Abstract
Specific granule deficiency (SGD) is a rare congenital disorder characterized by recurrent infections. The disease is caused by inactivating mutations of the CCAAT/enhancer binding protein-ε (C/EBP-ε) gene. As a consequence, specific and gelatinase granules lack most matrix proteins. Furthermore, azurophil granules contain diminished amounts of their most abundant proteins, α-defensins, also known as human neutrophil peptides (HNPs). In accordance with this, in vitro models have demonstrated induction of HNPs by C/EBP-ε. Since mice do not express myeloid defensins, they cannot per se be used to characterize the role of C/EBP-ε in controlling HNP expression in vivo. We therefore crossed a transgenic HNP-1-expressing mouse with the Cebpe-/- mouse to study the in vivo significance of C/EBP-ε for HNP-1 transcription and expression. Surprisingly, neither expression nor processing of HNP-1 was affected by lack of C/EBP-ε in these mice. Transduction of C/EBP-ε into primary bone marrow cells from HNP-1 mice induced some HNP-1 expression, but not to levels comparable to expression human cells. Taken together, our data infer that the HNP-1 of the transgenic mouse does not show an expression pattern equivalent to endogenous secondary granule proteins. This limits the use of these transgenic mice as a model for human conditions.
Highlights
Specific granule deficiency (SGD) is a rare congenital disorder caused by a defect in formation of peroxidase negative neutrophil granules
CCAAT/enhancer binding protein-e (C/EBP-e) is critical for transcription of most granule proteins localized to specific and gelatinase granules as well as for azurophil granule proteins expressed in the late promyelocyte stage such as bactericidal permeability increasing protein (BPI) and human neutrophil peptides (HNPs) [1,4,6]
HNP-1 expression is not affected by lack of C/EBP-e in mice Transgenic HNP-1 mice were crossbred with Cebpe-/- mice to test in vivo the significance of C/EBP-e for HNP-1 expression
Summary
Specific granule deficiency (SGD) is a rare congenital disorder caused by a defect in formation of peroxidase negative neutrophil granules. The patients suffer from recurrent infections, often in the form of abscesses Their number of neutrophils is generally within the normal range, but these are structurally characterized by the pseudo-Pelger-Huet nuclear abnormality and by lack or minimal levels of proteins localized to the matrix of peroxidase negative granules such as lactoferrin and vitamin-B12binding protein [1]. Their azurophil granules are lighter than normal [2] and contain little or none of the most abundant of azurophil granule proteins, human neutrophil peptides (HNPs), which constitute 30–50% of the azurophil granule content in neutrophil from healthy donors [3]. HNPs are reduced by over 90% in SGD [11]
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