Inflammation-induced IgE promotes epithelial hyperplasia and tumour growth

IgE is the least abundant circulating antibody class but is constitutively present in healthy tissues bound to resident cells via its high-affinity receptor, FcεRI. The physiological role of endogenous IgE antibodies is unclear but it has been suggested that they provide host protection against a variety of noxious environmental substances and parasitic infections at epithelial barrier surfaces. Here we show, in mice, that skin inflammation enhances levels of IgE antibodies that have natural specificities and a repertoire, VDJ rearrangements and CDRH3 characteristics similar to those of IgE antibodies in healthy tissue. IgE-bearing basophils are recruited to inflamed skin via CXCL12 and thymic stromal lymphopoietin (TSLP)/IL-3-dependent upregulation of CXCR4. In the inflamed skin, IgE/FcεRI-signalling in basophils promotes epithelial cell growth and differentiation, partly through histamine engagement of H1R and H4R. Furthermore, this IgE response strongly drives tumour outgrowth of epithelial cells harbouring oncogenic mutation. These findings indicate that natural IgE antibodies support skin barrier defences, but that during chronic tissue inflammation this role may be subverted to promote tumour growth

C3 Drives Inflammatory Skin Carcinogenesis Independently of C5

Nonmelanoma skin cancer such as cutaneous squamous cell carcinoma (cSCC) is the most common form of cancer and can occur as a consequence of DNA damage to the epithelium by UVR or chemical carcinogens. There is growing evidence that the complement system is involved in cancer immune surveillance; however, its role in cSCC remains unclear. Here, we show that complement genes are expressed in tissue from patients with cSCC, and C3 activation fragments are present in cSCC biopsies, indicating complement activation. Using a range of complement-deficient mice in a two-stage mouse model of chemically-induced cSCC, where a subclinical dose of 7,12-dimethylbenz[a]anthracene causes oncogenic mutations in epithelial cells and 12-O-tetradecanoylphorbol-13-acetate promotes the outgrowth of these cells, we found that C3-deficient mice displayed a significantly reduced tumor burden, whereas an opposite phenotype was observed in mice lacking C5aR1, C5aR2, and C3a receptor. In addition, in mice unable to form the membrane attack complex, the tumor progression was unaltered. C3 deficiency did not affect the cancer response to 7,12-dimethylbenz[a]anthracene treatment alone but reduced the epidermal hyperplasia during 12-O-tetradecanoylphorbol-13-acetate-induced inflammation. Collectively, these data indicate that C3 drives tumorigenesis during chronic skin inflammation, independently of the downstream generation of C5a or membrane attack complex

Epithelial damage and tissue γδ T cells promote a unique tumor-protective IgE response

IgE is an ancient and conserved immunoglobulin isotype with potent immunological function. Nevertheless, the regulation of IgE responses remains an enigma, and evidence of a role for IgE in host defense is limited. Here we report that topical exposure to a common environmental DNA-damaging xenobiotic initiated stress surveillance by γδTCR+ intraepithelial lymphocytes that resulted in class switching to IgE in B cells and the accumulation of autoreactive IgE. High-throughput antibody sequencing revealed that γδ T cells shaped the IgE repertoire by supporting specific variable-diversity-joining (VDJ) rearrangements with unique characteristics of the complementarity-determining region CDRH3. This endogenous IgE response, via the IgE receptor FcεRI, provided protection against epithelial carcinogenesis, and expression of the gene encoding FcεRI in human squamous-cell carcinoma correlated with good disease prognosis. These data indicate a joint role for immunosurveillance by T cells and by B cells in epithelial tissues and suggest that IgE is part of the host defense against epithelial damage and tumor development

Reconstruction of cell population dynamics using CFSE

Background: Quantifying cell division and death is central to many studies in the biological sciences. The fluorescent dye CFSE allows the tracking of cell division in vitro and in vivo and provides a rich source of information with which to test models of cell kinetics. Cell division and death have a stochastic component at the single-cell level, and the probabilities of these occurring in any given time interval may also undergo systematic variation at a population level. This gives rise to heterogeneity in proliferating cell populations. Branching processes provide a natural means of describing this behaviour. Results: We present a likelihood-based method for estimating the parameters of branching process models of cell kinetics using CFSE-labeling experiments, and demonstrate its validity using synthetic and experimental datasets. Performing inference and model comparison with real CFSE data presents some statistical problems and we suggest methods of dealing with them. Conclusion: The approach we describe here can be used to recover the (potentially variable) division and death rates of any cell population for which division tracking information is available

Förtryck eller frihet? : En kritisk diskursanalys av slöjan och slöjbärare i svensk media från 2018-2019

