Abstract An excess of atopic allergies has been found in patients with depression, and conversely, increased amounts of depressive symptoms have been reported in patients with atopic disorders. Thus far, however, the findings have mainly been based on clinical samples. In this thesis, the association between atopic disorders and depression was investigated at epidemiological level by using data from the Northern Finland 1966 Birth Cohort. An unselected cohort of 12058 liveborn children was followed prospectively from prenatal stages until 1997. During the 31-year follow-up, 6025 cohort members underwent skin prick tests. Data on lifetime depression diagnoses and atopic conditions were obtained from postal questionnaires and Finnish Hospital Discharge Registers, and the severity of the depressive symptoms was assessed with Hopkins Symptom Checklist-25. Information on the family histories of the atopic disorders was obtained from questionnaires of the 31-year follow-up. Females with positive skin prick test responses and self-reported histories of allergic symptoms exhibited a 2.7-fold probability of developing lifetime depression. The corresponding probability increased in line with the increased severity of depressive symptoms in atopic but not in non-atopic females, ranging from 3.0 to 4.7-fold. Among males, the atopy-depression association was seen only in the highest depression scores, the odds ratio being up to 6.3-fold. While the most severe, hospital-treated manifestations of both disorders were considered, atopic disorders increased the risk of depression 3-fold independently of the subject's gender and sociodemographic characteristics. When investigating the effect of familial atopy on a child's depression, maternal atopy increased the probability of lifetime depression nearly 2-fold in females, and over 4-fold, when a female cohort member's own atopy was also present. At epidemiological level, the presence of atopic conditions seemed to increase the probability of lifetime depression especially in females. Since both atopic disorders and depression are illnesses of major public health importance in Western countries, also the co-morbidity between these disorders should be seriously taken into account in clinical practice. Further investigations are called for in evaluating whether this association is specific to atopic disorders, since increased risks of depression have been noted in connection with many other physical diseases as well.

Submitted by Fabio Sobreira Campos da Costa (fabio.sobreira@ufpe.br) on 2016-04-12T14:55:01Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) TESE ANA LUCIA.pdf: 1458077 bytes, checksum: cbbeca0fd53136913a74cf4a72f10bf8 (MD5) / Made available in DSpace on 2016-04-12T14:55:01Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) TESE ANA LUCIA.pdf: 1458077 bytes, checksum: cbbeca0fd53136913a74cf4a72f10bf8 (MD5) Previous issue date: 2015-07-22 / CNPq / A resposta imune contra Giardia lamblia e as alergias, em área endêmica para infecções por helmintos e este protozoário. tem sido estudada. IgE e isotipos IgG anti-Ascaris lumbricoides (Asc) podem modular a atopia e a alergia. Neste estudo, avalia-se a presença de anticorpos IgE ,IgG1, IgG4 anti Asc e a produção de citocinas Th1 (IL-2/IFN-γ/TNF-α), Th2 (IL-4/IL-10), Th17 (IL-17/IL-6) em crianças infectadas por G.lamblia, sem infecção concomitante por helmintos, bem como a frequência de asma e/ou rinite. Para isso, um estudo caso-controle aninhado em um estudo transversal utilizando questionário padrão para a alergia de vias aéreas, análises coproparasitológicas. Realizou-se testes imunoenzimáticos para detecção de anticorpos anti-Asc e cultura de células de sangue para mensuração dos níveis de citocinas em sobrenadante e intracelular. A amostra foi composta por 211 crianças: 53 infectadas / asma/rinite (GA); 39 não infectadas/asma/rinite (A); 62 infectadas / não / asma / rinite (G); 57 não asma/rinite/não