title: A novel syndrome of severe neutrophil dysfunction: unresponsiveness confined to chemotaxin-induced functions.
abstract: We have identified a patient with a number of neutrophil dysfunctions. The patient was a female baby who lived for 8 months. During her life, she developed severe bacterial infections and showed omphalitis, impaired wound healing, and a pronounced leukocytosis. She was not a patient with leukocyte adhesion deficiency, because all leukocyte CD18 complex proteins were expressed at normal levels. Yet, neutrophil polarization and chemotaxis to platelet-activating factor, leukotriene B4, or formyl-methionyl-leucyl-phenylalanine (FMLP) were completely absent. We found a strong defect in actin polymerization in response to chemotactic stimuli, but only a retarded or even normal reaction with other stimuli. This indicates that the cellular dysfunctions were not due to an intrinsic defect in actin metabolism. Instead, the regulation of actin polymerization with chemotactic stimuli seemed to be defective. We concentrated on FMLP-induced responses in the patient's neutrophils. Functions dependent on activation of complement receptor type 3, such as aggregation or adherence to endothelial cells, were normally induced. Binding to serum-coated coverslips was normal in cell number; however, spreading was not observed. Exocytosis from the specific granules was readily induced. In contrast, FMLP failed to induce a respiratory burst activity or degranulation of the azurophil granules. FMLP induced a normal increase in free intracellular Ca2+, but a decreased formation of diglycerides (especially the 1-O-alkyl,2-acyl compounds). Thus, we have described a patient whose neutrophils show a severe defect in functional activation via chemotaxin receptors, resulting in a selective absence of NADPH oxidase activity, exocytosis from the azurophil granules, and actin polymerization. Our findings show that actin polymerization for neutrophil spreading and locomotion is regulated differently from that for phagocytosis. Also, the release of azurophil and specific granule contents is clearly shown to be regulated in a different way.
authors.affiliation: Central Laboratory, Netherlands Red Cross Blood Transfusion Service, Amsterdam.
authors.forename: D
authors.initials: D
authors.lastname: Roos
authors.forename: T W
authors.initials: TW
authors.lastname: Kuijpers
authors.forename: F
authors.initials: F
authors.lastname: Mascart-Lemone
authors.forename: L
authors.initials: L
authors.lastname: Koenderman
authors.forename: M
authors.initials: M
authors.lastname: de Boer
authors.forename: R
authors.initials: R
authors.lastname: van Zwieten
authors.forename: A J
authors.initials: AJ
authors.lastname: Verhoeven
mesh_terms: D000199:Actins / Q000378:metabolism; D015703:Antigens, CD / Q000097:blood*; D018821:CD18 Antigens; D015704:CD4 Antigens / Q000097:blood; D016827:CD8 Antigens / Q000097:blood; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000097:blood; D002448:Cell Adhesion; D002449:Cell Aggregation / Q000187:drug effects; D002634:Chemotaxis, Leukocyte; D003571:Cytochalasin B / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000502:physiology; D005260:Female; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000097:blood* / Q000276:immunology; D066298:In Vitro Techniques; D007231:Infant, Newborn; D007700:Kinetics; D007958:Leukocyte Count; D007975:Leukotriene B4 / Q000494:pharmacology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D010101:Oxygen Consumption / Q000187:drug effects; D010972:Platelet Activating Factor / Q000494:pharmacology; D012016:Reference Values; D018805:Sepsis / Q000097:blood / Q000209:etiology; D013577:Syndrome; D016176:T-Lymphocyte Subsets / Q000276:immunology
chemical_list: D000199:Actins; D015703:Antigens, CD; D018821:CD18 Antigens; D015704:CD4 Antigens; D016827:CD8 Antigens; D010972:Platelet Activating Factor; D007975:Leukotriene B4; D000001:Calcimycin; D003571:Cytochalasin B; D009240:N-Formylmethionine Leucyl-Phenylalanine; D002118:Calcium