Lysosome enlargement in the Chediak-Higashi syndrome

The Chediak-Higashi syndrome (CHS) is characterized by the occurrence of large inclusions in granulocytes and other cells. Analogs of the human disease are known in several species. Severity of clinical manifestations and extent of neutrophil alteration correlate closely and decrease in the order: man, mink, and mouse. The megabodies in granulocytes of Aleutian mink with CHS represent abnormal primary lysosomes that develop through fusion between stored lysosomal granules. The CHS alteration in mink affects azurophil granules of neutrophils more severely than the granules of eosinophils or basophils and spares specific granules of neutrophils. Several other types of cells exhibit megabodies that apparently cause little or no dysfunction in beige mice showing the CHS defect. Mast cells in these mice contain enlarged storage lysosomes, and Type II pneumocytes and gastric chief cells show enlarged secretory granules. Gastric chief cells, parietal cells, and hepatocytes enclose hypertrophied secondary lysosomes that function in autophagy whereas proximal renal tubules and cultured fibroblasts display hypertrophic secondary lysosomes of heterophagic nature. The cell distribution of megabodies in beige mice suggests they result from increased fusion between organelles delimited by membranes adapted to sequestration of hydrolytic enzymes.