Phenotypic and functional alterations of peripheral blood monocytes in neutrophil-specific granule deficiency.
Neutrophil-specific granule deficiency (SGD) is a rare, congenital disease characterized by atypical neutrophil structure and function, resulting in recurrent bacterial infections from early infancy. Homozygous recessive mutations in the CCAAT/enhancer-binding protein epsilon (C/EBPepsilon) gene were described in two of five SGD patients, indicating loss of C/EBPepsilon function as the primary genetic defect in this disease. C/EBPepsilon is expressed in murine and human macrophages. Macrophages from the C/EBPepsilon-deficient mice show impaired differentiation, phagocytic activity, and transcription of macrophage-specific genes. To determine if monocyte/macrophage cells are impacted in SGD, we analyzed phenotypic features of peripheral blood (PB) monocytes in a SGD individual lacking functional C/EBPepsilon. Flow cytometric analysis of PB leukocytes revealed aberrant expression of CD45, CD11b, CD14, CD15, and CD16 on cells from the SGD individual. Also, the PB CD14(+) cells from this individual, weakly stained for the monocyte-specific enzyme, nonspecific esterase, and electron microscopic examination, indicated morphologic differences between the SGD cells and those from normal controls. Serum interleukin (IL)-6 levels in the SGD individual during a severe bacterial infection were lower compared with levels in other non-SGD individuals with sepsis. In contrast, serum IL-8 levels were markedly elevated in the SGD individual compared with those of non-SGD individuals in sepsis. PB CD14(+) cells from the SGD individual expressed higher IL-8 mRNA levels compared with normal controls in response to lipopolysaccharide and interferon-gamma. These phenotypic and functional alterations of PB monocytes in the SGD individual suggest that C/EBPepsilon plays a critical role in monocyte/macrophage development of humans and is consistent with observations in the murine system. This study implicates abnormalities in monocytes/macrophages and neutrophils in the onset and development of SGD.
Shiohara
Masaaki
M
Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, 390-8621 Japan. mjshio@poa.matsumoto.ne.jp
Gombart
Adrian F
AF
Sekiguchi
Yukio
Y
Hidaka
Eiko
E
Ito
Susumu
S
Yamazaki
Takashi
T
Koeffler
H Phillip
HP
Komiyama
Atsushi
A
D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics; D043182:Carboxylesterase / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D003594:Cytoplasmic Granules / Q000473:pathology*; D005260:Female; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000097:blood* / Q000151:congenital; D016130:Immunophenotyping; D016209:Interleukin-8 / Q000235:genetics; D051379:Mice; D008854:Microscopy, Electron; D009000:Monocytes / Q000276:immunology / Q000473:pathology*; D009154:Mutation; D009504:Neutrophils / Q000473:pathology* / Q000648:ultrastructure; D012333:RNA, Messenger / Q000032:analysis
D015703:Antigens, CD; D022762:CCAAT-Enhancer-Binding Proteins; D016207:Cytokines; D016209:Interleukin-8; D012333:RNA, Messenger; D043182:Carboxylesterase