In patients with Chediak–Higashi syndrome, abnormal giant lysosomes and granules accumulate in T lymphocytes, myeloid cells, platelets, and melanocytes. The hair is typically a metallic silver color, vision is poor because of abnormalities in retinal pigment cells, and platelet dysfunction causes increased bleeding. Because the phagocytes of these patients have defective phagolysosomal fusion, the patients experience defective killing of intracellular and extracellular pathogens in addition to defective cytolytic activity of CTLs and NK cells. Affected children therefore suffer early in life from severe, recurrent infections by a range of bacteria and fungi. This is typically followed by development of hemophagocytic lymphohistiocytosis, often triggered by viral infection such as EBV, leading to an accelerated phase of the disease. Three variants of Griscelli syndrome have been identified, each caused by a distinct gene defect: in the type 2 variant (RAB27A mutation), the defect results in both immunodeficiency and pigment abnormalities; in types 1 and 3, only the pigment abnormalities are found. Although the immune defects in children
Fig. 13.9 Defects in components involved in the exocytosis of cytotoxic granules cause familial hemophagocytic lymphohistiocytosis (FHL) syndromes. Following antigen recognition, there is polarization of perforin-containing cytotoxic granules of the Ctl toward the target cell at the site of immunological synapse formation. Cytotoxic granules are transported along microtubules to the plasma membrane, where they dock through a RaB27a-dependent interaction. Docked vesicles are primed by Munc13-4-mediated triggering of a conformational change in syntaxin 11, which is part of a large SnaRe (soluble N-ethylmaleimide-sensitive factor accessory protein receptor) complex connecting the docked vesicle with the plasma membrane. through the actions of Munc18-2, a fusion reaction is initiated via the syntaxin 11-containing SnaRe complex that releases the contents of the cytotoxic granules into the synapse-bounded intercellular space, allowing perforin-mediated pore formation in the target-cell plasma membrane. the sites in the exocytic pathway that are affected by inherited defects in each of the proteins highlighted in red are indicated, as is the associated familial hemophagocytic lymphohistiocytosis syndrome.
with type 2 Griscelli syndrome have much in common with those of Chediak– Higashi syndrome, their myeloid cells lack the giant intracellular granules that are characteristic of the latter.
13-12 X-linked lymphoproliferative syndrome is associated with fatal infection by Epstein–Barr virus and with the development of lymphomas.