Aspergillus fumigatus is an opportunistic fungal pathogen that causes lethal invasive pulmonary disease in immunocompromised hosts and allergic asthma in sensitized individuals. This dissertation explores how eosinophils may protect hosts from acute infection while driving asthma pathogenesis by co-producing IL-23 and IL-17 in both contexts. In an acute model of pulmonary aspergillosis, eosinophils were observed to associate with and kill A. fumigatus spores in vivo. In addition, eosinopenia was correlated with higher mortality rates, decreased recruitment of inflammatory monocytes to the lungs, and decreased expansion of lung macrophages. As IL-17 signaling must occur on a local level to elicit its stereotypical response, such as the up-regulation of antimicrobial peptides and specific chemokines from stromal cells, eosinophils were discovered to be a significant source of pulmonary IL-17 as well as one of its upstream inducers, IL-23. In the context of asthma, this discovery opens a new paradigm whereby eosinophils might be driving asthma pathogenesis.

A rinite alérgica (RA) é a mais comum doença mediada por IgE, que afeta aproximadamente 500 milhões de pessoas em todo o mundo. A RA é a expressão clínica da ligação entre anticorpos do tipo IgE e antígenos na mucosa nasal resultando em inflamação. Estes anticorpos foram detectados na secreção nasal de pacientes com rinite alérgica. Na abordagem da doença, temos a imunoterapia específica (IT) como único tratamento imunomodulatório antígeno específico. Foi demonstrado que IT gera uma diminuição da resposta tardia ao alérgeno tanto na pele como na mucosa do trato respiratório e esta redução se correlaciona com diminuição no número de células infiltrando os tecidos e na quantidade de mediadores inflamatórios. Objetivo: Determinar a resposta local de IgE específica e IgG4 específica no lavado nasal de pacientes com rinite alérgica antes e após o tratamento com imunoterapia alérgeno específica para Dermatophagoides pteronyssinus por um período de 6 meses; determinar a resposta inflamatória padrão Th1/ Th2/ Th17 e avaliar escore de sintomas e contagem de células no lavado nasal. Método: Selecionamos pacientes sensibilizados ao Dermatophagoides pteronissinus com diagnóstico de rinite alérgica persistente. Realizamos as analises de sintomas nasais através da escala NIS e antes de iniciar o tratamento estes indivíduos realizaram provocação nasal com alérgeno e coleta de lavado nasal. Após 6 meses de tratamento IT e placebo estes pacientes foram reavaliados. Realizamos a analise de Imunoglobulinas (IgE especifica para Der p1 e 2, IgE total, e IgG4 especifica para Der p 1), contagem de células totais, citocinas padrão Th1/Th2 e Th17. Resultados: Analisamos 19 pacientes no grupo imunoterapia e 17 no grupo placebo. A avaliação dos sintomas pela escala NIS após 6 meses de intervenção, demonstrou diferença significativa nos grupos placebo e imunoterapia, em favor da IT. A concentração do extrato utilizado na provocação nasal foi maior no grupo imunoterapia após os 6 meses de tratamento mas sem significância estatística. Quanto a dosagem das imunoglobulinas observamos diminuição da IgE total após a intervenção assim como da contagem de células totais no lavado nasal. A dosagem das citocinas livres no lavado nasal não sofreram alterações significativas. Na provocação nasal observamos aumento de IL-13, IL-10 em ambos os grupos, independente da fase de tratamento. Conclusão: Não observamos nenhuma resposta local de IgE específica e IgG4 específica no lavado nasal de pacientes com rinite alérgica antes e após o tratamento com imunoterapia alérgeno específica para Dermatophagoides pteronyssinus por um período de 6 meses. Houve melhora no escore de sintomas e diminuição da IgE total e da contagem de células no lavado nasal / Allergic rhinitis (AR) is the most common disease mediated by IgE, affecting approximately 500 million people worldwide. The AR is the clinical expression of the link between the IgE-antibodies and antigens in the nasal mucosa resulting in inflammation. Such antibodies were detected in nasal secretions of allergic rhinitis patients. As treatment for this morbidity there is specific immunotherapy (IT) as only