed algorithm of our approach to the treatment of patients with autoimmune lymphoproliferative syndrome (ALPS) and associated mild-moderate and moderate-severe autoimmune disease, with or without clinically significant lymphoproliferation.

Adapted from George et al. . BID, twice daily.