Die Infektion mit Schistosoma mansoni resultiert in einer Th2-Immunantwort mit Eosinophilie und erhöhtem IgE-Titer, wobei der wasserlösliche Extrakt der S. mansoni Eier (SEA) ausreicht um diese Reaktion auszulösen. In der vorliegenden Arbeit konnte demonstriert werden, dass sich IL-4-produzierende CD4+ T-Lymphozyten in Zellkulturen mit SEA-konditionierten Dendritischen Zellen (DCs) trotz gleichzeitig vorkommenden IFN-gamma entwickeln und SEA die Expression von Faktoren in DCs, die üblicherweise mit einer Th1-Antwort einhergehen, auf Transkriptions- und Proteinebene selektiv hemmt. Um den Faktor aus S. mansoni Eiern zu isolieren, der zur Expression von IL-4 in CD4+ Zellen und zur Inhibition von IL-12 in DCs führt, wurde eine Gelfiltrationschromatographie der exkretorisch/sekretorischen Ei-antigene (ES) durchgeführt und die Fraktionen in vitro getestet. Darin wurde gezeigt, dass Fraktionen mit einer Proteinbande von 30 kD die Expression von IL-4 in CD4+ Zellen induzieren. Dieses ES-Protein wurde durch N-terminale Sequenzierung als hepatotoxische Ribonuclease Omega-1 identifiziert, welches ebenfalls die Expression von IL-12 in DCs inhibiert und die Produktion von IL-4 in CD4+ Zellen bei einer 10-fach geringeren Proteinkonzentration als mit dem Kontrollansatz SEA induziert. Zudem sollte untersucht werden, inwieweit Toll-like Rezeptoren in der Generierung einer Th2 Antwort gegen schistosomale Antigene involviert sind. Dazu wurden TLR2-, TLR3-, TLR4- und MyD88-defiziente Mäuse mit S. mansoni infiziert und immunologische und pathologische Daten in der akuten und chronischen Phase der Infektion analysiert. Demnach sind TLR2, TLR3, TLR4 und MyD88-abhängige Signaltransduktionswege nicht für eine-Th2 Antwort notwendig, jedoch ist letzteres Molekül in der Ausprägung der typischen Leberfibrose involviert. / Infection with Schistosoma mansoni results in the induction of a Th2 immune response, eosinophilia and increased levels of IgE. The water-soluble extract of S. mansoni eggs (SEA) is sufficient to promote TH2 polarization in a dendritic cell-dependent manner. In this thesis, it was demonstrated that IL-4+ CD4+ cells emerge in cultures with SEA-conditioned dendritic cells (DCs) in the presence of IFN-gamma and that SEA inhibits selectively the expression of IL-12 and co-stimulatory markers in DCs on the transcriptional and protein level. To identify the putative protein in S. mansoni eggs mediating a Th2 induction, a gel filtration chromatography of the excretory/secretory egg antigens (ES) was conducted and the fractions tested in vitro. Fractions containing a single band of 30 kD were sufficient to promote IL-4 induction in naïve CD4+ cells. Using N-terminal sequencing this ES-protein was identified as the hepatotoxic S. mansoni ribonuclease omega-1 which displayed both biological functions observed with SEA: inhibition of IL-12 in LPS-stimulated DCs and induction of IL-4+ CD4 cells at a 10 fold lower protein concentration than SEA. In order to understand, if the innate immune receptors TLR2, TLR3, TLR4 or the TLR adaptor molecule MyD88 are involved in the generation of the Th2 response against schistosomal antigens, the respective knock out mice were infected and immunological and pathological parameters were analyzed during acute and chronic phase of infection. This study showed that during S. mansoni infection TLR2, TLR3, TLR4 and TLR activation through the MyD88-dependent pathway are neither required for the induction (priming and polarization) nor for the down-regulation of Th2 responses, however, the fibrotic response against S. mansoni eggs was significantly reduced in MyD88-deficient mice suggesting a detrimental role of this pathway in liver pathology.

