Estudamos a propriedade de Bishop-Phelps-Bollobás para operadores, (BP BP ), defi- nidos entre espaços de Banach. Nosso objetivo foi o de procurar pares de espaços de Ba- nach que possuem a BP BP . Assim, provamos que, se o par de espaços de Banach reais L i (c 0 ( i=1 ` 2 ) , Y ) satisfaz a BP BP , onde Y é um espaço de Banach estritamente convexo, então Y é uniformemente convexo. No estudo da BP BP aparecem diversas outras propri- edades, dentre elas destacamos a Approximate hyperplane series property (AHSP ). Nesta direção, considerando (K, (X t ) tK , Z) um espaço de função módulo, provamos que Z satisfaz a AHSP desde que X t satisfaça a AHSP para todo t K. Além disso, sob determinadas condições provamos a recíproca desse resultado. Como consequência, provamos que um es- paço de Banach X tem a AHSP se, e somente se, C 0 (L, X) tem a AHSP , para todo espaço localmente compacto Hausdorff L não-vazio. Concomitantemente ao estudo da BP BP , estudamos técnicas de caracterização dos con- juntos compactos de c 0 . Com essas técnicas, caracterizamos os conjuntos compactos de L i c 0 i=1 ` p , 1 p e do prédual do espaço de Lorentz, d (w, 1). / We study the Bishop-Phelps-Bollobás property for operators, (BP BP ), defined between Banach spaces. Our goal was to look for pairs of Banach spaces satisfying the BP BP . We L i prove that if the pair of real Banach spaces (c 0 ( i=1 ` 2 ) , Y ) satisfy BP BP , where Y is a strictly convex Banach space, then Y is an uniformly convex space. In the study of BP BP , it appears other properties, such the Approximate hyperplane series property for Banach spaces. In this sense, we proved that if (K, (X t ) tK , Z) is function module space, then Z satisfies AHSP if X t has the AHSP for all t K. Moreover, under certain conditions we proved the reciprocal of this result. As a consequence, a Banach space X has the AHSP if, and only if, C 0 (L, X) has the AHSP , for every non-empty locally compact Hausdorff space L. Concomitantly to the study of BP BP , we study techniques of characterization of com- pact sets of c 0 . With these techniques, we characterize the compact sets of the spaces L i c 0 i=1 ` p , 1 p and the predual of Lorentz sequence space d (w, 1).

Les cellules dendritiques (DCs) détectent les particules virales et présentent les antigènes viraux afin d’organiser la réponse immunitaire. La réplication virale dans les DCs induit une réponse immune cytosolique. Comment les DCs tolèrent les virus afin de maintenir leur intégrité fonctionnelle est inconnu. Les DCs sont organisées en sous-populations distinctes d’un point de vue ontogénique. Nous avons observé que le virus du VIH et de la grippe infectaient préférentiellement les DCs CD1c+ par rapport au DCs CD141+ et aux pDCs. La réplication de ces virus au sein des DCs CD1c+ est essentielle afin d’établir une activation efficace des lymphocytes T CD8+ et d’assurer une détection cytosolique. Les DCs CD141+ et les pDCs, quant à elles, répondent aux virus exogènes. L’étape de fusion virale virale est constitutivement réduite dans les DCs CD141+ et les pDCs en comparaison des DCs CD1c+. La petite GTPase RAB15 est exprimée sélectivement dans les DCs CD141+ et les pDCs et contribue à la résistance de ces deux sous-populations de DCs au VIH et à la grippe. La résistance sélective des sous-populations de DC à l’infection virale pourrait représenter un mécanisme de tolérance afin d’augmenter la réponse antivirale. / Dendritic cells (DCs) sense viral particles and present viral antigens to induce immune responses. Viruses also replicate in DCs, engaging cytosolic immune responses. How DCs tolerate viruses to ensure functional integrity is unknown. DCs are developmentally organized in distinct subsets. We find that HIV and influenza preferentially infect CD1c+ DCs over CD141+ DCs and pDCs. Replication in CD1c+ DCs was essential for efficient CD8+ T cell activation and cytosolic sensing, while CD141+ DCs and pDCs responded to exogenous virus. Viral fusion was constitutively reduced in CD141+ and pDCs compared to CD1c+ DCs. The small GTPase RAB15 expressed selectively in CD141+ and pDCs contributed to the resistance. Selective resistance of DC subset to viral infections may thus represent a tolerance mechanism to maximize antiviral responses.

