Defects in NK Cells and Other Leukocytes The Chediak Higashi Syndrome

The Chediak-Higashi syndrome is a rare autosomal recessive disorder characterized by recurrent infections by pyogenic bacteria, partial oculocutaneous albinism, and infiltration of various organs by non-neoplastic lymphocytes. The neutrophils, monocytes, and lymphocytes of these patients contain giant lysosomes. This disease is caused by mutations in the gene encoding the lysosomal trafficking regulator protein LYST, resulting in defective phagosome-lysosome fusion in neutrophils and macrophages (causing reduced resistance to infection), defective melanosome formation in melanocytes (causing albinism), and lysosomal abnormalities in cells of the nervous system (causing nerve defects) and platelets (leading to bleeding disorders). Giant lysosomes form in neutrophils during the maturation of these cells from myeloid precursors. Some of these neutrophil precursors die prematurely, resulting in moderate leukopenia. Surviving neutrophils may contain reduced levels of the lysosomal enzymes that normally function in microbial killing. These cells are also defective in chemotaxis and phagocytosis, further contributing to their deficient microbicidal activity. NK cell function in these patients is impaired, probably because of an abnormality in the cytoplasmic granules that store proteins mediating cyto-toxicity. The severity of the defect in cytotoxic T lymphocyte (CTL) function is variable among patients. A mutant mouse strain called the beige mouse is an animal model for the Chediak-Higashi syndrome. This strain is characterized by deficient NK cell function and giant lysosomes in leukocytes. The beige mutation has been mapped to the mouse Lyst locus.

Other mutations that affect both CTL and NK cell function will be considered later when we discuss defects in T lymphocyte activation and function. A mutation in CD16/FcyRIII, the Fc receptor on NK cells that is required for antibody-dependent cellular cytotoxicity (see Chapter 12), has been described in a patient with recurrent viral infections.

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