infectadas (NA+NG), com idades entre 2-10 anos. Infecção por G.lamblia foi acompanhado pelo aumento dos níveis de IgG1, mas não IgE ou IgG4.anti Asc. A produção de IL-6 foi semelhante entre os grupos, mas a produção de IL-2, IL-4 e IFN- foi maior em crianças infectadas. TNF-α foi produzido em níveis mais elevados em crianças alérgicas, enquanto que a IL-10 esteve em níveis elevados em crianças infectadas/asma/rinite. Em crianças infectadas com IgG1 anti-Asc positivo houve maior produção do TNF-α e IL-10 e menor frequência de alergia quando comparou com IgG1 anti-Asc negativo (OR = 0,392; IC = ,168-,914; p = 0,02). Para análise do coteúdo de citocinas intracelular, foi observada menor frequência de células CD4+/IFN-+ e CD4+/IL-17+ no grupo GA, quando comparado com o grupo NG+NA. Não houve diferença na frequência de células CD4+/IL-4+ entre os grupos. A frequência de células CD4+/IL-17+ foi inferior em crianças somente infectadas (G). Em conjunto, um perfil Th1/Th2 foi estimulado nos pacientes infectados, com IgG1 anti-Asc circulante e houve maior produção de IL-10 e TNF-α com frequência de alergia vias aéreas mais baixa. Além disso, estes achados apontam um perfil predominante de Th2 (IL-4 acompanhada de menor nível de IFN-) com baixo potencial inflamatório (menos IL-17) em crianças infectadas por G. lamblia com asma e/ou rinite. Estes resultados destacam a importância de uma melhor avaliação dos subtipos de IgG em A. lumbricoides e G. lamblia em áreas endêmicas, especialmente no que diz respeito à estratégia de prevenção ou dessensibilização para reações alérgicas. / Immunity to Giardia lamblia and allergies in endemic area for helminths/protozoa infections had been studied. Anti-Ascaris lumbirocides (Asc) IgE and IgG isotypes can modulate the atopic and allergy. In this study, we evaluate the presence of anti-Asc IgE, IgG4, IgG1 antibodies and Th1 (IL-2/IFN-γ/TNF-α), Th2 (IL-4/IL-10), Th17 (IL-17/IL-6) cytokine production in G. lamblia-infected children, without concomitant helminths infection, as well as asthma and/or rhinitis frequency. For this, a case-control nested in a cross-sectional study was conducted using standard questionnaire for airway allergy, parasitological analyses, immunoassay tests for anti-Asc antibodies and blood cell culture for cytokines measurement in supernatant and intracellular. The sample comprised 211 children (53 allergic/infected (GA); 39 allergic/uninfected (A); 62 non-allergic/infected (G); 57 non-allergic/non-infected (NA+NG) aged 2-10 years. Protozoan infection was accompanied by increased of anti-Asc IgG1 levels, but not IgE or IgG4. There were similar IL-6 production, but IL-2, IL-4 and IFN- were higher in infected children. TNF-α was produced in higher levels for allergic children, whereas the IL-10 was high levels in allergic/infected children. For positive anti-Asc IgG1 and allergic/infected children, higher TNF-α and IL-10 production and lower allergy frequency was observed when compared to negative anti-Asc IgG1 (OR=0.392; IC=0.168-0.914; p=0.02). For intracellur cytokine content, was observed lower frequency of IFN-+CD4+ and IL-17+CD4+ cells in the GA group when compared to the NG+NA group. There was no difference in IL-4+CD4+ cells frequency among the groups. The IL-17+CD4+ cells frequency was lower in infected children only (G). Take together, the a Th1/Th2 profile was stimulated in the infected patients, which with circulating anti-Asc IgG1 the production of IL-10 and TNF-α was strengthened and there was lower frequency airway allergy. Besides of this, the finding point out a predominant Th2 profile (IL-4 accompanied of less IFN-) with low inflammatory potential (less IL-17) in G. lamblia infected children with asthma and/or rhinitis. These findings highlight the importance of improved evaluation of IgG subtypes in A. lumbricoides and G. lamblia endemic areas, especially with regard to the prevention strategy or desensitization for allergic reactions.