This dissertation addresses the role for Janus Kinase 3 (Jak3) in CD4+ T cell homeostasis and function. Jak3 is a protein tyrosine kinase whose activity is essential for signals mediated by the γc dependent cytokines IL-2, -4, -7, -9, -15, and -21. Previous data have demonstrated that peripheral CD4+ T cells from Jak3-deficient mice have a memory phenotype and are functionally impaired in both proliferative and IL-2 responses in vitro. Interestingly, Jak3/γc activity has been previously shown to play a role in the prevention of T cell anergy. These studies were initiated to more precisely define the role for Jak3/γc cytokines in the prevention of T cell anergy and the maintenance of functional CD4+ T cell responses. We began to address this question by assessing global gene expression changes between wild type and Jak3-/- CD4+ T cells. These data indicate that Jak3-/- CD4+ T cells have an increase in gene expression levels of inhibitory surface receptors as well as immunosuppressive cytokines. Further analyses confirmed that Jak3-deficient T cells express high levels of PD-1, secrete a Trl-type cytokine profile following direct ex vivo activation, and suppress the proliferation of wild type T cells in vitro. These characteristics indicate that CD4+ Jak3-/- T cells share properties with regulatory T cell subsets that have an important role in peripheral tolerance and the prevention of autoimmunity. We next addressed whether these regulatory characteristics were T cell intrinsic or rather the result of expanding in a Jak3-deficient microenvironment characterized by a number of immune abnormalities and a disrupted splenic architecture. Jak3-/- CD4+ T cells proliferate in vivoin a lymphopenic environment and selectively acquire regulatory T cell characteristics in the absence of any additional activation signals. While the precise mechanism by which Jak3-deficient T cells acquire these characteristics remains unclear, our data indicate that one important component is a T cell-intrinsic requirement for Jak3 signaling. These findings indicate several interesting aspects of T cell biology. First, these studies, demonstrate that the homeostatic proliferation of CD4+ T cells is not dependent on signaling via γc-dependent cytokine receptors. And, second, that the weak activation signals normally associated with homeostatic expansion are sufficient to drive Jak3-/- T cells into a non-conventional differentiation program. Previous data indicate that, for wild type T cells, signaling through both the TCR as well as γc-dependent cytokine receptors promote the homeostatic proliferation of T cells in lymphopenic hosts. Since Jak3-/- T cells are unable to receive these cytokine signals, their proliferation is likely to be wholly dependent on TCR signaling. As a consequence of this TCR signaling, Jak3-/- T cells proliferate, but in addition, are induced to up regulate PD-1 and to selectively activate the IL-10 locus while shutting off the production of IL-2. Since this fate does not occur for wild type T cells in a comparable environment, it is likely that the unique differentiation pathway taken by Jak3-/- T cells reflects the effects of TCR signaling in the absence of γc-dependent cytokine signaling. Interestingly, wild type T cells undergoing homeostatic expansion in lymphopenic hosts show many common patterns of gene expression to freshly-purified unmanipulated Jak3-/- T cells. For instance, micro array analysis of gene expression in wild type CD4+ T cells after lymphopenia induced homeostatic expansion show a similar pattern of upregulation in surface markers (PD-1 and LAG-3), and cytokine signaling molecules (IL-10 and IFN-γ cytokine, receptors, and inducible gene targets) to that of Jak3-/- CD4+ T cells immediately ex vivo. These data suggest that the process of homeostatic proliferation normally induces immune attenuation and peripheral tolerance mechanisms, but that full differentiation into a regulatory T cell phenotype is prevented by γc-dependent cytokine signals. Taken together these data suggest that Jak3 plays an important role in tempering typical immune attenuation mechanisms employed to maintain T cell homeostasis and peripheral tolerance.

