Effects of intestinal worms on skin immunity and control of co-infection

Intestinal helminth infections remain a major health concern in developing areas of the world. Consequences of infection range from gastrointestinal discomfort to systemic manifestations. It has been suggested that individuals infected with intestinal helminths are more susceptible to other infections and mount weaker immunity to vaccination. Regions heavily burdened by intestinal helminths geographically coincide with areas plagued by infections with mycobacteria and the protozoan parasite Leishmania spp, causing tuberculosis (TB) and leishmaniasis, respectively. Further, it has been reported that people carrying intestinal worms mount weaker immune responses to the intradermally administered tuberculosis vaccine Mycobacterium bovis Bacillus Calmette Guérin (BCG). Intestinal helminth infections induce type 2 responses that aid in the expulsion of the worms, but also regulatory responses that facilitate chronicity of the worm infection. Both type 2 and regulatory responses are known to counteract type 1 immune responses required for protection against the intracellular pathogens mycobacteria and Leishmania, suggesting that worm infection may dampen protection to these infections. Yet, little is known about the systemic implications of intestinal worm infection, and the aim of the work in this thesis was to investigate the effects of intestinal helminth infection on skin immunity and control of co-infection. To this end, mice were infected with the strictly intestinal nematode Heligmosomoides polygyrus, and at various time points after infection subjected to secondary infection, immunization, or were culled. At the end of each experiment, composition and function of immune cells in skin, skin-draining lymph nodes (LNs), liver, spleen and other tissues involved in responses to secondary infection, were analysed. In Paper I, we found that mice infected with H. polygyrus were more susceptible to systemic infection with BCG and skin infection with Leishmania major. Increased susceptibility to BCG was accompanied by weaker IFN-γ production and fewer mycobacteria-specific transgenic p25 cells in spleen, and less inos expression and granuloma formation in livers. Delayed type hypersensitivity responses (DTH) induced in ears to BCG and L. major-derived antigens were dampened. Dendritic cell (DC) migration from footpad skin to the draining LN was reduced in worm-infected mice, as well as in mice where the footpad skin had been preconditioned with either H. polygyrus excretory-secretory (HES) products or recombinant human transforming growth factor β (TGF-β). In vitro, BCG-induced IFN-γ production by mycobacteria-specific T cells was reduced by HES, soluble worm antigens, or by TGF-β. This led us to hypothesize that H. polygurus-induced reduction of immunity to the T helper cell type 1(TH1)-controlled organisms mycobacterium BCG and L. major was mediated by enhanced TGF-β production in worm-infected mice. In Paper II, we saw that (similar to the situation with H. polygyrus – BCG co-infected animals) worm-infected mice were more susceptible to systemic infection with the TH1- controlled pathogen Leishmania donovani. Reduced protection was accompanied by lower inos levels and granuloma formation in livers and higher il10 levels in spleens. In Paper III, we sought for the explanation to the weaker skin immunity seen in worminfected mice (in Paper I). We found that mice infected with H. polygyrus had substantially smaller skin-draining LNs compared to worm-free animals. Both T cell and B cells were fewer, whereas no significant difference was observed in myeloid and stromal cell populations. As mentioned, numbers of DCs migrating from BCG-injected skin as well as p25 cells were less in skin-draining LNs of worm-infected mice. Notably however, numbers were directly proportional to the total number of cells in that particular LN. This led us to hypothesize that cells enter or are retained in an LN dependent on the original size of that node. As oppose to the atrophic skin draining LNs, the gut-draining mesenteric LNs were instead (as expected) dramatically increased in size. The lymphocyte pool cannot expand without limitation, and we suggested that worm-induced expansion of one LN occurred at the expense of other LN. Removal of worms restored the sizes of the non-draining nodes. However, this took time, since (according to out hypothesis) the atrophy of skin draining LNs and hyperplasia of mesenteric LN in itself decreased or increased infiltration or retention of cells into the respective nodes, maintaining this new “homeostasis”. In the last paper, Paper IV, we proceeded by investigating immune cells in the skin itself after H. polygyrus infection. We found that mice infected with H. polygyrus had fewer CD4+ cells producing IFN-γ in ear skin injected with whole cell lysate (WCL) from Mycobacterium tuberculosis in response to mycobacteria-specific ex-vivo re-stimulation, compared to wormfree mice. IFN-γ production was also lower in the contralateral, untouched ear. Interestingly however, the total number of CD4+ cells were higher in ear skin of worm-infected mice. CD4+ T cell numbers were also higher when comparing H. polygyrus-infected and noninfected animals without any skin stimulation, indicating that the intestinal infection, in itself, caused accumulation of CD4+ T cells in the skin. We found that the accumulated CD4+ T cells responded to H. polygyrus antigen by producing TH2 associated cytokines and that they remained in the skin for several weeks after removal of worms from the intestine. In accordance, skin-homing chemokine receptors were up-regulated on CD4+ T cells in the mesenteric LNs and blood. We hypothesized that the increased number of TH2 cells in the skin, in concert with the atrophy of skin draining LNs, were responsible for the lower protection to TH1-controlled organisms in the skin. In conclusion, mice chronically infected with the strictly intestinal nematode H. polygyrus were more susceptible to systemic and skin infection by TH1-controlled organisms compared to worm-free mice. We suggest that less inos and granuloma formation contributed to lower protection to systemic infection and that a combination of atrophic skin-draining LNs and increased numbers of TH2 cells in the skin caused weaker skin immunity. Taken together, this indicates that deworming may increase protection against secondary infection and increase beneficial effects of BCG vaccination