I denna uppsats undersöker jag hur den muslimska slöjan och slöjbäraren framställs i artiklar från de rikstäckande dags- och kvällstidningarna Dagens Nyheter, Svenska Dagbladet, Aftonbladet och Expressen. Jag har genom att använda kritisk diskursanalys synliggjort vilka diskurser som finns i 15 utvalda artiklar från ovanstående medier under 2018-2019. För att förklara vilka diskurser som omger artiklarna har tre teorier valts ut: postkolonial teori, orientalism och postkolonial teori ur feministisk synvinkel. De slutsatser som framkommer är att slöjan och slöjbäraren innefattas av olika diskurser under 2018-2019 i de 15 artiklarna. Den största diskursen är att slöjan med ord som ”förtryck” och ”förbud” och slöjbäraren talas om som någon som behöver räddas från detta förtryck. Den förändringsdiskurs som denna undersökning hittar skildrar slöjan och slöjbäraren som en del av svensk kultur och i behov av representation. I slutet görs även en ämnesdidaktisk reflektion där uppsatsens slutsatser diskuteras i koppling till ämnet religionskunskap i gymnasieskolan

Immunoregulation after intestinal and cutaneous exposure to food proteins : tolerance versus sensitisation

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Visst kan "vi" göra fel men de värsta felen begås av "de andra"! : En innehållsanalys av läroböckerna Se samhället och Reflex 123 i samhällskunskap utifrån framställningen av "vi" och "de andra".

I denna undersökning har framställningen av ”vi” och ”de andra” i två utvalda läroböcker i samhällskunskap undersökts genom kvalitativ innehållsanalys. En jämförelse mellan två läroböcker har gjorts. Läroboken Se samhället har anpassat språk och är riktad mot introduktionsprogrammet och läroboken Reflex 123 är inte språkligt anpassad och riktad mot övriga gymnasieprogram. I resultatet framkommer det att ”vi” och ”de andra” framställs i likhet med den tidigare forskning som tas upp i undersökningen. ”Vi:et” i båda läroböckerna framställs som bland annat demokratiskt med god moral, svenskt och bidragande. ”De andra” framställs i båda läroböckerna som odemokratiska, stereotypa och omoraliska. De främsta skillnaderna som denna undersökning har identifierat är hur framställningen är påverkad av hur läroböckerna är skrivna. Den språkligt anpassade boken tenderar att ha en mer tillrättavisande ton och den icke språkligt anpassade boken tenderar att ha en mer diskuterande ton. Resultatet har analyserats med hjälp av den postkolonial teorin och läromedelsteorin. Med hänvisning till dessa teorier är undersökningens slutsats att framställningen av ”vi” och ”de andra” reproduceras i utvalda läroböcker vilket i sin tur skulle kunna bidra till att läsaren påverkas av denna framställning

Immunoregulation after intestinal and cutaneous exposure to food proteins: Tolerance versus sensitisation.

The prevalence and severity of allergic diseases is rising and poses an increasing clinical problem. Food allergies are a major course of life-threatening hypersensitivity reactions, but the immunological mechanisms underlying the induction of sensitisation or tolerance to food proteins are poorly understood. This study examined the immunological outcome of exposure to peanut protein and chicken egg ovalbumin (OVA) at the intestinal mucosae and skin surfaces. The aim was to determine whether skin exposure to allergens may interfere with oral tolerance and promote food allergies. A murine BALB/c model of oral tolerance or sensitisation to peanut protein was developed and compared to a model of oral tolerance to OVA. Tolerance to peanut required a significantly higher oral dose than tolerance to OVA and low doses of peanut protein were more likely to induce sensitisation. Oral tolerance mediated suppression of both Th1 and Th2 responses. A high dose feed of peanut protein induced a population of CD4 CD25 CTI \-4 T cells with regulatory properties, suggesting that apopulation of cells similar to the naturally occurring thymic derived CD4 CD25"T can be induced in the periphery. Epicutaneous exposure to peanut proteinand OVA on abraded skin (epicutaneous immunisation) induced potent Th2-type immunity with high levels of antigen-specific IL-4, IgE and IgG1 with no IgG2a. Abrasion of the skin increased expression of activation markers on Langerhans cells (LCs), but rapid migration from epidermis to draining lymph nodes was observed only after both skin abrasion and exposure to antigen, suggesting that maturation and migration of LCs are independently regulated events. Primary skin exposure prevented the induction of oral tolerance. Upon oral challenge mice were further sensitised and developed strong specific IL-4 and IgE responses as well as clinical signs of anaphylaxis. This suggests that epicutaneous exposure to protein allergens specifically drives Th2 responses and may promote food allergy. Primary epicutaneous immunisation changed responses elicited by subcutaneous antigen in complete Freund's adjuvant from Thl to Th2. Additionally, epicutaneous immunisation converted an existing antigen-specific Thl response to a Th2 response, indicating dominance of the skin-induced immunity. Together these results suggest that epicutaneous immunisation may be a useful non-invasive, non-adjuvant-dependent method of vaccination and therapy