Microbicidal/cytotoxic proteins of neutrophils are deficient in two disorders: Chediak-Higashi syndrome and "specific" granule deficiency.

Ganz, Tomas; Metcalf, Julia A.; Ji, Gallin; Boxer, L; Lehrer, RI

doi:10.1172/jci113631

Cited by 176 publications

(94 citation statements)

References 27 publications

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“…The propensity for infections in CHS is believed in part to be due to neutropenia and to deficient chemotaxis and delayed bacterial killing of neutrophils [6][7][8]. The latter is most likely caused by reduced content of certain microbicidal/cytotoxic proteins in CHS neutrophils [9] and by diminished mobilization of the giant granules [7,10,11], which contain the majority of the microbicidal substances of neutrophils.…”

Section: Introductionmentioning

confidence: 99%

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

Kjeldsen

Calafat

Borregaard

1998

Journal of Leukocyte Biology

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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.

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Section: Introductionmentioning

confidence: 99%

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

Kjeldsen

Calafat

Borregaard

1998

Journal of Leukocyte Biology

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“…Human-specific granule deficiency (SGD) is a rare congenital disease in which the patients have an absence of or severe deficiency in neutrophil secondary and tertiary granules and associated components. 8,9,16 Numerous abnormalities exist in the neutrophils from these patients rendering them susceptible to severe, lifethreatening microbial infections typically caused by Staphylococcus aureus or Pseudomonas aeruginosa. [17][18][19][20] It has been shown that an underlying cause of two cases of SGD is a loss of function mutation in the CCAAT/ enhancer-binding protein (C/EBP ).…”

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confidence: 99%

Stimulus-Dependent Impairment of the Neutrophil Oxidative Burst Response in Lactoferrin-Deficient Mice

Ward

Mendoza-Meneses

Park

et al. 2008

The American Journal of Pathology

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Lactoferrin (LF) is an iron-binding protein found in milk, mucosal secretions, and the secondary granules of neutrophils in which it is considered to be an important factor in the innate immune response against microbial infections. Moreover, LF deficiency in the secondary granules of neutrophils has long been speculated to contribute directly to the hypersusceptibility of specific granule deficiency (SGD) patients to severe, life-threatening bacterial infections. However, the exact physiological significance of LF in neutrophil-mediated host defense mechanisms remains controversial and has not yet been clearly established in vivo using relevant animal models. In this study, we used lactoferrin knockout (LFKO) mice to directly address the selective role of LF in the host defense response of neutrophils and to determine its contribution, if any, to the phenotype of SGD. Neutrophil maturation, migration, phagocytosis, granule release, and antimicrobial response to bacterial challenge were unaffected in LFKO mice. Interestingly, a stimulus-dependent defect in the oxidative burst response of LFKO neutrophils was observed in that normal activation was seen in response to opsonized bacteria whereas an impaired response was evident after phorbol myristate-13-acetate stimulation. Taken together, these results indicate that although LF deficiency alone is not a primary cause of the defects associated with SGD, this protein does play an immunomodulatory role in the oxidative burst response of neutrophils.

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“…Human neutrophil defensin (HNP-3) deviates from the proposed paradigm, as mRNA for HNP-3, an azurophilic granule protein, mirrors the profile of lactoferrin, a specific granule constituent, rather than those of myeloperoxidase or other azurophilic granule markers. Although not explained by the authors, such a finding is not wholly unanticipated because neutrophils from subjects with specific granule deficiency were previously reported to lack defensins [9].…”

Section: Inflammation Program and Departments Of Medicine Universitymentioning

confidence: 68%

Neutrophil granules: heterogeneity of their contents reflects targeting by timing

Nauseef

1999

Journal of Leukocyte Biology

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Microbicidal/cytotoxic proteins of neutrophils are deficient in two disorders: Chediak-Higashi syndrome and "specific" granule deficiency.

Cited by 176 publications

References 27 publications

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

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

Stimulus-Dependent Impairment of the Neutrophil Oxidative Burst Response in Lactoferrin-Deficient Mice

Neutrophil granules: heterogeneity of their contents reflects targeting by timing

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