immunomodulatory specific antigen approach. It was demonstrated that IT generates a decrease in the late response to the allergen both in the skin and in the mucosa of the respiratory tract and this reduction correlates with the decrease in the number of infiltrating cells and in the amount of inflammatory mediators. Objective: To determine the local response of specific IgE and IgG4 in nasal lavage fluids of patients with allergic rhinitis before and after treatment with specific allergen immunotherapy to house dust mite for a period of 6 months; determine the standard inflammatory response of Th1 / Th2 / Th17 and evaluate symptom score and cell counts in nasal lavage. Method: We selected patients sensitized to Dermatophagoides pteronissinus diagnosed with persistent allergic rhinitis. Nasal symptoms were assessed by Nasal Index Score, and before treatment, allergen nasal challenge and collection of nasal lavage fluid were performed. After 6 months of treatment or placebo, the patients were reevaluated. IgE specific for Der p 1 and 2, total IgE and IgG4 specific for Der p 1, total cell count were determined as well as Th1 / Th2 and Th17 cytokines. Results: We analyzed 19 patients in the immunotherapy group and 17 in the placebo group. The evaluation of symptoms by NIS scale after 6 months of intervention showed significant differences in favor of the immunotherapy group. The concentration of the extract used in the nasal challenge was higher in the immunotherapy group after 6 months of treatment but without statistical significance. The total IgE decreased after the intervention as well as the total cell count in nasal lavage. The dosage of the free cytokines in nasal lavage fluid did not change significantly. In the nasal provocation we observe an increasing in IL-13 and IL-10 in both treatment groups. Conclusion: We observed no local changes in specific IgG4 or specific IgE response in nasal lavage fluid of patients with allergic rhinitis before and after treatment with specific allergen immunotherapy to house dust mite for a period of 6 months. There was an improvement in symptom scores and a decreased of total IgE and cell counts in nasal lavage

Para identificar, quantificar e correlacionar os eosinófilos, mastócitos, miofibroblastos e células TGF-beta positivas nos pólipos nasais de pacientes com e sem asma foi realizado a imunoistoquímica. A quantidade de eosinófilos, miofibroblastos e células TGF-beta positivas esteve aumentada no pólipo nasal de indivíduos asmáticos. O número de mastócitos não mostrou diferença entre os grupos. O miofibroblasto foi o denominador comum na correlação entre eosinófilos, mastócitos, células TGF-beta positivas e presença de asma / Introduction: Nasal polyposis is a chronic inflammatory disease of the nasal mucosa or paranasal sinuses characterized by the formation of benign polyps. The pathogenesis is not known, although nasal polyps are associated with several systemic diseases, with asthma being the most frequent. The aim of the present study was to identify, quantify, compare and correlate eosinophils, mast cells, myofibroblasts and TGF-ß-positive cells in nasal polyps of patients with and without asthma. Material and Methods: Seventy-eight subjects with nasal polyps undergoing endoscopic sinus surgery were selected. Control specimens were obtained from eight subjects with a normal sinus mucosa. One group consisted of polyps from 56 patients with asthma and the other of polyps from 22 patients without asthma. Immunohistochemistry was performed using monoclonal antibodies against eosinophil cationic protein to stain eosinophils, against tryptase to stain mast cells, against alpha-smooth muscle actin to stain myofibroblasts, and against TGF-ß to stain TGF-ß-positive cells. Results: The number of eosinophils, myofibroblasts and TGF-ß-positive cells was significantly higher in the asthma group than in the nonasthma group, whereas no significant difference in the number of mast cells was observed between the two groups. The number of eosinophils, mast cells, myofibroblasts and TGF-ß-positive cells was significantly higher in nasal polyps than in the control group. Myofibroblasts showed a significant correlation with eosinophils, mast cells, TGF-ß-positive cells, and asthma. Conclusion: Eosinophils, mast cells, myofibroblasts and TGF-ß-positive cells were identified in all nasal polyps, although the number of eosinophils, myofibroblasts and TGF-ß-positive cells was higher in the asthma group. The number of mast cells was similar regardless of the presence or absence of asthma. Myofibroblasts were a common denominator in the correlation between eosinophils, mast cells, TGF-ß-positive cells, and asthma