IFNγ is an essential and pleiotropic activator of monocytes, but little is known about the effects IFNγ on cellular metabolism. Therefore, we sought to characterize and elucidate the mechanisms by which IFNγ reprograms monocyte metabolism to support its immunologic activities. First, we identified a critical role for IFNγ in the induction of immunoresponsive gene 1 (IRG1) and its product, itaconate. The immunometabolite, itaconate, has been reported to have antibacterial, anti-inflammatory and antioxidant activity. Irg1-/- mice, lacking itaconate, are highly susceptible and phenotypically similar to IFNγ knock out (GKO) mice upon infection with Mycobacterium tuberculosis. Therefore, we assessed the role of IRG1/itaconate in the context of non-tuberculous mycobacterial (NTM) infection, the most common type of infection in patients with immunodeficiencies caused by defects in IFNγ signaling. Our data suggest that impaired induction of itaconate in the context of mycobacterial infection may contribute to mycobacterial susceptibility and immune dysregulation in patients with defects in IFNγ signaling. Next, we evaluated the metabolic phenotype of IFNγ-stimulated human monocytes and found that IFNγ increased oxygen consumption rates (OCR), indicative of reactive oxygen species generation by both mitochondria and NADPH oxidase. Transcriptional profiling of human macrophages revealed that this oxidative phenotype was dependent on IFNγ-induced, nicotinamide phosphoribosyltransferase (NAMPT)-mediated NAD+ salvage to generate NADH and NADPH for oxidation by mitochondrial complex I and NADPH oxidase, respectively. These data identify an IFNγ-induced, NAMPT-dependent, NAD+ salvage pathway that is critical for complete induction of the respiratory burst in IFNγ stimulated human monocytes.

Les neutrophiles constituent une première ligne de défense contre les agents infectieux. En revanche, leur activation incontrôlée peut exacerber certaines pathologies inflammatoires telles que les allergies cutanées. Notre équipe a montré précédemment que le facteur de transcription Nrf2 connu pour son rôle anti-oxydant, régulait l’inflammation cutanée dans l’hypersensibilité de contact (HSC). Ainsi ce travail a été mené pour évaluer in vitro l’implication de la voie Nrf2 dans les fonctions des neutrophiles et pour identifier son rôle dans le recrutement et l’activation des neutrophiles dans l’HSC.In vitro, nous montrons que la protéine Nrf2 est fortement exprimée dans les neutrophiles de la moelle osseuse. Nrf2 est fonctionnelle dans les neutrophiles stimulés : il active la transcription de gènes cibles cytoprotecteurs et diminue celle des gènes de l’inflammation. Ainsi, le prétraitement des neutrophiles avec un activateur de Nrf2 tel que le sulforaphane, réduit la production des formes réactives de l’oxygène (FRO)en réponse à une stimulation. En parallèle, l’absence de Nrf2 ne semble pas affecter la phagocytose et la nétose, deux fonctions clés du neutrophile. Enfin, Nrf2 est indispensable pour une migration optimale des neutrophiles en réponse aux chimiokines.Au cours de l’HSC induite par le dinitrochlorobenzène (DNCB), Nrf2 régule indirectement le recrutement des neutrophiles, en contrôlant le stress oxydant cutané et les voies inflammatoires impliquées dans la production de chimiokines, notamment CCL2, CCL4 et CCL11. En outre, Nrf2 induit l’augmentation d’expression du scavenger CD36 dans les macrophages et augmente ainsi leur capacité à éliminer les neutrophiles apoptotiques pour initier la résolution de l’inflammation.En conclusion, l’activation de Nrf2 dans les neutrophiles participe au contrôle de la production des FRO et la migration. En outre, Nrf2 émerge comme un effecteur clé dans le contrôle du recrutement et de la clairance des neutrophiles au cours de la réponse inflammatoire cutanée aux molécules allergisantes. La mise en évidence de ces mécanismes protecteurs de Nrf2 nous permet de proposer cette protéine comme nouvelle cible thérapeutique dans le contrôle d’inflammations cutanées chroniques. / Neutrophils form the first line of defense against infectious agents. However, their uncontrolled activation may exacerbate certain inflammatory conditions such as cutaneous allergies. Our team has previously shown that Nrf2 transcription factor known for its antioxidant role, regulates skin inflammation in contact hypersensitivity (CHS). Thus, our work was carried out to evaluate in vitro the involvement of Nrf2 pathway in neutrophil functions and to identify Nrf2 role in neutrophil recruitment and activation in CHS.In vitro, we showed that the protein Nrf2 was highly expressed in bone marrow neutrophils. Nrf2 is functional in stimulated neutrophils: it activates the transcription of cytoprotective genes and downregulates that of inflammatory genes. Thus, pretreatment of neutrophils with an Nrf2 activator such as sulforaphane reduces the production of reactive oxygen species (ROS) in response to stimulation. In parallel, Nrf2 does not affect two key functions of neutrophil, phagocytosis and netosis.Finally, Nrf2 is essential for optimal migration of neutrophils toward chemokines. In CHS induced by the dinitrochlorobenzene (DNCB), Nrf2 indirectly regulates the recruitment of neutrophils, through regulation of skin oxidant stress and inflammatory pathways that are involved in chemokines production, including CCL2, CCL4 and CCL11. In addition, Nrf2 induces the up-regulation of scavenger CD36 in macrophages and thus increases their ability to eliminate apoptotic neutrophils leading to the resolution of inflammation.In conclusion, Nrf2 activation in neutrophils participates in the control of ROS production and migration. In addition, Nrf2 emerges as an important effector in the control of neutrophil recruitment and clearance during the skin inflammatory response to allergenic molecules. The demonstration of Nrf2 protective mechanisms leads us to suggest this protein as a new therapeutic target in the control of chronic skin inflammations.

