Evans, Rhys D R;
(2020)
An investigation into the effect of salt (sodium chloride) on immunity in patients with kidney disease.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
The salt (sodium chloride; NaCl) content of a western diet far exceeds the amount that we consumed through most of our evolutionary history. It is accepted that excess sodium intake causes hypertension and cardiovascular disease, but it has been recently shown that sodium also affects immunity, and high salt diets worsen animal models of autoimmune disease. Sodium has been shown to activate multiple immune cells, including Th17 cells, which provide protection from bacterial and fungal infection but which are also implicated in autoimmune disease. The mechanism by which sodium polarises Th17 cells, whether salt depletion has clinical consequences, and if altering sodium balance affects the development of inflammatory kidney diseases are unknown. In this project, I investigate the effect of salt on IL-17 responses and how this is relevant in patients with kidney disease. I demonstrate that NaCl promotes IL-17 responses in both CD4+ (Th17) and CD8+ (Tc17) cells. This effect is mediated by sodium altering calcium flux during T cell activation and may be abrogated by inhibition of the sodium-potassium-chloride (NKCC) transporter and the epithelial sodium channel (ENaC) on immune cells. Patients with inherited salt losing tubulopathies (SLTs) have clinical features of immunodeficiency with increased infections and allergic disease. This is associated with a reduced ratio of circulating Th17:Th2 cells, and Th17 polarisation in SLT patients is impaired compared with controls. I show that SLT patients have reduced sodium stores and that the typical extracellular ionic environment in SLT is inhibitory to Th17 polarisation. Salt supplementation in vitro rescues IL-17 responses in SLT patients. Lastly, I demonstrate that Th17 cells are salt responsive in patients with inflammatory kidney disease despite in vivo immunosuppression. A high salt diet did not alter the development of an animal model of glomerulonephritis, but a low salt diet was a feasible therapeutic intervention in kidney transplant recipients.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | An investigation into the effect of salt (sodium chloride) on immunity in patients with kidney disease |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2020. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10103749 |
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