Background: Allergic diseases are characterised by dysregulated immune responses. The first manifestation of the atopic phenotype is often food allergy, with symptoms like eczema. Food allergy in children is generally outgrown before 3 years of age, but a temporary food elimination diet is often advocated. The prevalence of allergic diseases has increased in affluent countries during the last decades, possibly as a consequence of a changed lifestyle leading to decreased microbial load. Aim: To investigate humoral, mucosal and cell-mediated immunity in association to allergy and allergy development in young children and relate this to environmental factors. Subjects: Two cohorts of children were investigated; 1) Children from countries with high (Sweden) and low (Estonia) prevalence of allergy that were followed prospectively from birth to 5 years of age. 2) Infants with eczema and suspected food allergy that were followed prospectively to 4 ½ years of age. Methods: Endotoxin levels were analysed in house dust samples. Antibodies were measured in serum and saliva samples with ELISA. Food allergen induced cytokine responses were analysed in mononuclear cells. Results: The microbial load, delineated as endotoxin levels, was higher in house dust from Estonia than Sweden and was, in Swedish children, inversely associated with sensitisation and clinical symptoms of allergy. The decreased microbial load in Sweden may have an impact on mucosal immune responses as different IgA antibody patterns were observed in Sweden and Estonian children with much lower secretory (S)IgA antibody levels and high proportion of non-SIgA, i.e. IgA antibodies lacking the secretory component, in the Swedish children. Moreover, low levels of SIgA were associated with clinical symptoms in sensitised children. High IgG4 antibody levels to food allergens during infancy were associated with faster tolerance development in food allergic children. Cytokine responses by mononuclear cells after allergen stimulation was upregulated with age in children with prolonged food allergy, but not in children who develop tolerance before 4 ½ years of age, possibly because of the prolonged elimination diet in the former group. Summary: Reduced microbial exposure in affluent countries may affect the mucosal immune responses during infancy, possibly resulting in an increased risk of developing allergic disease. High levels of IgG4 antibodies during infancy are associated with faster achievement of tolerance in food allergic children. Allergen elimination during infancy may result in a dysfunctional cytokine response.

Schizophrenia (SCZ) is a debilitating mental illness that affects roughly 1% of the world's population. Current theories about the etiology of this disease highlight disruptions in dopamine (DA) and glutamine. However, a more recent theory, the 'synaptic hypothesis' proposes that the fundamental pathology of this illness involves disruptions in synaptic transmission. The synapsins are a family of neuron specific phosphoproteins that play an important role in neurotransmitter release, synapse formation and maintaining a reserve pool of synaptic vesicles. Previous research has suggested that synapsin II has a role in the etiology of SCZ. For example, synapsin II mRNA is significantly reduced in the medial prefrontal cortex (MPFC) of patients, and synapsin II knockout mice display a variety of behavioural abnormalities which mimic human SCZ. Considering that SCZ may result from changes in the synapse, we wanted to further elucidate the role of synapsin II by measuring protein expression in post-mortem PFC samples. Overall, our results revealed that synapsin IIa and IIb are not significantly different between patients and controls, however, we hypothesize that synapsin II expression has been normalized in patients due to antipsychotic drug (APD) use. In fact, we discovered that treatment with atypical APDs significantly increases synapsin II in the prefrontal cortex (PFC) of patients, which may underlie the beneficial effects of these drugs. Another objective of our work was to investigate the expression of various presynaptic proteins in post-mortem samples from patients with Parkinson's disease (PD) Parkinson's disease, like SCZ, is an illness which involves dysregulated dopaminergic transmission and synaptic dysfunction. Therefore, we hypothesized that synapsin II might also be disrupted in patients with PD. Our results demonstrated that synapsin IIa and IIb are significantly reduced in the substantia nigra (SN), but not the striatum (STR) or PFC of patients, when compared to controls. Further, no changes were observed in the other synapsins (I or III), or synaptophysin, which suggests that synapsin II dysregulation may be specific to disorders which involve disruptions in dopamine (DA). / Thesis / Master of Science (MS)

Le séquençage du génome humain et l'émergence de nouvelles technologies de génomique à haut débit, ont initié de nouveaux modèles d'investigation pour l'analyse systématique des maladies humaines. Actuellement, nous pouvons tenter de comprendre les maladies tel que le cancer avec une perspective plus globale, en identifiant des gènes responsables des cancers et en étudiant la manière dont leurs produits protéiques fonctionnent dans un réseau d’interactions moléculaires. Dans ce contexte, nous avons collecté les gènes spécifiquement liés à la Leucémie Lymphoblastique Aiguë (LLA), et identifié de nouveaux partenaires d'interaction qui relient ces gènes clés associés à la LLA tels que NOTCH1, FBW7, KRAS et PTPN11, dans un réseau d’interactions. Nous avons également tenté de prédire l’impact fonctionnel des variations génomiques tel que des fusions de gènes impliquées dans LLA. En utilisant comme modèles trois différentes translocations chromosomiques ETV6-RUNX1 (TEL-AML1), BCR-ABL1, et E2A-PBX1 (TCF3-PBX1) fréquemment identifiées dans des cellules B LLA, nous avons adapté une approche de prédiction d’oncogènes afin de prédire des perturbations moléculaires dans la LLA. Nous avons montré que les circuits transcriptomiques dépendant de Myc et JunD sont spécifiquement dérégulés suite aux fusions de gènes TEL-AML1 et TCF3-PBX1, respectivement. Nous avons également identifié le mécanisme de transport des ARNm dépendant du facteur NXF1 comme une cible directe de la protéine de fusion TCF3-PBX1. Grâce à cette approche combinant les données interactomiques et les analyses d'expression génique, nous avons fourni un nouvel aperçu à la compréhension moléculaire de la Leucémie Lymphoblastique Aiguë. / Doctorat en Sciences / info:eu-repo/semantics/nonPublished