Translational studies of epithelial cancer

Tumors stemming from specialized epithelial cells cause the most common cancer types and are among the leading causes of death in the western world. Although great strides have been made in early cancer detection, defining prognostic factors, and improving survival with novel treatments, cancers such as colorectal cancer and prostate cancer are incurable in their advanced stages. In the work presented in this thesis, we aim to explore the biological underpinnings of tumor initiation and progression and determine novel pharmaceutical treatment strategies against epithelial cancer. We do so by combining preclinical methodologies of cell culture and animal models of disease with epidemiological studies of population and patient cohorts. EphB tyrosine kinase receptors promote intestinal tumor proliferation via the tyrosine-protein kinase Abl1 (Abl kinase) (Genander et al., 2009; Holmberg et al., 2006). In paper I, we find that the Abl kinase inhibitor imatinib blocks EphB receptor regulated tumor initiation and growth in mouse models of early-stage intestinal tumors, reduces proliferation in ex vivo human adenomas and prolongs survival of tumor bearing mice. We propose imatinib as a possible prevention and early treatment strategy for people prone to develop intestinal adenomas. In paper II, we explore the immune system and antiviral immunity as potential markers of prostate cancer prognosis. In prostate cancer patients, the Human Leukocyte Antigen (HLA) alleles HLA-A*02:01 and HLA-A*11 are associated with poor disease recurrence free survival after prostatectomy. Immunity to the human herpesvirus cytomegalovirus (CMV) in prostate tumors is associated with particularly poor disease recurrence free survival in HLA-A*02:01+ prostate cancer patients. In paper III, we find that CMV commonly chronically infects epithelium in the healthy and malignant prostate, prostate cancer metastases and prostate cancer cell lines. Experimental and therapeutic inhibition of CMV in in vitro and in vivo models of prostate cancer reveal that CMV promotes its viability and growth and propose that CMV targeting drugs can be repurposed against prostate cancer. In paper IV, we describe that CMV seropositivity is associated with high CMV abundance in healthy and malignant prostate. Studying a large prospective population cohort, we find that CMV seropositivity is not associated with prostate cancer incidence but is associated with increased risk of dying from prostate cancer after receiving a prostate cancer diagnosis

Kafka’s Identity Crisis: Examining The Metamorphosis as a Response to Anti-Semitism and Assimilation in Turn-of-the-Century Europe

Franz Kafka’s The Metamorphosis chronicles the bizarre tale of Gregor Samsa’s transformation into an insect and the despairing isolation and personal quest for a meaningful existence that follows. A masterpiece of modern literature, it explores the universal concerns and struggles of Modernity, but also offers insight into the lives of assimilated Jews living in Prague at the turn-of-the-century. The acquisition of basic civil rights afforded European Jews opportunities in education, employment, and housing. Integration into Western society presented new challenges for the Jews as they carved out their new position in European society. The Jews’ difficult task of adapting to Western culture met further challenges from the ambivalent European society still unsure of integration. The new place for Jews as free citizens in Western society made them vulnerable to the pressures of assimilation. Western, most often interpreted as German, culture assisted as protection from anti-Semitism for the obtainment of European culture, in theory would serve as proof of the Jews’ loyalty to state culture. The literature of this time reflects both the anti-Semitic attitudes in politics and in the media and the Jews’ response to assimilation’s effects on their identity. Franz Kafka’s literature transcends the historical context in which it was written but The Metamorphosis reflects the anxiety that pervaded the psyche of assimilated Jews in turn- of-the-century Prague

