Immunopathogenesis of Asthma and Atopic Diseases – The specific Role of a selected Panel of Genes in human T helper Cell Differentiation

T helper cell (Th) functions are crucial for proper immune defence against various intra- and extracellular pathogens. According to the specific immune responses, Th cells can be classified into subtypes, Th1 and Th2 cells being the most frequently characterized classes. Th1 and Th2 cells interact with other immune cells by regulating their functions with specific cytokine production. IFN, IL-2 and TNF- are the cytokines predominantly produced by Th1 cells whereas Th2 cells produce Th2-type cytokines, such as IL-4, IL-5 and IL-13. Upon TCR activation and in the presence of polarizing cytokines, Th cells differentiate into effector subtypes from a common precursor cell. IFN and IL-12 are the predominant Th1 polarizing cytokines whereas IL-4 directs Th2 polarization. The cytokines mediate their effects through specific receptor signalling. The differentiation process is complex, involving various signalling molecules and routes, as well as functions of the specific transcription factors. The functions of the Th1/Th2 cells are tightly regulated; however, knowledge on human Th cell differentiation is, as yet, fairly poor. The susceptibility for many immune-mediated disorders often originates from disturbed Th cell responses. Thus, research is needed for defining the molecular mechanisms involved in the differentiation and balanced functions of the Th cells. Importantly, the new information obtained will be crucial for a better understanding of the pathogenesis of immune-mediated disorders, such as asthma or autoimmune diseases. In the first subproject of this thesis, the role of genetic polymorphisms in the human STAT6, GATA3 and STAT4 genes were investigated for asthma or atopy susceptibility in Finnish asthma families by association analysis. These genes code for key transcription factors regulating Th cell differentiation. The study resulted in the identification of a GATA3 haplotype that associated with asthma and related traits (high serum IgE level). In the second subproject, an optimized method for human primary T cell transfection and enrichment was established. The method can be utilized for functional studies for the selected genes of interest. The method was also utilized in the third subproject, which aimed at the identification of novel genes involved in early human Th cell polarization (0-48h) using genome-wide oligonucleotide arrays. As a result, numerous genes and ESTs with known or unknown functions were identified in the study. Using an shRNA knockdown approach, a panel of novel IL-4/STAT6 regulated genes were identified in the functional studies of the genes. Moreover, one of the genes, NDFIP2, with a previously uncharacterized role in the human Th differentiation, was observed to promote IFN production of the differentiated Th1 cells. Taken together, the results obtained have revealed potential new relevant candidate genes serving as a basis for further studies characterizing the detailed networks involved in the human Th cell differentiation as well as in the genetic susceptibility of Th-mediated immune disorders.

I volontari italiani nelle Waffen-SS. Il pensiero politico, la formazione culturale e le motivazioni al volontariato. Una storia orale

My doctoral dissertation examines the experiences of the Italian volunteers in the Waffen-SS troops using in-depth interviews with former volunteers as the main primary source. This phenomenon, even if significant in size (depending on the source, some 15 000-20 000 Italian men volunteered in the Waffen-SS), has been hitherto largely unknown to historical research. The available literature on the Italian volunteers, mainly written by military history enthusiast journalists and methodologically weak, concentrates mainly on the combat operations and military organization, and offers a rather stereotypical profile of the volunteers. My dissertation does not aim to reconstruct the military history of the different divisions of the Waffen-SS in which Italian volunteers operated but instead to examine the subjective, private and intimate experience of the volunteers in order to understand the motivations, attitudes, beliefs and cultural and family background, as well as their political ideas. The main objective of my doctoral dissertation is to discover the ideological precepts of the volunteers’ political credo. As the last phase of fascism and its ideology, often defined as the “Germanisation” or “Nazification” of fascism, is still the object of wide academic debate, a better understanding of the volunteers’ ideology also contributes to deepening overall knowledge of the nature of this last phase. The theoretical frame of my dissertation lies in oral history, in particular in the postmodernist approach to oral history, through which I reconstruct the volunteers’ ideology. In-depth interviews with former volunteers are the main primary source, but multiple data collection methods have been adopted. Phone interviews and correspondence with the volunteers have also been considered as primary sources. In addition to interviews and correspondence, family archives consisting of diaries, correspondence with the volunteers’ relatives and photographic material have also been collected and examined. An ethnographic observation of the volunteers’ domestic spaces has been conducted during the in-depth interviews, and photo self-elicitation techniques have been used in cases where the volunteers were willing to share their photographs. An exhaustive portrait of the ideological structure of the volunteers has been obtained, as well as of the cultural and social origins of the values that contributed to the rise and adoption of this ideology. Further, the volunteers’ motivations to enlist have been clearly reconstructed, together with their cultural, political, social and military backgrounds. The results of the research are particularly relevant both for comprehension of the Italian phenomenon of volunteering in the Waffen-SS and for the reconstruction of the ideological dynamics of the last phase of fascism. The volunteers’ political and ideological system, which can be defined as the Italian SS-fascist ideology, disagrees strongly with the vaguely described ideological profile offered by previous studies that describe volunteers as generically “super-fascist”. The research also offers the opportunity for a deeper understanding of the final fascist ideological trajectory, currently defined, not without a certain level of approximation, as the “Germanisation” or “Nazification” of fascist ideology.

