A single type of immune cell, the intraepithelial lymphocyte, sits at the crossroads of two seemingly unrelated conditions: allergic responses and the body’s early defence against skin cancer. This matters because the biological link between allergy and cancer has long been observed but poorly understood. The researcher has discovered a mechanism—called Lymphoid Stress-Surveillance—in which physical damage to skin cells triggers the same immune pathway that produces allergic IgE antibodies. This suggests that the IgE antibody, best known for causing allergies, may have a primary role in tumour surveillance. The work fills a gap in fundamental immunology: why the body mounts a Type 2 (allergic) response to sterile tissue damage, when microbial threats typically provoke a different immune reaction. If successful, this research will clarify the basic biology of how IgE responses are initiated at body surfaces. It may reveal a new population of B cells capable of rapid IgE switching. In the longer term, understanding this pathway could reshape how we think about the relationship between allergies and cancer risk. This is fundamental science—it does not promise an immediate treatment, but it lays the molecular groundwork for future work in tumour immunology and allergy.
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My proposal is built on my previous work, which showed that expression of epithelial stress-antigens induced by physico-chemical tissue-damage directly activates local intraepithelial lymphocytes (IEL) that in turn initiate local and systemic Th2 and IgE responses. We have termed this novel mechanism 'Lymphoid Stress-Surveillance' (LSS). This autologous response to sterile stress differs qualitatively from the Th1/Th17 responses induced by microbial stress-antigens. The Type 2 responses induced via LSS are regulated by IEL, which also have key host-protective function(s) in immune-surveillance of cutaneous tumours. These results demonstrate novel molecular links between pathways initiating early phases of tumour-surveillance and those initiating atopic IgE responses. The overarching aim of my proposal is to characterise and explore LSS; this novel pathway of cellular immunology that runs in parallel to conventional ab T cell biology. Key goals are: to investigate fundamental aspect s of LSS and to determine the role of early LSS-induced Th2 immunity and IgE antibodies in epithelial dysregulation and carcinogenesis. Through this work I aim to gain new insight into the primary function of the IgE class of antibody and possibly uncover a new population of B cells with rapid IgE-switching capacity. I will investigate how IgE-associated Th2 immunity is initiated at body-surfaces and what are the host-benefits of these responses. My work thus has clear implications for tumour im munology and allergy. The results will shed new light on the afferent induction of Th2 immunity and will further our understanding of the biological relationship between allergy and cancer.
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