Thesis Roel Gazendam
On 28 September 2016 Roel Gazendam defended his thesis ´Neutrophil microbial killing mechanisms. Lessons learned from primary immunodeficiencies´ at the University of Amsterdam.
He was awarderd the doctorate cum laude.
Promotor: prof TW Kuijpers MD PhD
Copromotores: TK van den Berg PhD and prof D Roos PhD
The research for this thesis was conducted at the Dept of Blood Cell Research of Sanquin Research and was financially supported by the Landsteiner Foundation for Blood Transfusion Research (LSBR) and Sanquin.
Summary
Humans and microbes have a balanced and longstanding relationship. Immunosuppresive therapies and primary immunodeficiencies (PIDs) may disturb this balance and result in infection. Patients with neutropenia or PIDs with neutrophil functional defects, including Chronic Granulomatous Disease (CGD), are susceptible to invasive fungal infections, accompanied by high rates of mortality. Neutrophils are the first line of defense, and important effector cells in the killing of invading pathogens and prevention of invasive infections.
We have studied in this thesis the antimicrobial function of neutrophils from patients with novel primary immunodeficiencies (PIDs), resulting in a susceptibility to bacterial and fungal infections. In additition, the antimicrobial function of G-CSF/dexamethasone-mobilized neutrophils used for transfusion purposes was determined. Experiments with these human “knock-out” neutrophils have expanded our knowledge about the role of Pathogen Recognition Receptors and signaling in microbial killing in humans. Neutrophils have distinct mechanisms for the killing of S. aureus, E. coli, C. albicans or A. fumigatus conidia and hyphae. The formation of Neutrophil Extracellular Traps (NETs) is not required for the killing of C. albicans or A. fumigatus. G-CSF/dexamethasone-mobilized neutrophils used for transfusion purposes, are impaired in Candida yeast killing, but normally kill bacterial and fungal pathogens.
Chapters
Chapter 1
Introduction
How neutrophils kill fungi
Immunological Reviews 2016 (273) Sept; in press
Chapter 2
Invasive fungal infection and impaired neutrophil killing in human CARD9 deficiency’’
Blood 2013; 121(13):2385-92.
Chapter 3
Chronic Candida albicans meningitis in a 4-year-old girl with a homozygous mutation in the CARD9 gene (Q295X)
Pediatr Infect Dis J 2015; 34(9):999-1002.
Chapter 4
Extrapulmonary Aspergillus infection in patients with CARD9 Deficiency.
J Allergy Clin Immunol 2016; resubmitted
Chapter 5
Defects in neutrophil granule mobilization and bactericidal activity in familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) syndrome caused by STXBP2/Munc18-2 mutations.
Blood 2013; 122(1):109-11.
Chapter 6
Impaired microbial killing by neutrophils from patients with PKC delta deficiency.
J Allergy Clin Immunol 2015; 136(5):1404-7.
http://www.ncbi.nlm.nih.gov/pubmed/26233929
Chapter 7
Neutrophil specific granule deficiency and impaired NETosis in Gray Platelet Syndrome.
J Clin Invest 2016; submitted
Chapter 8
Pro-inflammatory response to fungal but not to bacterial pathogens in Chronic Granulomatous Disease.
J Allergy Clin Immunol 2016 May; in press
Chapter 9
Two independent killing mechanisms of Candida albicans by human neutrophils: evidence from innate immunity defects.
Blood 2014; 124(4):590-7.
Chapter 10
Human neutrophils employ distinct mechanisms for the killing of Aspergillus fumigatus conidia and hyphae: evidence from phagocyte defects.
J Immunol 2016; 196(3):1272-83.
Chapter 11
G-CSF/dexamethasone mobilized granulocytes for transfusion purposes are impaired in Candida albicans killing.
Haematologica 2016; 101(5):587-96.
Chapter 12
Characterization of buffy-coat-derived granulocytes for clinical use: a comparison with GCSF/dexamethasone-treated donor-derived products.
Vox Sang 2016; submitted
Chapter 13
Discussion
Download
Download PhD thesis (university repository)