Orientador: Nilton Carlos Machado / Resumo: Introdução. As alergias alimentares são um problema crescente no mundo, e a única maneira de tratar continua sendo a exclusão de alimentos com a proteína implicada. A ANVISA estabeleceu requisitos para a rotulagem dos principais alimentos que causam alergias alimentares. Portanto a leitura dos rótulos dos alimentos embalados deve ser praticada por todo cuidador de crianças alérgicas. Objetivo. Qualificar os rótulos apresentados pelas indústrias de alimentos com base na resolução atual e propor medidas que beneficiem a leitura de rótulos pelo público alérgico. Métodos. Estudo observacional transversal para avaliar a rotulagem de alérgenos de alimentos embalados. No primeiro momento foi realizada uma busca em supermercados de diferentes marcas de gêneros alimentícios. No segundo momento mediante sorteio eletrônico foi obtida amostra para analise, composta do mínimo de 50% de marcas de alimentos embalados de cada gênero alimentício. Posteriormente, foi realizada fotografia digital de cada produto, em todas as suas dimensões (painel principal, laterais e fundos). Os alimentos embalados foram divididos com base nos Grupos da Pirâmide alimentar brasileira. Foram analisados: os ingredientes presentes e as características da rotulagem. Dados apresentados de forma descritiva. A classificação dos rótulos foi apresentada em escore baseado na resolução vigente, gerando pontuação de 0 a 10 aos diferentes alimentos dos Grupos da Pirâmide alimentar brasileira. Resultados. Os alimentos embal... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Introduction. Food allergies are a growing problem worldwide, and the only way to treat them is to exclude foods with the protein involved. ANVISA has established requirements for the labelling of major foods that cause food allergies. Therefore, the reading of packaged food labels should be practiced by all caregivers of allergic children. Aims. Qualify the labels presented by the food industries based on the current resolution and propose measures that benefit the reading of labels by the allergic public. Methods. Cross-sectional observational study to evaluate allergen labelling of packaged foods. At first, a search was done in supermarkets of different brands of foodstuffs. In the second moment, utilizing an electronic draw, a sample was obtained for analysis, composed of at least 50% of packaged food brands of each foodstuff. Subsequently, digital photography of each product was performed, in all its dimensions (main panel, sides and bottoms). The packaged foods were divided based on the Brazilian Food Pyramid Groups. Were analyzed: the present ingredients and the characteristics of the labelling. Data are presented descriptively. The classification of the labels was presented in a score based on the current resolution, generating a score from 0 to 10 to the different foods of the Brazilian Food Pyramid Groups. Results. Packaged foods have quality information, with labeling scores close to the maximum in all groups. Regarding the indication of the presence of allergens: ... (Complete abstract click electronic access below) / Mestre