A classificação isomorfa dos espaços de Banach separáveis C(K) é devida a Milutin no caso em que K são não enumeráveis e a Bessaga e Pelczynski no caso em que K são enumeráveis. Neste trabalho apresentamos uma extensão vetorial dessa classificação e tiramos várias consequências, por exemplo, considerando o espaço métrico compacto infinito K e Y um espaço de Banach: &nbsp; &nbsp; 1. Sendo 1 < p < &infin; e &Gamma; um conjunto infinito, classificamos, a menos de isomorfismo, os espaços de Banach C(K, Y &oplus; lp(&Gamma;)), quando o dual de Y contém uma cópia de lq, onde 1/p+ 1/q =1. &nbsp; &nbsp; 2. Classificamos os espaços de Banach C(K, Y &oplus; l&infin;(&Gamma;)), quando a densidade de Y é estritamente menor que 2|&Gamma;|. &nbsp; &nbsp; 3. Classificamos os espaços de Banach C(K &times;(S&oplus; &beta;&Gamma;)) e C(S &oplus; (K&times; &beta;&Gamma;)), onde S é um compacto disperso de Hausdorff arbitrário e &beta;&Gamma; é a compactificação de Stone-Cech de &Gamma;. Obtemos, também, algumas leis de cancelamento para espaços de Banach da forma C(K1,X)&oplus; C(K2,Y), onde K1 e K2 são espaços compactos métricos infinitos de Hausdorff e X, Y espaços de Banach satisfazendo condições adequadas. Estabelecemos também um teorema de quase-dicotomia envolvendo os espaços C(K,X), onde X tem cotipo finito. Finalmente, apresentamos algumas majorações nas distorções de isomorfismos positivos de C([0,&omega;k]) em C([0,&omega;]) e também de C([0,&omega;]) em C([0,&omega;k]), k&isin; N, k &ge; 2. / The isomorphic classification of separable Banach spaces C(K) is due Milutin in the case when K are uncountable and to Bessaga and Pelczynski in the case when K are countable. In this work we prove a vectorial extention of this classification and provide several consequences, for example considering the infinite metric compact space K and Y a Banach space: &nbsp; &nbsp; 1. Let 1 < p < &infin; and &Gamma; a infinite set, we classify, up to an isomorphism, the Banach spaces C(K, Y &oplus; lp(&Gamma;)), in the case where the dual of Y contains no copy of lq, where 1/p+ 1/q =1. &nbsp; &nbsp; 2. We classify the Banach spaces C(K, Y &oplus; l&infin;(&Gamma;)), when the density character of Y is strictly less that 2|&Gamma;|. &nbsp; &nbsp; 3. We classify the Banach spaces C(K &times;(S&oplus; &beta;&Gamma;)) and C(S &oplus; (K&times; &beta;&Gamma;)) where S is an arbitrary dispersed compact and &beta;&Gamma; is the Stone-Cech compactification of &Gamma;. We obtain also some cancellation laws for Banach spaces in the form C(K1,X)&oplus; C(K2,Y), where K1 and K2 are metric compact Hausdorff spaces and X, Y Banach spaces satisfying appropriate conditions. We established also a quasi-dichotomy theorem envolving the C(K,X) spaces, where X is of finite cotype. Finally, we present some upper bounds of distortions of positive isomorphisms of C([0,&omega;k]) on C([0,&omega;]) and also of C([0,&omega;]) on C([0,&omega;k]), k&isin; N, k &ge; 2.