Generering av grafiska användargränssnitt via en webbapplikation

An increasing amount of consumer products get smart functionalities to help people with their everyday life. Graphical user interfaces are used for controlling smart functionality using touchscreens. Developing user interfaces in a programming language can be difficult and time-consuming. The purpose of this degree project is to simplify and speed up the development of graphical user interfaces. A web-application has been developed using React, where users can drag and drop ready-made graphical objects onto a canvas in order to generate graphical user interfaces. Users also have the possibility of saving the generated user interfaces in a lightweight data format. A simple test that was performed showed that using the web-application decreased the development time of graphical user interfaces considerably

Thymic-Shared Antigen-1 (TSA-1) A Lymphostromal Cell Membrane Ly-6 Superfamily Molecule with a Putative Role in Cellular Adhesion

The seeding and colonization of the thymus by bone marrow stem cells and the maturation of these cells into mature T lymphocytes are dependent on cell-surface recognition events between different cell lineages within the thymic microenvironment. Positive and negative selection processes within the thymus produce a peripheral T-cell repertoire capable of recognizing peptides derived from foreign antigen bound to self MHC molecules. In addition to the TCR/ MHC-peptide interaction, many other cell-surface molecules act in concert to regulate the kinetics of cellular interactions and intracellular signaling events during thymopoiesis. We have investigated the complexity of the thymic stroma by using monoclonal antibodies to clone cellmembrane molecules of thymic stromal cells. Thymic-shared antigen-1 (TSA-1) is a molecule of interest because it is expressed by both immature thymocytes and stromal cells. We report herein the structural and evolutionary relationships between TSA-1 and molecules of the Ly-6 superfamily (Ly-6SF), and present evidence that TSA-1 functions as a cell-surface receptor by binding a cognate cell target molecule on the surface of a subset of thymocytes