Diabetes mellitus Typ 1 und Allergien vom Soforttyp gehören zu den häufigsten chronischen Erkrankungen des Kindes- und Jugendalters. Diabetes mellitus Typ 1 wird verursacht durch eine autoimmune Zerstörung der Beta-Zellen des Pankreas. Aus immunologischer Sicht wird dieser Prozess durch TH1-Zellen dominiert. Im Gegensatz dazu wird vermutet, dass Allergien vom Soforttyp, wie die allergische Rhinitis, das allergische Asthma und die allergische Urtikaria mit TH2-Zellen assoziiert seien. Die Hypothese, dass TH1- und TH2-Zellen sich gegenseitig in ihrer Aktivität hemmen, ist immer noch gültig. Ziel unserer Fall-Kontroll-Studie war es, die Assoziation zwischen Typ 1 Diabetes und IgE-vermittelten Allergien zu untersuchen. Zur Prüfung unserer Forschungshypothese wurden ein standardisierter, evaluierter Fragebogen sowie verschiedene Laboranalysen herangezogen. Es konnte gezeigt werden, dass Diabetes mellitus Typ 1 mit einem erhöhten Risiko für das gleichzeitige anamnestische Vorliegen IgE-vermittelter allergischer Symptome assoziiert sein könnte. Somit konnten wir bestätigen, dass die noch heute weit verbreitete TH1/TH2-Hypothese eine Vereinfachung tatsächlich viel komplizierterer immunologischer Vorgänge darstellt. Um diese Assoziation im Detail zu prüfen, bedarf es jedoch weiteren populationsbasierten epidemiologischen Studien.:I. Bibliographische Beschreibung 7 II. Abkürzungsverzeichnis 9 1. Einführung 11 1.1 Epidemiologie und Pathogenese des Diabetes mellitus Typ 1 11 1.2 Epidemiologie und Pathogenese von Allergien vom Soforttyp 13 1.3 Aktueller Forschungsstand zum Thema 14 2. Das Promotionsprojekt 17 2.1 Forschungshypothese und Fragestellung 17 2.2 Patienten und Methoden 17 2.3 Statistische Datenauswertung 19 2.4 Ergebnisse 20 2.5 Einordnung in den aktuellen wissenschaftlichen Diskurs 23 3. Publikationsmanuskript 29 4. Zusammenfassung der Arbeit 43 5. Literaturverzeichnis 47 III. Erklärung über die eigenständige Abfassung der Arbeit 55 IV. Curriculum Vitae 57 V. Liste der Veröffentlichungen 59 VI. Danksagung 61

Allergien sind häufige Erkrankungen in vielen industrialisierten Ländern. Ihre Entstehung beruht auf einem komplexen Zusammenspiel von genetischen und umweltassoziierten Einflüssen. Eine Vielzahl möglicher Faktoren ist beschrieben, die das Auftreten von AllerT gien beeinflussen können, etwa das Alter oder das Geschlecht. Es gibt allerdings nur sehr wenige Daten zur Verbreitung allergischer Erkrankungen in der älteren Bevölkerung. Das Ziel der vorliegenden Arbeit ist es, eine Übersicht zur Prävalenz allergischer ErkranT kungen und Sensibilisierungen in einer Stichprobe der 40T79Tjährigen Bevölkerung Leipzigs zu geben. Hierzu wurden insgesamt 4088 Probanden der zweiten ZwischenausT wertung (1. November 2011 bis 12. Juni 2013) der LIFETStudie untersucht. LIFE (Leipziger Forschungskomplex für Zivilisationserkrankungen) ist eine Kohortenstudie zur Erfassung von lebensstilT und umweltassoziierten Erkrankungen, beispielsweise Allergien, und mögT lichen Einflussfaktoren. In der vorliegenden Arbeit werden allergische Erkrankungen (alT lergische Rhinitis, Asthma bronchiale, atopisches Ekzem, Urtikaria, Anaphylaxie, NahT rungsmittelT und Insektengiftallergien) anhand eines AllergieTInterviews erfragt; SensibiliT sierungen