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Apoptosis is an energy-dependent, biochemically-mediated process of programmed cell death. Apoptosis is essential for many processes, including the elimination of infected or transformed cells, a properly functioning immune system, organismal development, and maintaining homeostasis and normal cell turnover in the body. The two main branches of apoptotic pathways are the intrinsic and extrinsic pathways of apoptosis, in which the signals initiating cell death originate from within or outside the cell, respectively.[1] The intrinsic pathway initiates from intracellular sensors that detect DNA damage, the presence of viral pathogens, or in response to the lack of survival signals provided externally from other cells. In contrast, the extrinsic pathway of apoptosis initiates with a pro-death signal originating from outside the cell, most often by Natural Killer (NK) lymphocytes or CD8-positive Cytotoxic T lymphocytes (CTLs).
A heterozygous mutation in the gene for Fas, also known as CD95, is the most prominent cause of the condition known as an autoimmune lymphoproliferative syndrome (ALPS). Since the Fas receptor functions as a trimer, heterozygotes suffer from the disease, as one defective copy of the protein will destroy the ability of the Fas receptor to function. Additional mutations that cause ALPS have been identified in FasL and caspase-8, among other proteins. The inability of ALPS patients to clear a large number of clonally expanded lymphocytes after clearance of an infection results in lymphadenopathy and splenomegaly that appear early in childhood.[14] ALPS patients most often also develop autoimmune disorders and are at increased risk for developing lymphomas, since the extrinsic pathway of apoptosis contributes to the elimination of self-reactive lymphocytes, as well as malignant lymphocytes. Patients may also present with cytopenias, hypergammaglobulinemia, and frequent infections. Management includes corticosteroids and IVIG for first-line therapy with rituximab also used for managing autoimmune symptoms.