Para identificar, quantificar e correlacionar os eosinófilos, mastócitos, miofibroblastos e células TGF-beta positivas nos pólipos nasais de pacientes com e sem asma foi realizado a imunoistoquímica. A quantidade de eosinófilos, miofibroblastos e células TGF-beta positivas esteve aumentada no pólipo nasal de indivíduos asmáticos. O número de mastócitos não mostrou diferença entre os grupos. O miofibroblasto foi o denominador comum na correlação entre eosinófilos, mastócitos, células TGF-beta positivas e presença de asma / Introduction: Nasal polyposis is a chronic inflammatory disease of the nasal mucosa or paranasal sinuses characterized by the formation of benign polyps. The pathogenesis is not known, although nasal polyps are associated with several systemic diseases, with asthma being the most frequent. The aim of the present study was to identify, quantify, compare and correlate eosinophils, mast cells, myofibroblasts and TGF-ß-positive cells in nasal polyps of patients with and without asthma. Material and Methods: Seventy-eight subjects with nasal polyps undergoing endoscopic sinus surgery were selected. Control specimens were obtained from eight subjects with a normal sinus mucosa. One group consisted of polyps from 56 patients with asthma and the other of polyps from 22 patients without asthma. Immunohistochemistry was performed using monoclonal antibodies against eosinophil cationic protein to stain eosinophils, against tryptase to stain mast cells, against alpha-smooth muscle actin to stain myofibroblasts, and against TGF-ß to stain TGF-ß-positive cells. Results: The number of eosinophils, myofibroblasts and TGF-ß-positive cells was significantly higher in the asthma group than in the nonasthma group, whereas no significant difference in the number of mast cells was observed between the two groups. The number of eosinophils, mast cells, myofibroblasts and TGF-ß-positive cells was significantly higher in nasal polyps than in the control group. Myofibroblasts showed a significant correlation with eosinophils, mast cells, TGF-ß-positive cells, and asthma. Conclusion: Eosinophils, mast cells, myofibroblasts and TGF-ß-positive cells were identified in all nasal polyps, although the number of eosinophils, myofibroblasts and TGF-ß-positive cells was higher in the asthma group. The number of mast cells was similar regardless of the presence or absence of asthma. Myofibroblasts were a common denominator in the correlation between eosinophils, mast cells, TGF-ß-positive cells, and asthma

A rinite alérgica (RA) é a mais comum doença mediada por IgE, que afeta aproximadamente 500 milhões de pessoas em todo o mundo. A RA é a expressão clínica da ligação entre anticorpos do tipo IgE e antígenos na mucosa nasal resultando em inflamação. Estes anticorpos foram detectados na secreção nasal de pacientes com rinite alérgica. Na abordagem da doença, temos a imunoterapia específica (IT) como único tratamento imunomodulatório antígeno específico. Foi demonstrado que IT gera uma diminuição da resposta tardia ao alérgeno tanto na pele como na mucosa do trato respiratório e esta redução se correlaciona com diminuição no número de células infiltrando os tecidos e na quantidade de mediadores inflamatórios. Objetivo: Determinar a resposta local de IgE específica e IgG4 específica no lavado nasal de pacientes com rinite alérgica antes e após o tratamento com imunoterapia alérgeno específica para Dermatophagoides pteronyssinus por um período de 6 meses; determinar a resposta inflamatória padrão Th1/ Th2/ Th17 e avaliar escore de sintomas e contagem de células no lavado nasal. Método: Selecionamos pacientes sensibilizados ao Dermatophagoides pteronissinus com diagnóstico de rinite alérgica persistente. Realizamos