werden mittels IgETDiagnostik für InhalationsT (SX1T) und NahrungsmittelallerT gene (FX5TScreeningtest) bzw. mittels Hautpricktest (Birke, Wiesenlieschgras, Beifuß, Dermatophagoides pteronyssinus, Alternaria alternata und Ambrosia) erfasst, weiterhin wird das GesamtTIgE bestimmt. Als mögliche Einflussfaktoren werden das Geschlecht, das Alter, der sozioökonomische Status und die allergologische Familienanamnese unterT sucht, hierzu werden neben den Prävalenzen auch OddsTRatios berechnet. Allergien sind häufige Erkrankungen in vielen industrialisierten Ländern. Ihre Entstehung beruht auf einem komplexen Zusammenspiel von genetischen und umweltassoziierten Einflüssen. Eine Vielzahl möglicher Faktoren ist beschrieben, die das Auftreten von Allergien beeinflussen können, etwa das Alter oder das Geschlecht. Es gibt allerdings nur sehr wenige Daten zur Verbreitung allergischer Erkrankungen in der älteren Bevölkerung. Das Ziel der vorliegenden Arbeit ist es, eine Übersicht zur Prävalenz allergischer Erkrankungen und Sensibilisierungen in einer Stichprobe der 40-79-jährigen Bevölkerung Leipzigs zu geben. Hierzu wurden insgesamt 4088 Probanden der zweiten Zwischenauswertung (1. November 2011 bis 12. Juni 2013) der LIFE-Studie untersucht. LIFE (Leipziger Forschungskomplex für Zivilisationserkrankungen) ist eine Kohortenstudie zur Erfassung von lebensstil- und umweltassoziierten Erkrankungen, beispielsweise Allergien, und möglichen Einflussfaktoren. In der vorliegenden Arbeit werden allergische Erkrankungen (allergische Rhinitis, Asthma bronchiale, atopisches Ekzem, Urtikaria, Anaphylaxie, Nahrungsmittel- und Insektengiftallergien) anhand eines Allergie-Interviews erfragt; Sensibilisierungen werden mittels IgE-Diagnostik für Inhalations- (SX1-) und Nahrungsmittelallergene (FX5-Screeningtest) bzw. mittels Hautpricktest (Birke, Wiesenlieschgras, Beifuß, Dermatophagoides pteronyssinus, Alternaria alternata und Ambrosia) erfasst, weiterhin wird das Gesamt-IgE bestimmt. Als mögliche Einflussfaktoren werden das Geschlecht, das Alter, der sozioökonomische Status und die allergologische Familienanamnese untersucht, hierzu werden neben den Prävalenzen auch Odds-Ratios berechnet. Insgesamt zeigt sich, dass allergische Erkrankungen und Sensibilisierungen in der untersuchten Stichprobe häufig sind. Die Einflussfaktoren zeigen unterschiedliche Effekte für das Risiko einer Allergie. Beispielsweise geht eine positive allergologische Familienanamnese mit einem erhöhten Risiko einher. Die möglichen Ursachen für Prävalenzunterschiede bei den allergischen Erkrankungen im Vergleich mit der Literatur und das Verhalten der Einflussfaktoren werden, ebenso wie die bestehenden Limitationen von LIFE, kritisch diskutiert. In der vorliegenden Arbeit wird erstmalig der Status quo von allergischen Erkrankungen in einer Probandengruppe der älteren Leipziger Bevölkerung gezeigt. Allergien sind bei den älteren Teilnehmern weniger häufig als bei den jüngeren, aber immer noch weit verbreitet. Weitere Untersuchungen sind notwendig, um mögliche Prävalenzänderungen zu dokumentieren und weitere Einflussfaktoren zu untersuchen. LIFE und seine geplanten Nachuntersuchungen bieten hierfür passende Möglichkeiten.

