The hemophagocytic lymphohistiocytosis (HLH) syndromes are a group of life-threatening immunodeficiency disorders in which NK cell and CTL granule secretion is defective. As a result, viral infections are not held in check, and uncontrolled macrophage activation is a feature of these syndromes. A late but striking feature of these disorders is the ingestion of red blood cells by activated macrophages (hemophagocytosis). Mutations in the perforin gene, as well as mutations in genes encoding the cellular machinery involved in granule exocytosis, can contribute to the phenotypes observed in this syndrome. Specifically, mutations in RAB27A, a small guano-sine triphosphatase involved in vesicular fusion, and in MUNC13-4, which encodes an adaptor that participates in granule exocytosis, compromise the fusion of lytic granules with the plasma membrane and thus contribute to various subtypes of HLH. Similarly, mutations in the gene for one component of the AP-3 cytosolic adaptor protein complex can also disrupt intracellular transport and contribute to a form of HLH. It is believed that T cells and macrophages respond strongly to microbes to compensate for the CTL and NK cell defects, and these compensatory responses are manifested by hemophagocytosis and lymphadenopathy in the context of immunodeficiency.
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