Date of Award

2014

Document type

Thesis

Degree Name

MSc by research (Master of Science by research)

First Supervisor

Professor Caroline Jefferies

Funder/Sponsor

Alliance for Lupus Research

Keywords

Lupus, SLE, Inflammation, Siglec, Nanopartcles

Abstract

Systemic Lupus Erythematosus (SLE) is an autoimmune disease which is well characterized by the over production of proinflammatory cytokines such as type I interferons (IFN) and TNFα, downstream of the pathogen recognition toll-like receptors, TLR-7 and TLR-9. Sialic Acid Immunoglobulin-Like Lectins (Siglecs) are cell surface receptors that have previously shown to be negative regulators of type I IFNs. Murine Siglec-E is one such negative regulator that has the ability to inhibit TLR driven IFN production. PLGA nanoparticles conjugated to the sialic acid ligand of Siglec-E (Sia NPs) were observed to inhibit production of the pro-inflammatory cytokine, TNFα in murine peritoneal macrophages. Biodistribution analysis in mice showed that fluorescently labeled- Sia NPs localized to areas known to have high levels of Siglec-E expression. The aim of this study was to evaluate the capability of these nanoparticles to activate the human orthologues of Siglec-E, Siglec-7 and Siglec-9, in human peripheral blood mononuclear cells in order to investigate their potential as a therapeutic modality in SLE patients. Expression analysis demonstrated that SLE patients display lower levels of Siglec-7 and Siglec-9 expression in resting immune cells compared to healthy controls. Following stimulation, Siglec-7 is upregulated in peripheral blood mononuclear cells. Unexpectedly however, addition of Sia NPs resulted in exacerbation of the proinflammatory response as measured by TNF-α and RANTES expression suggesting that Siglec-7, while it possesses an inhibitory motif, may in fact be acting in a pro- inflammatory manner. Screening of other potential ligands identified sialic acid GD3 as an inhibitor of TLR and immune complex driven cytokine production in immune cells. Whether this is mediated by Siglec 7 however was not determined. Further investigation into the role of Siglec-7 in SLE patient monocytes and immune cells is required before it can be determined to be a good target for activation with sialic acid coated nanoparticles.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 4.0 License.

File Size

1.63 MB

Comments

A thesis submitted for the degree of Master of Science from the Royal College of Surgeons in Ireland in 2014

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