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Parental divorce has not only been associated with negative long-term effects for children of divorce (CD), but also for adult children of divorce (ACD). ACD more often have poorer mental well-being than adult children of marriage (ACM). Neurological research further suggests that ACD have lower baseline levels of the “stress hormone” cortisol. However, research of Swedish ACD is extremely sparsely. Therefore, the study’s aim is to examine the possible long-term effects of Swedish ACD. Do ACD have lower well-being and experience more stress than ACM? A sample of 227 Swedish participants (81 ACD and 146 ACM) were included. The majority (75.7%) were between 18-30 years old, 157 females and 70 males. An online survey including the Perceived Stress Scale (PSS), the Temporal Satisfaction with Life Scale (TSWLS), and questions about the parental divorce was distributed via social media. Independent t-tests and one-way ANOVA analysis were performed to compare ACD’s and ACM’s results. The study found that ACD rated their well-being (satisfaction with the past) (p ≤ .001), and stress (p ≤ .019), significantly lower than ACM. Moreover, female ACD perceived more stress than female ACM (p ≤ .010), and male ACD (p ≤ .015). The group between 10-14-year-old at the time of the divorce rated significantly lower well-being (past) (p ≤ .035). In conclusion, the study suggests that Swedish ACD also suffer from long-term effects of divorce. Future research ought to investigate the matter further. / Skilsmässa har inte bara visat negativa långsiktiga effekter för skilsmässobarn (CD), utan också för vuxna skilsmässobarn (ACD). ACD har oftare ett sämre mentalt välbefinnande än vuxna med gifta föräldrar (ACM). Neurologisk forskning vidare påvisar att ACD också har lägre grundnivåer av ”stresshormonet” kortisol. Forskning kring svenska ACD är extremt sällsynt. Därför är det studiens mål att undersöka de möjliga långsiktiga effekterna av svenska ACD. Har ACD ett längre välbefinnande och upplever mer stress än ACM? Ett urval av 227 svenska deltagare (81 ACD och 146 ACM) var inkluderade. Majoriteten (75.7%) var mellan åldrarna 18-30 år gamla, 157 kvinnor och 70 män. En online enkät innehållandes Perceived Stress Scale (PSS), Temporal Satisfaction with Life Scale (TSWLS), och frågor kring skilsmässan distribuerades via sociala medier. Independent t-tests och one-way ANOVA analyser tillämpades för att jämföra ACD:s och ACM:s resultat. Studien fann att ACD uppskattade att deras välbefinnande (tillfredställelse med det förflutna) (p ≤ .001), och stress (p ≤ .019) signifikant längre än ACM. Fortsättningsvis, en signifikant skillnad upptäcktes där kvinnliga ACD upplevde mer stress än kvinnliga ACM (p ≤ .010), och manliga ACD (p ≤ .015). Gruppen mellan åldrarna 10–14 år gamla vid skilsmässan uppgav ett signifikant längre välbefinnande (förflutet) (p ≤ .035). Sammanfattningsvis, studien påvisar att svenska skilsmässobarn också lider av långsiktiga effekter från skilsmässa. Framtida forskning bör undersöka området vidare.

Myelodysplastic syndromes (MDS) belong to the most common hematological neoplasms in the elderly population, characterized by ineffective hematopoiesis, peripheral cytopenia and the risk of transformation into acute myeloid leukemia. A dysregulated innate immune response and pro-inflammatory bone marrow microenvironment play a crucial role in the MDS pathogenesis by providing chronic inflammation which makes those pathways the perfect candidate for future therapeutics. Specifically, it has been shown that the alarmin S100A9, an important ligand for dri-ving inflammation and promoting tumor progression, is elevated in MDS patients. Previous expe-riments performed in the Stem Cell Lab 2 provided evidence that mesenchymal stromal cells (MSCs), an important component of the BM niche with immunomodulatory capacity, can be tar-geted by the novel oral small molecular drug Tasquinimod (TASQ, Active Biotech) which has demonstrated S100A9 inhibitory activity. The inhibition of inflammation-related molecules such as IL-1b, IL-18, PD-L1, resulted in a significant improvement of the hematopoietic support by MSCs. However, almost nothing is known about potential effects of TASQ in the context of immunomo-dulation. Therefore, we aimed in this project to understand the mechanisms of S100A9+/- TASQ concerning the immunomodulatory capacity of MDS-MSCs in response to T cell-mediated in-flammation by analyzing adhesion (ICAM1, VCAM1), immune checkpoint (PDL1, PDL2), anti-inflammatory cytokine (COX2, IDO1), chemokines (CCL2, IL8) and extracellular matrix-related (COL4A2, COL1A1) gene expression with quantitative real-time PCR. We observed a general de-crease in the aforementioned genes except for COL4A2 and COL1A1 upon treatment with TASQ, though T cell-mediated inflammation and activity remained unaffected, suggesting that inhibition of S100A9 reduces the inflammation-mediated immunomodulatory potential of MDS-MSCs.:Motivation Aim Methods Result Conclusion