The functional significance of the Duffy negative polymorphism

Novitzky Basso, Igor Nicolas (2015). The functional significance of the Duffy negative polymorphism. University of Birmingham. Ph.D.

Preview

NovitzkyBasso15PhD.pdf
PDF - Accepted Version
Download (28MB)

Abstract

I investigated the impact of DARC expression on haematopoiesis using DARC-deficient (DD) mice and developed humanised transgenic DARC models expressing the \(FYB(ES)\) and \(FYB\) human genes.
I developed murine irradiation chimeras with differential DARC expression and showed that the absence of erythroid DARC but continued DARC endothelial expression was associated with reduced peripheral blood neutrophil counts. FYB(ES)TG mice showed reduced peripheral neutrophil counts and expansion of BM myelopoiesis, and reduced lymphopoiesis and erythropoiesis, compared to FYBTG mice. FYB(ES)TG and DD mice had reduced GMP cells and LSK cells, and proliferation and apoptosis of these cells were reduced. Microarray analysis of differentially expressed genes showed increased myeloid gene expression in GMP and LSK cells. Mixed irradiation chimeras showed that DD BM retained these changes, suggesting an intrinsic cell effect. Analysis of BM and serum showed a significant increase in G-CSF and eotaxin. Morphological analysis of myeloid cells in femur sections revealed increased myeloid cell clustering in DD and FYB(ES)TG mice. These data suggest that neutrophils are preferentially retained in the DD BM, possibly as a result of loss of optimal chemokine gradients created by erythroblast DARC which may favour neutrophil egress and thereby leading to peripheral neutropenia.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):