Giant granules of neutrophils in Chediak-Higashi syndrome are derived from azurophil granules but not from specific and gelatinase granules

Abstract

The abnormal giant granules of ChediakHigashi syndrome (CHS) neutrophils in humans are thought to be derived from both azurophil and specific granules, whereas the presence of gelatinase granules and their contribution to giant granule formation has not been investigated previously. We have examined the ultrastructure and mobilization of neutrophil granules from a patient with CHS by immunogold electron microscopy and exocytosis experiments of isolated leukocytes. The giant granules contained the azurophil granule components myeloperoxidase and CD63. We found no evidence of involvement of specific or gelatinase granules in the formation of giant granules because lactoferrin and gelatinase were contained in normalappearing peroxidase-negative granules. On stimulation of leukocytes with N-formyl-methionyl-leucylphenylalanine and the calcium ionophore, ionomycin, there was a diminished exocytosis of myeloperoxidase in CHS compared with a healthy control, indicating a lack of mobilization of the giant granules. On the other hand, there was a normal or augmented release of lactoferrin and gelatinase in CHS neutrophils, with gelatinase granules being the most easily mobilized, as known from normal neutrophils. In conclusion, giant granules from CHS neutrophils originate from azurophil granules but not from the specific and gelatinase granules. J. Leukoc. Biol. 64: 72-77; 1998.

Human Neutrophils Secrete Bioactive Paucimannosidic Proteins from Azurophilic Granules into Pathogen-Infected Sputum

“…The virulence-specific release of paucimannosidic proteins into sputum upon P. aeruginosa stimulation indicates an infectiondependent mobilization of azurophilic granules, aspects we are currently investigating by bacterial genome sequencing and proteomics. The importance of granule mobilization for innate immunity is well illustrated in the Chediak-Higashi syndrome where immobile azurophilic granules reduce the host response to pathogens (64). The induced secretion of paucimannosidic proteins from neutrophils presented here indicates that, as reported (40,62), granules fuse not only with the phagolysosome, but also with the plasma membrane upon activation.…”

Effects of recombinant granulocyte-colony stimulating factor administration duringMycobacterium aviuminfection in mice

“…We should note that our model of immunodeficiency was the beige mouse that does not mimic the defects in AIDS patients. Also, the neutrophil defects (related to the deficient development of the specific granules in neutrophils [48] caused by the mutation of the Lyst gene [49]) are not recovered by G-CSF, although we have found some reversion in oxidative metabolism (our unpublished observations). Therefore, it would be interesting to pursue these studies in other models of immunodeficiency that mimic more closely the defects of AIDS patients.…”

Chediak–Higashi Syndrome Presented as Accelerated Phase: Case Report and Review of the Literature

“…This gene effects protein synthesis or/and maintenance of storage and secretory lysosomal granules of leukocytes and fibroblasts, dense bodies of platelets, azurophilic granules of neutrophils and melanosomes of melanocytes. Granules are composed of abnormal fusion of primary granules (azurophilic) with secondary granules (specific) [1,8,12]. Patients with CHS exhibit alterations in neutrophils including neutropenia, decreased deformability resulting in impaired chemotaxis and delayed phagolysosomal fusion resulting in impaired bactericidal activity.…”

“…Lymphocytes contain large giant cytoplasmic granules and function poorly in antibody dependent cell mediated cytolysis of tumour cells. Natural killer cell function was also reduced [3,10,12]. A deficiency of granules containing serotonin and adenosine phosphate in platelets leads to defective platelet aggregation and prolonged bleeding time [5].…”