HISTORICAL PERSPECTIVE: It has recently been shown that intensive prophylactic dietary and environmental control measures during early infancy may reduce the incidence and/or postpone the onset of atopic disease. In order to institute this prophylactic regime, early identification of the infants genetically "at risk" for atopic disease is essential, since sensitisation begins at birth, or even during intra-uterine life. European and Scandinavian studies have shown that a raised concentration of cord blood serum immunoglobulin E (CBsIgE) is an excellent predictive marker for the subsequent development of atopic disease. Other potential predictive atopic markers such as cord blood eosinophils, platelets and anti-cow's milk serum IgG have also been suggested as having possible predictive relevance for newborns in terms of the development of subsequent atopic disease. PROBLEM DEFINITION: Most of the work in this field has been done on Caucasian neonates, in Westernised, First World countries. In South Africa, it has been shown that the Black adult ethnic group has serum immunoglobulin E concentrations (sIgE) which are significantly higher than that found in the South African White adult ethnic group. Furthermore, it has been suggested that the elevated sIgE in the adult Blacks may be raised independently of allergic disease. It is, therefore, important to ascertain whether this elevation of sIgE in Black South African adults is evident already at birth in the cord blood sera of Black South African newborns. If so, it is imperative to ascertain whether any such elevation is reflective of a high genetic load for atopy in these Black newborns, and furthermore whether these Black newborns are consequently "high-risk" for the development of subsequent atopic disease, as has been previously reported in the literature for White newborns. Arising from an awareness of these specific South African problems, the following hypothesis was developed. HYPOTHESIS: The hypothesis states that: "Black South African newborns without an atopic family history (aFH) have significantly higher CBslgE values than similar White and Mixed newborns. An aFH does not influence the CBsIgE values in the Black newborns, as it does in the White and Mixed newborns. The CBsIgE values in Black newborns are not, furthermore, predictive for the development of subsequent atopy in infancy, as they are in the other ethnic groups". A description of the three South African ethnic groups considered in this study is provided in Section IV, (Pg. 74). AIMS OF THE STUDY: The aims of the study were three-fold: 1. To test the hypothesis. 2. To assess the relevance of alternative cord blood markers (eosinophils, platelets and anti-cow's milk serum IgG) as predictive atopic markers in each of the three ethnic groups. 3. To provide epidemiological information with regard to genetic and environmental influences on CBslgE, cord blood total eosinophil counts (CBTEC's) cord blood platelet counts (CBPlC's) and cord blood anti-cow's milk serum IgG concentrations (CBacmlgG).

Preclinical models of lupus indicate that T cell-B cell collaboration drives antinuclear antibody (ANA) production and sustains T cell activation. Autoreactive B lymphocytes are present in the normal repertoire but persist as ignorant or anergic cells. Mechanisms that normally limit T cell activation of autoreactive B cells remain incompletely resolved, but potentially include the absence of autoreactive effector T cell subsets and/or the presence of autoAgspecific regulatory T cells (Tregs). Several studies have addressed this issue by using experimental systems dependent on transgenic autoreactive B cells, but much less is known about the activation of autoreactive B cells present in a polyclonal repertoire. In the second chapter of this thesis, I have explored the role of effector T cells and Tregs using mice that express an inducible pseudoautoAg expressed on B cells and other antigen presenting cells (APCs). In this system, activated Th2 cells, but not naïve T cells, elicit the production of ANAs, but ANA production is severely limited by autoAg-specific Tregs. Bone marrow chimera experiments further demonstrated that this B cell activation is constrained by radioresistant autoantigen-expressing APCs (rAPC) present in the thymus as well as by non-hematopoietic stromal cells located in peripheral lymphoid tissue. Importantly, peripheral rAPC expression of autoAg induced the expansion of a highly effective subset of CD62L+CD69+ Tregs. The third chapter of this thesis focuses on the contribution of CD8+ T cells to fibrosis resulting from sterile lung injury. Type 2 effector production of IL-13 is v a demonstrated requirement in several models of fibrosis, and is routinely ascribed to CD4+ Th2 cells. However, we now demonstrate a major role for pulmonary CD8+ T cells, which mediate an exaggerated wound healing response and fibrosis through robust differentiation into IL-13-producing pro-fibrotic type 2 effectors (Tc2). Remarkably, differentiation of these Tc2 cells in the lung requires IL-21. We further show that the combination of IL-4 and IL-21 skews naïve CD8+ T cells to produce IL-21, which in turn acts in an autocrine manner to support robust IL-13 production. TGF-β negatively regulates production of IL-13 by suppressing CD8+ T cell responsiveness to IL-21. Our data illuminate a novel pathway involved in the onset and regulation of pulmonary fibrosis, and identify Tc2 cells as key mediators of fibrogenesis.