[Già il sole dal gange = Päivännousu Gagnes-virralla]

Soitinnus: lauluääni (tenori), orkesteri.

Figura di tutto il mondo

Julkaisussa: Teatro del cielo e della terra

Carta particolare che mostra il Capo Buona Speranza con il mare verso ponte è con l'isole di Tristan d'Acunha è di Martin Vaz : la longitudine comincia da l'isola di Pico d'Aasores [i.e. Pico Azores] : d'America carta XVIII

Julkaisussa: Dell' arcano del mare di Ruberto Dudleo ... parte qvarta del libro sesto. Vol III

Les voiages de notre seigneur Jésus Christ et des apotres St. Pierre et St. Paul dans l'Asie, l'Afrique et l'Europe : l'on à ajouté tous les noms des regions et des lieux dont il est parlé dans le Nouveau Testament

Nimeketiedot nimiönkehyksissä

Development of a Glycocluster Adjuvant Mimicking Natural Yeast beta-(1,2)-Structures

Allergy is characterized by T helper (Th) 2-type immune response after encounter with an allergen leading to subsequent immunoglobulin (Ig) E-mediated hypersensitivity reaction and further allergic inflammation. Allergen-specific immunotherapy (SIT) balances the Th2-biased immunity towards Th1 and T regulatory responses. Adjuvants are used in allergen preparations to intensify and modify SIT. β-(1,2)-oligomannoside constituents present in Candida albicans (C. albicans) cell wall possess Th1-type immunostimulatory properties. The aim of this thesis was to develop a β-(1,2)-linked carbohydrate compound with known structure and anti-allergic properties to be applied as an adjuvant in SIT. First the immunostimulatory properties of various fungal extracts were studied. C. albicans appeared to be the most promising Th1-inducing extract, which led to the synthesis of various mono- or divalent oligomannosides designed on the basis of C. albicans. These carbohydrates did not induce strong cytokine production in human peripheral blood mononuclear cell (PBMC) cultures. In contrast to earlier reports using native oligosaccharides from C. albicans, synthetic -(1,2)-linked mannotetraose did not induce any tumor necrosis factor production in murine macrophages. Next, similarities with synthesized divalent mannosides and the antigenic epitopes of β-(1,2)-linked C. albicans mannan were investigated. Two divalent compounds inhibited specific IgG antibodies binding to below 3 kDa hydrolyzed mannan down to the level of 30–50% showing similar antigenicity to C. albicans. Immunomodulatory properties of synthesized carbohydrate assemblies ranging from mono- to pentavalent were evaluated. A trivalent acetylated dimannose (TADM) induced interleukin-10 (IL-10) and interferon-γ responses. TADM also suppressed birch pollen induced IL-4 and IL-5 responses in allergen (Bet v) stimulated PBMCs of birch pollen allergic subjects. This suppression was stronger with TADM than with other used adjuvants, immunostimulatory oligonucleotides and monophosphoryl lipid A. In a murine model of asthma, the allergen induced inflammatory responses could also be suppressed by TADM on cytokine and antibody levels.