A contribuição de células B para a memória imunológica se dá por duas distintas populações: células B de memória e células produtoras de anticorpos de longa vida (ASC). A inter-relação entre estas células bem como os mecanismos envolvidos para a manutenção destas tem sido pouco entendida. O veneno de Thalassophryne nattereri tem se mostrado capaz de induzir uma intensa resposta imune de memória. Nós avaliamos o efeito das Natterinas, que são as toxinas majoritárias e inéditas, na indução e manutenção da resposta imune de memória de células B. Este estudo, além de permitir um maior esclarecimento da resposta humoral de memória induzida pelo veneno do peixe T. nattereri, permitiu o estudo da complexa organização do compartimento de células B de memória e ASCs. Também evidenciamos a importância da atividade proteásica para a manutenção da cronicidade de resposta de células B no peritônio, no baço e na medula, como verificamos que a ativação de receptores inatos como osTLRs é decisiva para a geração e manutenção de ASCs B220pos/neg em resposta às Natterinas, dependentes das vias de sinalização MyD88 ou TRIF. Estas sinalizações controlam a magnitude, a qualidade e a longa duração da resposta humoral de memória. / The contribution of B cells for the immunological memory feels for two different populations: memory B cells and long-lived antibodies secreting cells (ASC). The interrelation among these cells as well as the mechanisms involved for the maintenance of these it has been little understood. The venom of Thalassophryne nattereri possesses the ability to induce an intense memory immune response. We evaluated the effect of Natterins that are majority toxins in the venom, in the induction and maintenance of the immune memory response of cells B. The study, besides allowing a larger explanation of the humoral memory response induced by the venom of the fish, it allowed the understanding of the complex organization of the memory B cells compartment, mainly of the subtype of long-lived cells (ASC). Also, we showed the importance of the protease activity of Natterins in the maintenance of the chronic B cell responses in the three analyzed compartments. We verify that the activation of Toll like receptors is decisive for the generation and maintenance of ASCs B220pos/neg in response to Natterins, dependent on the MyD88 or TRIF signaling that control the quality and the duration of the humoral memory response.

A contribuição de células B para a memória imunológica se dá por duas distintas populações: células B de memória e células produtoras de anticorpos de longa vida (ASC). A inter-relação entre estas células bem como os mecanismos envolvidos para a manutenção destas tem sido pouco entendida. O veneno de Thalassophryne nattereri tem se mostrado capaz de induzir uma intensa resposta imune de memória. Nós avaliamos o efeito das Natterinas, que são as toxinas majoritárias e inéditas, na indução e manutenção da resposta imune de memória de células B. Este estudo, além de permitir um maior esclarecimento da resposta humoral de memória induzida pelo veneno do peixe T. nattereri, permitiu o estudo da complexa organização do compartimento de células B de memória e ASCs. Também evidenciamos a importância da atividade proteásica para a manutenção da cronicidade de resposta de células B no peritônio, no baço e na medula, como verificamos que a ativação de receptores inatos como osTLRs é decisiva para a geração e manutenção de ASCs B220pos/neg em resposta às Natterinas, dependentes das vias de sinalização MyD88 ou TRIF. Estas sinalizações controlam a magnitude, a qualidade e a longa duração da resposta humoral de memória. / The contribution of B cells for the immunological memory feels for two different populations: memory B cells and long-lived antibodies secreting cells (ASC). The interrelation among these cells as well as the mechanisms involved for the maintenance of these it has been little understood. The venom of Thalassophryne nattereri possesses the ability to induce an intense memory immune response. We evaluated the effect of Natterins that are majority toxins in the venom, in the induction and maintenance of the immune memory response of cells B. The study, besides allowing a larger explanation of the humoral memory response induced by the venom of the fish, it allowed the understanding of the complex organization of the memory B cells compartment, mainly of the subtype of long-lived cells (ASC). Also, we showed the importance of the protease activity of Natterins in the maintenance of the chronic B cell responses in the three analyzed compartments. We verify that the activation of Toll like receptors is decisive for the generation and maintenance of ASCs B220pos/neg in response to Natterins, dependent on the MyD88 or TRIF signaling that control the quality and the duration of the humoral memory response.

Indiana University-Purdue University Indianapolis (IUPUI) / The modification of brucine derivatives as chiral ligands and the use of a multifaceted chiral ligand, brucine diol, under different reaction conditions to produce various optical isomers is described. In Chapter 1, the generation of a number of brucine derivatives is described. Taking the advantage of brucine-diol’s excellent molecular recognition capability for multiple organic functional groups, we focused on the synthetic modifications of brucine-diol and the synthesis of brucine N-oxide. We also produced various brucine derivatives with different functional moieties in good yields and selectivities. In Chapter 2, we described the investigation of brucine N-oxide catalyzed Morita-Baylis-Hillman (MBH) reaction of alkyl/aryl ketones. Brucine N-oxide was used as a nucleophilic organic catalyst in the MBH reaction of alkyl vinyl ketone. In addition, asymmetric MBH reactions of alkyl vinyl ketones with aldehydes were investigated using a dual catalysis of brucine N-oxide and proline. In this dual catalyst system, proline was found to form iminium intermediates with electron-deficient aryl aldehydes, while the N-oxide activated vinyl ketones provided enolates through the conjugate addition. Our dual catalysis approach also allowed the development of MBH reaction of aryl vinyl ketones. In Chapter 3, brucine diol-copper complex catalyzed asymmetric conjugate addition of glycine (ket)imines to nitroalkenes is discussed. Stereodivergent catalytic asymmetric conjugate reactions for glycine (ket)imines with nitroalkenes were achieved using various chiral catalysts derived from a single chiral source, brucine diol. Both syn- and anti-conjugate addition products were obtained with high diastereoselectivity and enantioselectivity. In Chapter 4, enantiodivergent production of endo-pyrrolidines from glycine (ket)imines using brucine diol-copper complex is described. The [3+2] cycloaddition reaction of glycine imines and activated alkenes was performed to produce endo-pyrrolidines. The reversal of enantioselectivity was observed for endo-pyrrolidines between concerted and stepwise reaction pathways. The three new brucine derivatives produced in this study would potentially work as organocatalysts and chiral ligands with metal ion in asymmetric synthesis. The brucine diol-metal complex catalyzed reactions laid a good foundation for catalytic asymmetric reactions, where a single chiral source was used to control the absolute and the relative stereochemical outcomes of reactions. Understanding the molecular-level interactions between catalyst and substrates will provide insightful mechanistic details for the stereodivergent approaches in asymmetric catalysis.

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