Brown, Georgina Rose; (2025) The interaction of surfactant protein D and mast cells with dendritic cells in allergic asthma. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Allergic asthma is a multi-factorial inflammatory disease characterised by a T2-type lymphocyte response, partly occurring when dendritic cells (DCs) aberrantly induce a Th2 response. How DC function fits into the wider innate immune network in allergy is not fully understood and disrupting this network presents a potential opportunity to treat allergic asthma. This project investigated how DCs interact with surfactant protein D (SP-D) and mast cells. SP-D is an innate immune molecule that binds to non-self-glycoproteins and has been found to be immunomodulatory. A recombinant form of SP-D (rfhSP-D) has been developed that preserves most functions of the native protein. Mast cells are inflammatory effector cells that have been found to influence DC behaviour. However, under some conditions, they can exert an anti-inflammatory influence. THP1-dual human monocytes were differentiated into THP-1-derived dendritic cells (TDDCs). The TDDCs were then challenged with allergen (Timothy grass pollen), SP-D or rfhSP-D, or co-cultured with immortalised LAD2 cells. Changing TDDC behaviour under these conditions was interrogated via activation of the NF-κB pathway, the cell surface marker profile (upregulated CD40, CD80, CD86, and HLA-DR), and cytokine expression including IL-1β, IL-8, IL-10, IL-13, TNF-α, and TGF-β. Global protein expression was investigated using proteomics. THP-1-derived DCs matured after encountering Timothy grass pollen, as indicated by a change in surface marker expression, albeit with suppressed cytokine secretion. Conversely, SP-D induced a pleiotropic inflammatory response in the cytokine profile and pathways of the DCs. rfhSP-D did not provoke as strong an immunomodulatory response but did perturb signalling within the DCs. A synergistic relationship was found between mast and dendritic cells in co-culture, with mast cells in the steady state becoming more capable of antigen presentation and demonstrating increased CD40 and HLA-DR expression. The cytokine environment in co-culture was also found to be both anti-inflammatory (increased IL-10 secretion) and allergic (increased IL-13 secretion). These results highlight that DCs may play a central role in allergy, and how innate immune components can modulate this.

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