as analises de sintomas nasais através da escala NIS e antes de iniciar o tratamento estes indivíduos realizaram provocação nasal com alérgeno e coleta de lavado nasal. Após 6 meses de tratamento IT e placebo estes pacientes foram reavaliados. Realizamos a analise de Imunoglobulinas (IgE especifica para Der p1 e 2, IgE total, e IgG4 especifica para Der p 1), contagem de células totais, citocinas padrão Th1/Th2 e Th17. Resultados: Analisamos 19 pacientes no grupo imunoterapia e 17 no grupo placebo. A avaliação dos sintomas pela escala NIS após 6 meses de intervenção, demonstrou diferença significativa nos grupos placebo e imunoterapia, em favor da IT. A concentração do extrato utilizado na provocação nasal foi maior no grupo imunoterapia após os 6 meses de tratamento mas sem significância estatística. Quanto a dosagem das imunoglobulinas observamos diminuição da IgE total após a intervenção assim como da contagem de células totais no lavado nasal. A dosagem das citocinas livres no lavado nasal não sofreram alterações significativas. Na provocação nasal observamos aumento de IL-13, IL-10 em ambos os grupos, independente da fase de tratamento. Conclusão: Não observamos nenhuma resposta local de IgE específica e IgG4 específica no lavado nasal de pacientes com rinite alérgica antes e após o tratamento com imunoterapia alérgeno específica para Dermatophagoides pteronyssinus por um período de 6 meses. Houve melhora no escore de sintomas e diminuição da IgE total e da contagem de células no lavado nasal / Allergic rhinitis (AR) is the most common disease mediated by IgE, affecting approximately 500 million people worldwide. The AR is the clinical expression of the link between the IgE-antibodies and antigens in the nasal mucosa resulting in inflammation. Such antibodies were detected in nasal secretions of allergic rhinitis patients. As treatment for this morbidity there is specific immunotherapy (IT) as only immunomodulatory specific antigen approach. It was demonstrated that IT generates a decrease in the late response to the allergen both in the skin and in the mucosa of the respiratory tract and this reduction correlates with the decrease in the number of infiltrating cells and in the amount of inflammatory mediators. Objective: To determine the local response of specific IgE and IgG4 in nasal lavage fluids of patients with allergic rhinitis before and after treatment with specific allergen immunotherapy to house dust mite for a period of 6 months; determine the standard inflammatory response of Th1 / Th2 / Th17 and evaluate symptom score and cell counts in nasal lavage. Method: We selected patients sensitized to Dermatophagoides pteronissinus diagnosed with persistent allergic rhinitis. Nasal symptoms were assessed by Nasal Index Score, and before treatment, allergen nasal challenge and collection of nasal lavage fluid were performed. After 6 months of treatment or placebo, the patients were reevaluated. IgE specific for Der p 1 and 2, total IgE and IgG4 specific for Der p 1, total cell count were determined as well as Th1 / Th2 and Th17 cytokines. Results: We analyzed 19 patients in the immunotherapy group and 17 in the placebo group. The evaluation of symptoms by NIS scale after 6 months of intervention showed significant differences in favor of the immunotherapy group. The concentration of the extract used in the nasal challenge was higher in the immunotherapy group after 6 months of treatment but without statistical significance. The total IgE decreased after the intervention as well as the total cell count in nasal lavage. The dosage of the free cytokines in nasal lavage fluid did not change significantly. In the nasal provocation we observe an increasing in IL-13 and IL-10 in both treatment groups. Conclusion: We observed no local changes in specific IgG4 or specific IgE response in nasal lavage fluid of patients with allergic rhinitis before and after treatment with specific allergen immunotherapy to house dust mite for a period of 6 months. There was an improvement in symptom scores and a decreased of total IgE and cell counts in nasal lavage

Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-09-26T20:24:00Z No. of bitstreams: 1 katiabatistadoamaral.pdf: 5840188 bytes, checksum: bc96f4a6457a961cca6e272ba1aaaa5d (MD5) / Approved for entry into archive by Diamantino Mayra (mayra.diamantino@ufjf.edu.br) on 2016-09-26T20:29:35Z (GMT) No. of bitstreams: 1 katiabatistadoamaral.pdf: 5840188 bytes, checksum: bc96f4a6457a961cca6e272ba1aaaa5d (MD5) / Made available in DSpace on 2016-09-26T20:29:35Z (GMT). No. of bitstreams: 1 katiabatistadoamaral.pdf: 5840188 bytes, checksum: bc96f4a6457a961cca6e272ba1aaaa5d (MD5) Previous issue date: 2015-12-11 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / O roedor Nectomys squamipes, também conhecido como rato d’água, é considerado o mais importante reservatório silvestre do parasito Schistosoma mansoni no Brasil, contribuindo para a epidemiologia da esquistossomose mansônica humana. Além disso, quando infectado, não apresenta sinais clínicos da doença, apresentando lesões teciduais extremamente brandas decorrentes da infecção. Parâmetros relacionados à infecção esquistossomótica em modelos murinos de infecção experimental já foram bem documentados; porém, em modelos de infecção natural, ainda são pouco conhecidos. A relação parasito-hospedeiro neste modelo de infecção natural é de grande relevância e motivou o desenvolvimento deste trabalho. Foi realizado estudo comparativo da esquistossomose mansônica em N. squamipes naturalmente infectado pelo parasito S. mansoni e no camundongo Swiss experimentalmente infectado, nas fases aguda e crônica da infecção, através de análises histopatológicas, bioquímicas e ultraestruturais, objetivando obter uma melhor compreensão de como o rato d’água lida com o parasitismo pelo S. mansoni. Foram realizadas análises de frequências e tipos de granulomas, suas áreas médias e do comprometimento tecidual dos órgãos alvos da infecção (fígado e intestinos), nos dois modelos experimentais. A participação dos eosinófilos durante a resposta inflamatória granulomatosa também foi avaliada, visto que estas células estão presentes em grandes números nos granulomas. Dosagens bioquímicas das transaminases hepáticas auxiliaram na avaliação do dano hepatocelular. Além disso, a influência da esteatose hepática neste modelo de infecção natural foi estudada, visto que seus efeitos não são conhecidos em animais silvestres. Assim, dosagens séricas de glicose, colesterol total e triglicerídeos foram importantes para avaliar o perfil glicêmico e lipídico dos animais estudados. Os tecidos hepáticos dos animais foram submetidos à espectroscopia Raman, para avaliar o grau de insaturação presente. Finalmente, análises ultraestruturais ajudaram a aprofundar o conhecimento sobre os papéis dos eosinófilos e dos corpúsculos lipídicos presentes nos hepatócitos nestes dois modelos de esquistossomose mansônica. Os resultados revelaram que N. squamipes apresentou excelente modulação das lesões teciduais no fígado, com baixo comprometimento tecidual neste órgão e uma reação granulomatosa mais exacerbada no intestino delgado, favorável à eliminação dos ovos do parasito nas fezes. Além disso, os níveis séricos das transaminases não se alteraram em decorrência da infecção neste roedor silvestre, ao contrário do que ocorreu no camundongo Swiss. N. squamipes infectados e não infectados apresentaram os maiores graus de insaturação presentes nos tecidos hepáticos. Características ultraestruturais intrigantes dos eosinófilos de N. squamipes foram observadas por MET. Através dos dados obtidos, concluímos que o rato d’água apresenta uma relação ecológica bem estabelecida com o parasito S. mansoni, sendo que esta adaptação ao parasitismo pode estar relacionada ao metabolismo lipídico deste reservatório silvestre. / The rodent Nectomys squamipes, also known as water rat, is considered the most important wild reservoir of the parasite Schistosoma mansoni in Brazil, contributing to the epidemiology of human schistosomiasis. Furthermore, when infected, it shows no clinical signs of the disease with extremely soft tissue injuries resulting from infection. Parameters related to the infection in murine models of experimental infection have been well documented; however, in natural infection models, they are still largely unknown. The host-parasite relationship in this model of natural infection