Jenkins, Harry H.
(2022)
Helicobacter pylori: cellular immunity and protection from Multiple Sclerosis.
PhD thesis, University of Nottingham.
Abstract
Helicobacter pylori colonises the stomachs of almost half the world’s population, subverting host immunity to usually establish a life-long infection. Although asymptomatic in most cases, peptic ulcer disease and gastric cancer develop in a minority of those colonised. Recently, more evidence is emerging that the reducing prevalence of infections in developed countries is linked with the stark rise of allergy, asthma, and autoimmune diseases such as multiple sclerosis (MS).
The ‘Old friend’s hypothesis’, suggests that the lack of exposure to certain microbes, likely by increasing antibiotic use and improved sanitation, causes dysregulated immunity leading to immune and inflammatory conditions. The microbiota also regulates host immunity, during homeostasis and in the response to infection and susceptibility for disease development. The induction of tolerogenic dendritic cells and IL-10-producing regulatory T-cells, is an important H. pylori persistence mechanism. In the literature, these responses are also linked to the mitigation of extra-gastric diseases. Inadequate Treg responses are associated with a negative prognosis, especially in MS. This is the most common neurological condition affecting young adults, causing chronic progressive disability with a devastating impact on quality of life. Using the mouse model experimental autoimmune encephalomyelitis (EAE), the research group previously reported a reduced severity of EAE when infected with H. pylori.
For the current studies, it was hypothesised that protection from MS may be mediated through H. pylori modulation of the T-helper response. Gastric mucosal inflammation induced by H. pylori may alter lymphocyte homing patterns and reduce infiltration to the central nervous system. The regulatory T-cell response has previously been shown to facilitate repair in a demyelinated central nervous system by the secreted factor CCN3. This was proposed as a potential mechanism for H. pylori to mediate a protective effect in EAE or MS. Murine glia were cultured with CD4 supernatants to investigate the myelinating capacity of oligodendrocytes.
Firstly, differences in the peripheral blood T-helper and cytokine responses were investigated between infected and uninfected patients, and infected patients before and after H. pylori eradication therapy. Differences in IL-17A, IL-12p70 and IL-10 concentrations were detected according to presence of H. pylori infection and gastro-duodenal pathology. The CD4+ T-helper cytokines IL10 and IL17A were differentially expressed at the mRNA level in PBMCs between infected and uninfected patients. IL10 mRNA was elevated following H. pylori eradication, concurrent with a reducing anti-Hp humoral IgG response. This indicates that the infection exerts important effects on the immune system.
Using the EAE model, a strain-specific mitigation of disease severity was observed when infected with H. pylori strain SS1 compared to PMSS1, independently of the CD4 T-helper subsets quantified. A fluorescence-based technique was developed for in vivo imaging of EAE CD4+ T-cells adoptively transferred to infected or uninfected recipient mice. The CD4+ T-cell populations from the spleens and mesenteric lymph nodes of H. pylori infected mice contained higher frequencies of both pro- and anti-inflammatory T-helper subsets. CCN3 mRNA was markedly elevated in cells from infected mice. There was a marked increase in myelin production from glia treated with supernatants from CD4 cells, and this was slightly higher using the cell supernatants from infected mice. The differences observed were modest, and further work is required to confirm and expand on these preliminary findings.
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