As células dendríticas (DCs) são células do sistema imune inato que são especializadas na instrução de repostas imunes adaptativas No baço murinho, as DCs convencionais podem ser classificadas em CD8α+ DEC205+ e CD8α- DCIR2+. Anticorpos monoclonais (mAbs) αDEC205 e αDCIR2 (33D1) conjugados a proteínas antigênicas e são utilizados como estratégia de direcionamento de antígenos para as DCs CD8α+ e CD8α-. Foi utilizado o antígeno quimérico MSP119PADRE conjugado aos mAbs αDEC205 e αDCIR2 e o Poly I:C como adjuvante. A montagem da resposta celular e humoral foi analisada 3, 4, 5 e 6 dias após primeira e a segunda As DCS CD8α- são especializadas na instrução de células TFH. Porém, num segundo dose de mAbs há a instrução de uma resposta Th2/Th17. E, o direcionamento de antígenos para DCS CD8α+ induz uma resposta Th1, indicando que essas células são especializadas na instrução desse perfil de resposta auxiliar. Apesar disso, na segunda imunização há a diferenciação de células TFH. / As dendritic cells (DC) are innate immune cells that are specialized to prime adaptive immune cells. In the murine spleen, conventional DCs can be classified into CD8α+ DEC205+ and CD8α-DCIR2+. Monoclonal antibodies (mAbs) αDEC205 and αDCIR2 (33D1) conjugated to antigenic proteins have benn used as antigen targeting strategy to CD8α+ and CD8α- DCs. MSP119PADRE chimeric antigen conjugated to mAbs αDEC205 and αDCIR2 and Poly I: C as adjuvant was used. The assembly of the cellular and humoral response was analyzed 3, 4, 5 and 6 days after the first and second doses of imnunization. DCs CD8α- are specialized in the instruction of TFH cells. However, there is an a promotion of Th1 response by CD8α+, indicating that these cells are specialized in the instruction of the helper response profile. Nevertheless, in the second immunization there is a differentiation of TFH cells.

Submitted by Vanessa Rocha Ribeiro null (va_rocharibeiro@aluno.ibb.unesp.br) on 2017-03-08T15:02:28Z No. of bitstreams: 1 Dissertação Vanessa Rocha Ribeiro.pdf: 3324263 bytes, checksum: c662d084e05ff3055723d93ba4f2eee2 (MD5) / Approved for entry into archive by LUIZA DE MENEZES ROMANETTO (luizamenezes@reitoria.unesp.br) on 2017-03-13T14:49:32Z (GMT) No. of bitstreams: 1 ribeiro_vr_me_bot.pdf: 3324263 bytes, checksum: c662d084e05ff3055723d93ba4f2eee2 (MD5) / Made available in DSpace on 2017-03-13T14:49:32Z (GMT). No. of bitstreams: 1 ribeiro_vr_me_bot.pdf: 3324263 bytes, checksum: c662d084e05ff3055723d93ba4f2eee2 (MD5) Previous issue date: 2017-02-22 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Introdução: A pré-eclâmpsia (PE) é uma patologia obstétrica e uma das principais causas de morbimortalidade materna e fetal. Na PE ocorre um estado de má adaptação da tolerância imunológica, caracterizada por ativação anormal do sistema imune inato e adaptativo. As células T reguladoras (Treg) representam uma população de linfócitos T responsáveis pela manutenção da tolerância e controle da inflamação, enquanto células Th17 medeiam diferentes tipos de reações inflamatórias. Portanto, o balanço entre células Treg e Th17 pode ser crítico para a tolerância ao feto e prevenção da PE. Objetivo: Avaliar as subpopulações de células T CD4+ (Th1, Th2, Th17 e Treg) e o perfil de citocinas produzido por essas células, em gestantes portadoras de pré-eclâmpsia, classificadas em PE precoce e PE tardia. Métodos: Foram estudadas 60 gestantes, sendo 20 normotensas e 40 portadoras de PE, pareadas pela idade gestacional. As gestantes com PE foram classificadas de acordo com o aparecimento das manifestações clínicas em PE precoce (< 34 semanas de gestação; n=20) e PE tardia (≥ 34 semanas de gestação; n=20). Células mononucleares do sangue periférico (PBMCs), obtidas das gestantes foram avaliadas quanto à produção de citocinas pró e anti-inflamatórias e à expressão de fatores de transcrição envolvidos na caracterização das subpopulações de células T CD4+. A expressão dos fatores de transcrição intracitoplasmáticos de células Th1 (T-bet), Th2 (GATA-3), Th17 (RORc) e Treg (FoxP3) foi avaliada por citometria de fluxo e a expressão gênica desses fatores de transcrição foi determinada por PCR em tempo real com transcrição reversa (RT-qPCR), logo após a colheita de sangue para avaliação da expressão endógena dessas diferentes subpopulações de células T. A determinação das citocinas de perfil Th1 (IFN-γ e TNF-α), Th2 (IL-4), Th17 (IL-6, IL-17 e IL-22) e Treg (IL-10 e TGF-β1) foi realizada no plasma das gestantes pela técnica de ELISA. Os resultados foram analisados por meio de testes paramétricos ou não paramétricos com nível de significância de 