is highly relevant and motivated the development of this work. So, It was conducted a comparative study of schistosomiasis in N. squamipes naturally infected by the parasite Schistosoma mansoni and in Swiss experimentally infected mice, at the acute and chronic phases of the infection through histological, biochemical and ultrastructural analysis, aiming to gain a better understanding of how the water rat handles with parasitism by S. mansoni. Analysis of frequencies and types of granulomas were held, their average areas and tissue impairment of the target organs of infection (liver and intestines) in both experimental models. The involvement of eosinophils during granulomatous inflammatory response was also evaluated, as these cells are present in large numbers in the granulomas. Biochemical testing of liver transaminases contributed to the evaluation of hepatocellular damage. Furthermore, the influence of hepatic steatosis in the natural infection model was studied, since their effects are not known in wild animals. Thus, serum levels of glucose, total cholesterol and triglycerides were important to assess the glycemic and lipid profile of the animals studied. The liver tissues of animals were subjected to Raman spectroscopy, to assess the degree of unsaturation. Finally, ultrastructural analysis helped to deepen understanding of the roles of eosinophils and lipid bodies present in hepatocytes in these two models of schistosomiasis. The results revealed that N. squamipes showed excellent modulation of tissue lesions in the liver, with low tissue impairment and a more exacerbated granulomatous reaction in the small intestine, favoring the elimination of the parasite eggs in feces. Furthermore, serum transaminases levels did not change as a result of the infection in wild rodents, unlike what occurred in Swiss mice. N. squamipes infected and uninfected showed the highest degree of unsaturation present in liver tissue. Intriguing ultrastructural characteristics of N. squamipes eosinophils were observed by TEM. Through the data obtained, we concluded that the water rat has a wellestablished ecological relationship with the parasite Schistosoma mansoni, and this adaptation to parasitism may be related to lipid metabolism of this wild reservoir.

<p>Asthma involves a systemic element that includes the mobilization and lung-accumulation of bone marrow-derived endothelial progenitor cells (EPC). This traffic may be driven by the stromal cell derived factor-1α (SDF-1α)/CXCR4 axis, where SDF1-α is a potent progenitor cell chemoattractant.</p> <p>Interfering with EPC lung-accumulation by administering AMD3100, a CXCR4 antagonist, was previously shown to be associated with the modulation of airway angiogenesis and airway hyperresponsiveness. However, since eosinophils express CXCR4, it is unknown whether AMD3100 acted directly on EPC or indirectly through its anti-inflammatory effects on eosinophils.</p> <p>We investigated the role that eosinophilic inflammation plays in the lung-homing of EPCs and airway angiogenesis in allergic asthmatic response by utilizing eosinophil deficient (PHIL) mice.</p> <p>Wild-type BALB/c (WT) and PHIL mice underwent a chronic house dust mite (HDM) exposure protocol. Treatment groups were administered AMD3100. Outcome measurements were made 24hrs post final exposure and included: flow cytometry to enumerate lung-extracted EPCs, immunostaining for von Willebrand factor to assess bronchial vascularity, bronchoalveolar lavage for airway inflammation, haematoxylin and eosin stain to enumerate eosinophils, picrosirius red stain to assess collagen deposition, and measurement of airway resistance to increasing intranasal doses of methacholine.</p> <p>HDM exposed mice had a significant increase in EPC lung accumulation, bronchial vascularity, airway inflammation, collagen deposition and airway hyperresponsiveness (AHR) in both WT and PHIL groups, with some indices at lower levels in PHIL mice. Concurrent treatment with AMD3100 significantly attenuated EPC lung homing, bronchial vascularity, eosinophil numbers in lung tissue and AHR, but not collagen deposition in WT mice. AMD3100 treatment significantly attenuated all indices in PHIL mice.</p> <p>The findings of this study show that, EPC-driven angiogenesis and the development of AHR in allergic airway responses are independent of eosinophils, the presence of these cells, however, may have a role in worsening of the pathology of allergic airways disease.</p> / Master of Science (MSc)