Att rena mark med växter

Idag pågår ett stort arbete med inventeringar av många förorenade områden runt om i Sverige. Sanering av dem är ett aktuellt ämne då många av de förorenade områdena återfinns på nedlagda industriområden i centrala delar av städer som nu är aktuella för exploatering. Examensarbetet undersöker den ännu relativt okända saneringsmetoden; fytoremediering. Fytoremediering är en metod som med hjälp av växters biologiska processer antingen kan ta upp, bryta ner eller stabilisera mark- och vattenföroreningar. Till skillnad från schaktsanering som är den vanligaste metoden idag anses fytoremediering vara en ekonomiskt och ekologiskt hållbar saneringsmetod. Fytoremediering kan därför ha möjlighet att få en betydande roll i omvandlingen av gamla industriområden. Fytoremediering är ett nytt område inom landskapsarkitektur och målet med det här arbetet har därför varit att sammanställa den forskning och kunskap om fytoremediering som finns idag ur två perspektiv; fytoremedieringens processer under mark och de upplevelsevärden som växterna kan bidra till ovan mark. Det som framkommit som landskapsarkitektens roll för att kunna bidra till en ökad användning av metoden är bland annat att visa på de mervärden som metoden kan ge till platsen. Till exempel genom att tillfälliga gröna miljöer skapas i utvecklandet av industriområden som ofta har en brist på grönområden. Arbetet syftar till att bland annat undersöka fytoremedieringens möjligheter och utmaningar som saneringsmetod i Sverige. Genom litteraturstudien har det framkommit att tidsperspektivet, både i den fysiska planeringen vid efterbehandling av förorenade områden och den långa tid som metoden behöver för att kunna nå resultat, är hindrande faktorer för att metoden ska testas. Fytoremediering är en komplex metod som kan anses vara osäker då metoden består av många moment, och många olika kompetenser måste därför vara inblandade för att kunna nå ett lyckat resultat. Möjligheterna med fytoremediering har dock visat sig vara många; växternas biomassa kan användas för bioenergi för att ge ytterligare ekonomiska fördelar, metoden kan användas i ett pedagogiskt syfte med involvering av medborgare i planteringsprocessen samt att den kan bidra till ökade rekreationsvärden i det förorenade området. Examensarbetet avslutas med en undersökning av fytoremedieringens lämplighet att användas vid tre vanligt förekommande postindustriella kontexter; gasverkstomter, nedlagda bensinstationer samt soptippar, genom generella principer för utformning av reningsmodeller. Dessa generella principer är utvecklade utifrån den kunskap som presenteras i arbetet och är avsedda att även ge en visuell känsla till de mervärden som kan skapas till platsen genom att använda fytoremediering som saneringsmetod. De framtagna reningsmodellerna i detta arbete visar att det finns möjlighet att kunna skapa variationsrika och spännande miljöer under den pågående reningsprocessen. Resultatet från reningsmodellerna visar bland annat att fytoremediering har potential som saneringsmetod på både gasverkstomter, nedlagda bensinstationer och soptippar. Den komplexa föroreningssituationen som gasverkstomterna har gör dock att fytoremediering möjligen inte kan användas som enda saneringsmetod men skulle däremot vara möjlig att använda som metod både parallellt med andra saneringsmetoder men också parallellt med att platsen exploateras och bebyggs. På grund utav att fytoremediering är en tidskrävande metod och att en snabb saneringsprocess ofta är nödvändig, framkommer det dock att de förorenade platserna som har låg prioritet för åtgärd är de platser där fytoremediering troligtvis har störst möjlighet att testas som metod. Nedlagda bensinstationer och deponier kan vara exempel på sådana platser.In Sweden today, there is a lot of work finding and rebuilding polluted areas. The decontamination of these areas is an important topic since many of them are situated in old industry areas in central parts of cities, which are to be exploited with new buildings and parks. This essay is investigating the relatively unknown decontamination method; phytoremediation. Phytoremediation is a method that uses the biological processes of plants, either by absorbing, by breaking down or by stabilizing ground- and water pollution. Unlike shaft remediation, which is the most common decontamination method, the phytoremediation method is considered as an economical and ecologically sustainable method. These two facts are clearly indicating that the method might be considered when rebuilding old industry areas in cities. Phytoremediation is a new research area within landscape architecture and the aim for this essay has been to summarize the research and knowledge about the method out of two perspectives; the processes of phytoremediation beneath the ground and the experiences the plants can give the citizens above the ground. In order to make the method more popular, it has shown through out my work that the landscape architect has an important role to play. It can be promoted by stating that contemporary green areas can add something to an old industry area while it’s being remediated and rebuilt. One of the aims for the essay is to investigate the possibilities and challenges for the phytoremediation method as a decontamination method in Sweden. The literature study has shown that ‘the time perspective’, both in the planning process for decontamination of polluted sites and the fact that the method in it self is time consuming, might be factors that makes the method less attractive. It is also a complex method due to the many different steps in the process and the need for a lot of different competences in order to reach a good result. The possibilities of the phytoremediation method has still shown to be many; the biomass of the plants can be used as bioenergy in order to produce economic profit, the method can be used as an educational tool since citizens can be involved in the planning and the actual planting process of the area and it can also add increased recreation values in the area. In the final part of the essay there is an investigation of the phytoremediation method connected to three common post-industrial contexts; gasworks sites, disused gas stations and old dumps. This investigation is carried out as general principles for the design of remediation models. These general principles are developed based on the knowledge presented in the essay and their purposes are to investigate the possibilities for the method at these three brownfield sites but also to give a visual feeling to the values phytoremediation as a decontamination method can give to the polluted areas. The remediation models show that it is possible to create diverse and exciting environments during the clean up process. The result from the remediation models shows, among other things, that phytoremediation has potential as a remediation method at gasworks sites, disused gas stations and old dumps. Phytoremediation may, however, not be possible to use as the only clean up method since the pollution situation can be very complex. As gasworks sites are relatively large, phytoremediation have, however the ability to run both in parallel with other remediation methods but also in parallel with the site being exploited and built over. Since phytoremediation is a time consuming method and a quick clean-up process is often necessary, it appears that the contaminated sites that have low priority for decontamination are the places where phytoremediation probably have the greatest opportunity to be tested as a method. Disused gas stations and old dumps can be examples of that kind of areas

From the President of ISTS

As we approach the time for our annual change in leadership, I would like to reflect with you on ISTS-where we are and where we can go

An Open Letter from the Chairman of the Science Teaching Section of the Iowa Academy

When was the last time you took advantage of the opportunity to exchange ideas relative to science instruction and emerging and changing science programs with fellow teachers

Analyse og feilsøking av oppvarmingsanlegget til en privat enebolig

En enebolig har et varmeanlegg som ikke fungerer ifølge huseier. Det har derfor blitt utarbeidet en årsakrapport og kommet med eventuelle forbedringsforslag. Dette er gjort ved hjelp av en kartleggingsprosess av varmeanlegget tilhørende boligen. Det har tidligere vært innleide firmaer som ikke har klart å finne noen årsak til problemet. Eneste løsningen de har er å bytte ut hele anlegget./A residence has a heating system that does not work according to the homeowner. A cause report has therefore been prepared and suggestions for improvements have been made. This is done by means of a mapping process of the heating system belonging to the residence. There have previously been hired companies that are unable to find any cause of the problem. There only solution is to replace the entire heating system