5%. Resultados: Os perfis inflamatórios Th1 e Th17 foram identificados por aumento significativo da média de intensidade de fluorescência (MIF) e da percentagem de células expressando os fatores de transcrição específicos nas gestantes portadoras de PE precoce e PE tardia em relação aos grupos de gestantes normotensas com idade gestacional correspondente. A percentagem de células Th17 foi significativamente maior nas gestantes com PE precoce do que nas com PE tardia. Por outro lado, a análise dos perfis anti-inflamatórios Th2 e Treg mostrou que a percentagem de células expressando GATA-3 e FoxP3 foi significativamente menor nos grupos de PE precoce e PE tardia comparados aos grupos de normotensas, enquanto a comparação entre gestantes pré-eclâmpticas mostrou percentagem de células Treg significativamente menor nas gestantes portadoras de PE precoce. A expressão gênica do fator de transcrição T-bet por PBMCs não mostrou diferenças significativas entre os grupos de gestantes pré-eclâmpticas e de normotensas. Aumento significativo da expressão gênica do fator de transcrição RORc e diminuição da expressão dos genes GATA-3 e FoxP3 foram observados nos grupos de gestantes pré-eclâmpticas em relação aos grupos de normotensas de idade gestacional correspondente. Entre as gestantes pré-eclâmpticas, encontrou-se menor nível transcricional do fator de transcrição GATA-3 na PE precoce. Os níveis plasmáticos das citocinas IFN-γ, IL-6, IL-17 e TNF-α foram significativamente maiores nas gestantes portadoras de PE, enquanto as concentrações de IL-10 e TGF-β1 foram significativamente menores em comparação aos grupos de gestantes normotensas correspondentes. Observaram-se ainda, maiores níveis de IL-6, IL-17, TGF-β1 e TNF-α na PE precoce do que na PE tardia. A expressão proteica de IL-4 (perfil Th2) e IL-22 (perfil Th17), não apresentou diferença significativa entre os grupos estudados. Conclusão: Os resultados demonstram que o balanço entre células Treg e Th17 é deficiente na PE, havendo polarização para perfil Th17 na PE precoce. Esse desbalanço pode ser atribuído ao predomínio de citocinas pró-inflamatórias sobre as anti-inflamatórias, presentes na circulação de gestantes portadoras de pré-eclâmpsia. / Introduction: Preeclampsia (PE) is an obstetric pathology and one of the main causes of maternal and fetal morbidity and mortality. In PE there is a state of maladaptation of immunological tolerance, characterized by abnormal activation of the innate and adaptive immune system. Regulatory T cells (Treg) represent a population of T lymphocytes responsible for tolerance maintenance and inflammation control, whereas Th17 cells mediate different types of inflammatory reactions. Therefore, the balance between Treg and Th17 cells may be critical for fetal tolerance and PE prevention. Objective: To evaluate the subpopulations of CD4+ T cells (Th1, Th2, Th17 and Treg) and the cytokine profile produced by these cells in pregnant women with PE, classified in early-onset PE and late-onset PE. Methods: Sixty pregnant women, 20 normotensive and 40 preeclamptic women, matched by gestational age, were studied. Pregnant women with PE were classified according to clinical manifestations in early-onset PE (<34 weeks gestation; n = 20) and late-onset PE (≥ 34 weeks gestation; n = 20). Peripheral blood mononuclear cells (PBMCs) obtained from pregnant women were evaluated for the production of pro and anti-inflammatory cytokines and expression of transcription factors involved in the characterization of CD4+ T cell subpopulations. Expression of the intracytoplasmic transcription factors of Th1 (T-bet), Th2 (GATA-3), Th17 (RORc) and Treg (FoxP3) cells was assessed by flow cytometry and the gene expression of these transcription factors was determined by reverse-transcription quantitative polymerase chain reaction (RT-qPCR) shortly after blood collection to evaluate the endogenous expression of these different T-cell subpopulations. The cytokine profile of Th1 cells (IFN-γ and TNF-α), Th2 (IL -4), Th17 (IL-6, IL-17 and IL-22) and Treg (IL-10 and TGF-β1) were measured in the plasma of the pregnant women by the ELISA. The results were analyzed using parametric or non-parametric tests with a significance level of 5%. Results: Th1 and Th17 inflammatory profiles were identified by a significant increase in mean fluorescence intensity (FMI) and by the percentage of cells expressing specific transcription factors in pregnant women with early-onset PE and late-onset PE in relation to the normotensive groups with corresponding gestational age. The percentage of Th17 cells was significantly higher in early-onset