Les allergies aux produits chimiques et aux médicaments constituent un problème majeur de santé publique. L’objectif de ce travail est de mieux comprendre l’interaction entre les cellules dendritiques (DC) et les lymphocytes T (LT) dans les allergies induites par les haptènes métalliques (nickel et cobalt) et les médicaments [benzylpénicilline (BP)]. En présence des signaux de danger, les DC acquièrent un phénotype dit « mature » et présentent l’antigène apprêté aux LT spécifiques de cet antigène. Les LT représentent les cellules effectrices responsables d’une manière directe ou non des symptômes observés lors des réactions allergiques. Dans un premier temps, nous montrons que le nickel est capable d’induire un ratio d’interleukines (IL) IL-23/IL-12p70 élevé dans les DC favorisant ainsi la polarisation Th17 qui est détectée chez la majorité des patients allergiques au nickel. Nous montrons aussi pour la première fois une production de l’IL-27 par les DC activées par le nickel. Nous avons ensuite montré l’implication du TLR4 et de la voie Jak-STAT dans la régulation des cytokines membres de la famille de l’IL-12. L’activation de la voie Jak-STAT est nécessaire pour la réponse Th1 en favorisant la production de l’IL-12p70 et en inhibant la production de l’IL-23 par les DC activées par du nickel. Par ailleurs, nous avons identifié et, pour la première fois, une activation du facteur de transcription NFIL-3, au sein des DC, par le nickel et le cobalt voire d’une manière plus intense avec ce dernier. D’autre part, nous avons mis en évidence l’existence d’un répertoire de LT naïfs CD4+ et CD8+, provenant de la population générale, spécifiques du nickel. L’activation de ces LT requiert les molécules du complexe majeur d’histocompatibilité (CMH) et ils présentent un faible taux de réactivité croisée avec le cobalt. Simultanément, nous avons mis en évidence la possibilité de détecter des LT naïfs CD8+ spécifiques de la BP. L’activation de ces LT dépend des molécules du CMH de classe I et du protéasome. D’une manière générale, notre travail contribue à une meilleure compréhension des mécanismes des réactions allergiques d’une part, en montrant la fine régulation des cytokines membres de la famille de l’IL-12 dans les DC et d’autre part en élucidant les mécanismes de l’immunisation contre les molécules allergisantes. / Drug and chemical allergy is a major public health concern. The aim of this work is to understand the interaction between dendritic cells (DCs) and T-lymphocytes (LT) in allergic manifestations induced by metallic haptens (nickel and cobalt) and benzylpenicillin (BP). DCs capture the antigen, start maturation, migrate to the regional lymph node and activate hapten-specific T-cells. The latter will represent the effector cells responsible directly or not for the symptoms observed during allergic reactions. We showed that nickel induced a high ratio of interleukin (IL) IL-23 compared to IL-12p70 in DCs leading to Th17 polarization as seen in allergic patients. We also showed for the first time the production of IL-27 by nickel-activated DCs. Moreover, we showed the involvement of TLR4 and Jak-STAT pathways in IL-12 cytokine family regulation. The activation of the Jak-STAT pathway seems to maintain the IL-23/IL-12p70 balance by limiting IL-23 production and promoting Th1 polarization. Furthermore, we identified for the first time the activation of NFIL-3 in DC by nickel and cobalt, more intensely with the latter. In addition, nickel-recognizing CD4+ and CD8+ naïve T-cells repertoire was identified from the general population. These positive T-cells were shown to recognize nickel in the context of major histocompatibility complex (MHC) molecules. We also showed that a low frequency of nickel-recognizing CD4+ naïve T-cells cross-reacted with cobalt. Simultaneously, we showed the possibility of detecting a naïve CD8+ T-cells repertoire for BP. The activation of these specific T-cells requires MHC class I molecule and proteasome. In resume, our work contributes to a better understanding of allergic reactions, on one hand, by studying the fine regulation of the IL-12 cytokines family in DCs and on the other hand, by clarifying the mechanisms of immunization against drugs and chemicals.