A classificação isomorfa dos espaços de Banach separáveis C(K) é devida a Milutin no caso em que K são não enumeráveis e a Bessaga e Pelczynski no caso em que K são enumeráveis. Neste trabalho apresentamos uma extensão vetorial dessa classificação e tiramos várias consequências, por exemplo, considerando o espaço métrico compacto infinito K e Y um espaço de Banach: &nbsp; &nbsp; 1. Sendo 1 < p < &infin; e &Gamma; um conjunto infinito, classificamos, a menos de isomorfismo, os espaços de Banach C(K, Y &oplus; lp(&Gamma;)), quando o dual de Y contém uma cópia de lq, onde 1/p+ 1/q =1. &nbsp; &nbsp; 2. Classificamos os espaços de Banach C(K, Y &oplus; l&infin;(&Gamma;)), quando a densidade de Y é estritamente menor que 2|&Gamma;|. &nbsp; &nbsp; 3. Classificamos os espaços de Banach C(K &times;(S&oplus; &beta;&Gamma;)) e C(S &oplus; (K&times; &beta;&Gamma;)), onde S é um compacto disperso de Hausdorff arbitrário e &beta;&Gamma; é a compactificação de Stone-Cech de &Gamma;. Obtemos, também, algumas leis de cancelamento para espaços de Banach da forma C(K1,X)&oplus; C(K2,Y), onde K1 e K2 são espaços compactos métricos infinitos de Hausdorff e X, Y espaços de Banach satisfazendo condições adequadas. Estabelecemos também um teorema de quase-dicotomia envolvendo os espaços C(K,X), onde X tem cotipo finito. Finalmente, apresentamos algumas majorações nas distorções de isomorfismos positivos de C([0,&omega;k]) em C([0,&omega;]) e também de C([0,&omega;]) em C([0,&omega;k]), k&isin; N, k &ge; 2. / The isomorphic classification of separable Banach spaces C(K) is due Milutin in the case when K are uncountable and to Bessaga and Pelczynski in the case when K are countable. In this work we prove a vectorial extention of this classification and provide several consequences, for example considering the infinite metric compact space K and Y a Banach space: &nbsp; &nbsp; 1. Let 1 < p < &infin; and &Gamma; a infinite set, we classify, up to an isomorphism, the Banach spaces C(K, Y &oplus; lp(&Gamma;)), in the case where the dual of Y contains no copy of lq, where 1/p+ 1/q =1. &nbsp; &nbsp; 2. We classify the Banach spaces C(K, Y &oplus; l&infin;(&Gamma;)), when the density character of Y is strictly less that 2|&Gamma;|. &nbsp; &nbsp; 3. We classify the Banach spaces C(K &times;(S&oplus; &beta;&Gamma;)) and C(S &oplus; (K&times; &beta;&Gamma;)) where S is an arbitrary dispersed compact and &beta;&Gamma; is the Stone-Cech compactification of &Gamma;. We obtain also some cancellation laws for Banach spaces in the form C(K1,X)&oplus; C(K2,Y), where K1 and K2 are metric compact Hausdorff spaces and X, Y Banach spaces satisfying appropriate conditions. We established also a quasi-dichotomy theorem envolving the C(K,X) spaces, where X is of finite cotype. Finally, we present some upper bounds of distortions of positive isomorphisms of C([0,&omega;k]) on C([0,&omega;]) and also of C([0,&omega;]) on C([0,&omega;k]), k&isin; N, k &ge; 2.

Analyses of protein sequences from diverse genomes have revealed the ubiquitous nature of multi-domain proteins. They form up to 70% of proteomes of most eukaryotic organisms. Yet, our understanding of protein structure, folding and evolution has been dominated by extensive studies on single-domain proteins. We provide quantitative treatment and proof for prevailing intuitive ideas on the strategies employed by nature to stabilize otherwise unstable domains. We find that domains incapable of independent stability are stabilized by favourable interactions with tethered domains in the multi-domain context. Natural variations (nsSNPs) at these sites alter communication between domains and affect stability leading to disease manifestation. We emphasize this by using explicit all-atom molecular dynamics simulations to study the interface nsSNPs of human Glutathione S-transferase omega 1. We show that domain-domain interface interactions constrain inter-domain geometry (IDG) which is evolutionarily well conserved. The inter-domain linkers modulate the interactions by varying their lengths, conformations and local structure, thereby affecting the overall IDG. These findings led to the development of a method to predict interfacial residues in multi-domain proteins based on difference evolutionary information extracted from at least two diverse domain architectures (single and multi-domain). Our predictions are highly accurate (∼85%) and specific (∼95%). Using predicted residues to constrain domain–domain interaction, rigid-body docking was able to provide us with accurate full-length protein structures with correct orientation of domains. Further, we developed and employed an alignment-free approach based on local amino-acid fragment matching to compare sequences of multi-domain proteins. This is especially effective in the absence of proper alignments, which is usually the case for multi-domain proteins. Using this, we were able to recreate the existing Hanks and Hunter classification scheme for protein kinases. We also showed functional relationships among Immunoglobulin sequences. The clusters obtained were functionally distinct and also showed unique domain-architectures. Our analysis provides guidelines toward rational protein and interaction design which have attractive applications in obtaining stable fragments and domain constructs essential for structural studies by crystallography and NMR. These studies enable a deeper understanding of rapport of protein domains in the multi-domain context.