PE than in late-onset PE group. On the other hand, analysis of Th2 and Treg anti-inflammatory profiles showed percentages of cells expressing GATA-3 and FoxP3 significantly lower in the early- and late-onset PE groups compared to the normotensive groups, whereas the comparison between preeclamptic groups showed significantly lower percentage of Treg cells in pregnant women with early-onset PE. The gene expression of the T-bet transcription factor by PBMCs did not show significant differences between the preeclamptic and normotensive pregnant groups. Significant increase in the gene expression of RORc and decrease in the expression of the GATA-3 and FoxP3 genes were observed in both groups of preeclamptic women compared with the normotensive ones of corresponding gestational age. Among the preeclamptic pregnant women lower transcriptional level of GATA-3 transcription factor was detected in early-onset PE. Plasma levels of the cytokines IFN-γ, IL-6, IL-17 and TNF-α were significantly higher in pregnant women with PE, whereas IL-10 and TGF-β1 concentrations were significantly lower than in the normotensive corresponding groups. It was also observed higher levels of IL-6, IL-17, TGF-β1 and TNF-α in early-onset than in late-onset PE group. Protein expression of IL-4 (Th2 profile) and IL-22 (Th17 profile), did not show significant differences between the groups studied. Conclusion: The results show that the balance between Treg and Th17 cells is deficient in PE, with polarization to the Th17 profile in early-onset PE. This imbalance can be attributed to the predominance of pro-inflammatory cytokines over the anti-inflammatory ones present in the circulation of pregnant women with preeclampsia. / FAPESP: 2014/25124-7 / FAPESP: 2012/24697-8

In chronic lymphocytic leukemia (CLL), the presence of multiple subsets expressing ‘stereotyped’ B-cell receptors (BCRs) has implicated antigen(s) in leukemogenesis. These stereotyped subsets display similar immunoglobulin (IG) gene usage, almost identical complementarity determining region 3’s and may share clinical features. For instance, subsets #1 (IGHV1/5/7/IGKV1-39) and #2 (IGHV3-21/IGLV3-21) have inferior outcome compared to non-subset patients, whereas subset #4 (IGHV4-34/IGKV2-30) display a favourable prognosis. The aim of this thesis was to investigate genomic aberrations, gene expression patterns and methylation profiles in stereotyped subsets and compare epigenetic profiles in CLL and mantle cell lymphoma (MCL). In paper I, we investigated genomic aberrations in subsets #2, #4 and #16 and in non-stereotyped samples (n=101) using high-density 250K SNP arrays. Subset #2 and non-subset #2 IGHV3-21 cases displayed a higher frequency of aberrations than subset #4 cases. The high incidence of del(11q) in both subset #2/non-subset #2 may reflect the adverse survival reported for IGHV3-21 patients. In contrast, the lower frequency of genetic events and lack of poor-prognostic aberrations in subset #4 may partially explain their indolent disease. In paper II, we analysed the global RNA expression in subset #4, #16 and non-subset IGHV4-34 CLL patients (n=25). Subsets #4 and 16 showed distinct gene expression profiles, where genes involved in cell regulatory pathways were significantly lower expressed in subset #4, in line with their low-proliferative disease. In paper III, a genome-wide methylation array was applied to investigate methylation profiles in subsets #1, #2 and #4 (n=39). We identified differential methylation patterns for all subsets and found affected genes to be involved in e.g. apoptosis and therapy resistance. When performing functional annotation, a clear enrichment of genes involved in adaptive immunity was observed. These genes were preferentially methylated in subset #1 when compared to either subset #2 or #4, possibly due to different antigen responses. In paper IV, the genome-wide methylation profiles for 30 CLL and 20 MCL patients were investigated. Distinct methylation profiles were observed, where MCL displayed a more homogeneous profile. Homeobox transcription factor genes showed a higher degree of methylation in MCL, while apoptosis-related genes and proliferation-associated genes were methylated in CLL. In summary, this thesis demonstrates that stereotyped CLL subsets display differences in gene expression profiles, genetic aberrations and methylation patterns, underscoring the functional relevance of subgrouping according to BCR stereotypy. The distinct methylation profiles of CLL and MCL suggests that different epigenetic mechanisms are involved in the pathogenesis of these B-cell malignancies.