Indiana University-Purdue University Indianapolis (IUPUI) / More than 300 million people world-wide suffer from breathlessness, wheezing, chest tightness, and coughing characteristic of chronic bronchial asthma, the global incidence of which is on the rise. Allergen-sensitization and challenge elicits pulmonary expression of chemoattractants that promote a chronic eosinophil-rich infiltrate. Eosinophils are increasingly recognized as important myeloid effectors in chronic inflammation characteristic of asthma, although few eosinophil molecular signaling pathways have successfully been targeted in asthma therapy. p21 activated kinases (PAKs), members of the Ste-20 family of serine/threonine kinases, act as molecular switches in cytoskeletal-dependent processes involved in cellular motility. We hypothesized that PAK1 modulated eosinophil infiltration in an allergic airway disease (AAD) murine model. In this model, Pak1 deficient mice developed reduced inflammatory AAD responses in vivo with notable decreases in eosinophil infiltration in the lungs and broncho-alveolar lavage fluids (BALF). To test the importance of PAK1 in hematopoietic cells in AAD we used complementary bone marrow transplant experiments that demonstrated decreased eosinophil inflammation in hosts transplanted with Pak1 deficient bone marrow. In in vitro studies, we show that eotaxin-signaling through PAK1 facilitated eotaxin-mediated eosinophil migration. Ablating PAK1 expression by genetic deletion in hematopoietic progenitors or siRNA treatment in derived human eosinophils impaired eotaxin-mediated eosinophil migration, while ectopic PAK1 expression promoted this migration. Together these data suggest a key role for PAK1 in the development of atopic eosinophil inflammation and eotaxin-mediated eosinophil migration.

<p>Food allergies are immune system-driven diseases that lead to reproducible adverse reactions which can be fatal. These severe systemic reactions are primary mediated by immunoglobulin E (IgE) that is derived from B cells which have been activated by T helper type 2 (Th2) cells. While much work has advanced the clinical and pharmacological management of patients with allergic diseases, much remains to be elucidated about how individuals initially acquire allergy. This Thesis details a mechanism linking initial gastrointestinal exposure to peanut (PN) allergen, to the generation of Th2 cells: PN allergen activates epithelial cell secretion of interleukin (IL)-33 and eosinophil degranulation of eosinophil peroxidase, which causes CD103+ dendritic cell (DC) activation and migration to mesenteric lymph nodes where DC OX40L engages naïve T cells to secrete IL-4 in an autocrine/paracrine manner to promote and consolidate Th2 cell differentiation. These events are followed by B cell activation and PN-specific IgE production, which sensitizes mast cells to be hypersensitive to PN re-exposure by causing immediate allergic reactions including anaphylaxis. This is later followed by eosinophilic inflammation that is partially mediated by innate lymphoid cells. As food allergy also serves as a unique model to better understand mechanisms of adaptive immunity, especially Th2 immunobiology, both basic science and clinical implications are discussed in this Thesis. Major themes include Th2 and disease heterogeneity, identification of ‘the original source of IL-4’, an unprecedented <em>in vivo </em>requirement for eosinophils in priming adaptive immune responses, and the need to weigh basic science findings against the human disease <em>in natura </em>litmus test. Looking forward, many questions remain to be answered in the field of food allergy research, but the findings of this Thesis may be one step towards the prevention, management or cure of a disease with growing public concern, potentially fatal consequences, and an unmet need in understanding its pathogenesis.</p> / Doctor of Philosophy (Medical Science)