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.
Highlights
Autoimmune lymphoproliferative syndrome (ALPS) is a rare condition characterized by defective apoptotic mechanisms that disrupt lymphocyte homeostasis[1,2,3,4]
Over the past 10–15 years, improvements in genomic technologies have led to the description of a number of ALPS-like autoimmune and lymphoproliferative disorders, including RAS-associated leukoproliferative disease (RALD); caspase-8 deficiency state (CEDS); p110delta activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency (PASLI or activated PI3K delta syndrome); CTLA-4 haploinsufficiency with autoimmune infiltration (CHAI); gain-of-function (GOF) signal transducer and activator of transcription 3 (STAT3) mutations; and lipopolysaccharideresponsive vesicle trafficking, beach and anchor containing (LRBA) deficiency with autoantibodies, regulatory T-cell defects, autoimmune infiltration, and enteropathy (LATAIE) (Table 1)[8,9]
One of the first wellcharacterized human genetic diseases of apoptosis, ALPS is most commonly associated with autosomal dominant transmission of heterozygous germline mutations in FAS, described in up to about 70% of genetically defined ALPS13,23,24
Summary
Autoimmune lymphoproliferative syndrome (ALPS) is a rare condition characterized by defective apoptotic mechanisms that disrupt lymphocyte homeostasis[1,2,3,4]. Required criteria Chronic (>6 months), non-malignant, non-infectious lymphadenopathy or splenomegaly or both Elevated CD3+TCRab+CD4−CD8− “double negative T cells” (DNT) cells > 1.5% of total lymphocytes or 2.5% of CD3+ lymphocytes with normal or elevated lymphocyte counts Accessory: primary Defective lymphocyte apoptosis Somatic or germline mutation in FAS, FAS ligand gene (FASLG), or caspase-10 gene (CASP10) Accessory: secondary Elevated plasma soluble FAS ligand (sFASL) (>200 pg/mL) or elevated plasma interleukin-10 (IL-10) levels or elevated serum or plasma vitamin B12 levels or elevated plasma IL-18 levels Typical immunohistological findings as reviewed by an experienced hematopathologist Autoimmune cytopenias and elevated IgG levels Family history of a non-malignant/non-infectious lymphoproliferation with or without autoimmunity. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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