Σκοπός. Η διαβητική κετοξέωση (ΔΚ) και η υπεργλυκαιμική υπερωσμωτική κατάσταση (ΥΥΚ) είναι δύο από τις πιο σοβαρές οξείες επιπλοκές του Σακχαρώδη διαβήτη, που εξακολουθούν να αποτελούν σημαντική αιτία νοσηρότητας και θνητότητας μεταξύ των διαβητικών. Οι λοιμώξεις, συχνός εκλυτικός παράγων και επιπλοκή της ΔΚ και ΥΥΚ, αποτελούν την κύρια αιτία θανάτου και η έγκαιρη διάγνωση και αντιμετώπιση της σήψης είναι κριτικής σημασίας για την επιβίωση των ασθενών. Διερευνήσαμε την επίδραση των ανωτέρω καταστάσεων στην ανοσοποιητική απόκριση, μελετώντας τους υποπληθυσμούς των Τ λεμφοκυττάρων – παραμέτρους οξείας φάσης και την ιντερλευκίνη 6 (IL-6) στο περιφερικό αίμα των ασθενών μας, σε μια προσπάθεια να διαπιστώσουμε τυχόν υποκείμενες διαταραχές και να προσδιορίσουμε πιθανόν διαγνωστικούς και προγνωστικούς δείκτες για τη σήψη. Μέθοδος. Η μελέτη μας περιέλαβε 61 διαβητικούς ασθενείς με ΔΚ ή ΥΥΚ. Ξεχωρίσαμε μια ομάδα ασθενών που είχαν συμπτώματα Συνδρόμου συστηματικής φλεγμονώδους αντίδρασης (SIRS). Προσδιορίσαμε στον ορό όλων των ασθενών τις συγκεντρώσεις των παραγόντων οξείας φάσης (συμπεριλαμβανομένης της C αντιδρώσας πρωτεΐνης ,CRP) και της IL-6 (ως κύρια κυτταροκίνη για την παραγωγή πρωτεϊνών οξείας φάσης), κατά την εισαγωγή και στην ύφεση (μετά τη βελτίωση των συμπτωμάτων και σε κατάσταση ευγλυκαιμίας). Σε μια ομάδα 28 ασθενών με ΔΚ ή ΥΥΚ (σε σύγκριση και με αντίστοιχη ομάδα ελέγχου) μελετήσαμε επιπλέον υποπληθυσμούς των Τ λεμφοκυττάρων, τα ολικά (CD3) / τα βοηθητικά (CD4) / τα κατασταλτικά (CD8) Τ κύτταρα και τα κύτταρα φυσικοί φονείς (ΝΚ) χρησιμοποιώντας μονοκλωνικά αντισώματα και μικροσκόπιο ανοσοφθορισμού, προ και αμέσως μετά τη διόρθωση της μεταβολικής διαταραχής. Αποτελέσματα. Παρατηρήσαμε ότι οι υποπληθυσμοί των Τ λεμφοκυττάρων ήταν σημαντικά ελαττωμένοι κατά την εισαγωγή, συγκρινόμενοι με τους υγιείς μάρτυρες (ενώ οι περισσότερες μελέτες διαβητικών τύπου 1 καταγράφουν αυξημένα βοηθητικά Τ κύτταρα) και παρέμειναν και αμέσως μετά τη διόρθωση της μεταβολικής διαταραχής. Οι ασθενείς που τελικά απεβίωσαν είχαν σημαντικά ελαττωμένους τους υποπληθυσμούς των Τ λεμφοκυττάρων (εκτός των ΝΚ κυττάρων) συγκρινόμενοι και με τους υγιείς μάρτυρες και με όσους ασθενείς επιβίωσαν. Από τους 61 ασθενείς της μελέτης με ΔΚ ή ΥΥΚ, οι 49 ασθενείς είχαν συμπτώματα SIRS. Οι 27 ασθενείς είχαν SIRS χωρίς στοιχεία λοίμωξης, ενώ οι 22 ασθενείς είχαν SIRS με αποδεδειγμένη λοίμωξη. Διαπιστώσαμε σημαντικά αυξημένες συγκεντρώσεις CRP και IL-6 στον ορό των σηπτικών διαβητικών ασθενών συγκριτικά με όσους ασθενείς μας είχαν SIRS χωρίς λοίμωξη. Οι ασθενείς που τελικά απεβίωσαν είχαν σημαντικά πιο αυξημένες συγκεντρώσεις CRP και IL-6 κατά την εισαγωγή, που μειώθηκαν σημαντικά στην ύφεση. Συμπεράσματα. Η διαβητική κετοξέωση και η υπεργλυκαιμική υπερωσμωτική κατάσταση προκαλούν συχνά κλινικό σύνδρομο που ομοιάζει με σύνδρομο συστηματικής φλεγμονώδους αντίδρασης. Διαταραχές στην ισορροπία των υποπληθυσμών των Τ λεμφοκυττάρων, κυρίως η ελάττωση των βοηθητικών Τ κυττάρων μπορεί να συμβάλλουν στην υψηλή θνησιμότητα αυτών των μεταβολικών διαταραχών. Οι μετρήσεις των συγκεντρώσεων C αντιδρώσας πρωτεΐνης και ιντερλευκίνης 6 στον ορό αυτής της ομάδας των διαβητικών ασθενών, είναι ένας χρήσιμος τρόπος αποκλεισμού λοίμωξης και επιβεβαίωσης και παρακολούθησης της σήψης. / Aims / hypothesis. Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS) are two of the most serious acute complications of diabetes mellitus, being important causes of morbidity and mortality among patients with diabetes. Infection is a common precipitating event in DKA and HHS and the major cause of death. An early diagnosis of sepsis in patients with DKA and HHS is crucial and life saving. We studied the immune responses in these states, investigating the peripheral T lymphocyte subsets, acute phase reactants and interleukin 6 (IL-6) to find out how useful these might be for identifying sepsis. Methods. Sixty one diabetic patients with DKA or HHS were enrolled. Patients with signs and symptoms of systemic inflammatory response syndrome (SIRS) were identified. Acute phase reactants, including serum C-reactive protein (CRP) and IL-6, the main cytokine responsible for the induction of acute phase proteins, were measured (concentrations in peripheral blood) on admission and when patients were clinically improved and were euglycaemic. Peripheral T lymphocyte subsets including total (CD3), helper (CD4) and suppressor (CD8) T cells and natural killer (NK) cells, were studied in twenty one patients with DKA plus seven patients with HHS and twenty eight healthy matched control (using monoclonal antibodies), prior to and after treatment of metabolic disorders. Results. Peripheral T lymphocyte subsets were decreased in the twenty eight patients with DKA and HHS in admission compared to healthy controls (while helper T cells are mostly increased in diabetics type 1), and remained so after treatment of metabolic disorders. Patients who finally died had significantly decreased T lymphocyte subsets (except NK cells) compared with both healthy controls and patients who survived. A total of forty nine out of sixty one patients with DKA and HHS had signs of SIRS. Twenty seven patients had SIRS and no signs of infection and twenty two patients had SIRS due to proven infection. We detected a significant increase in serum CRP and IL-6 values in patients infected compared to patients with no septic SIRS. Patients who finally died had much higher levels of these proteins, while there was a prompt reduction of serum CRP and IL-6 early during remission. Conclusion / interpretation. Diabetic ketoacidosis and hyperglycemic hyperosmolar state can often cause a clinical syndrome resembling systemic inflammatory response syndrome. An imbalance of subpopulations of T lymphocytes, especially decreased helper T cells (CD4), may be correlated with the high morbidity and mortality in these states. Determination of serum C-reactive protein and interleukin-6 is a useful way of early excluding an underlying infection as well as confirming and monitoring sepsis.

For a locally compact group G, the papers [13] and [7] have many results about G-invariant subsets of G-modules, and the relationship between G-module maps, L1(G)-module maps and M(G)-module maps. In both papers, the results were given for one specific module action. In this thesis we extended many of their results to arbitrary Banach G-modules. In addition, we give detailed proofs of most of the results found in the first section of the paper [21].

For a locally compact group G, the papers [13] and [7] have many results about G-invariant subsets of G-modules, and the relationship between G-module maps, L1(G)-module maps and M(G)-module maps. In both papers, the results were given for one specific module action. In this thesis we extended many of their results to arbitrary Banach G-modules. In addition, we give detailed proofs of most of the results found in the first section of the paper [21].

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 4 uppsatser.