Asthma and allergies are some of the most common illnesses worldwide that almost everybody will come in contact with. This thesis studied persons with allergic asthma, non-allergic asthma, allergic rhinitis and atopic dermatitis in a population-based sample. At an early stage, these illnesses were regarded as psychosomatic. Over time, as knowledge about asthma/allergy has increased more of a biomedical perspective was taken by the research field. In considering early documentations well as contemporary research, a psychobiosocial perspective was taken in this thesis when conducting the three studies. Thus, as psychological factors may affect the illness and be a result of the illness, it is important to incorporate these factors to better understand asthma and allergy. Study I examined the co- and multimorbidity in asthma/allergy with the environmental intolerances in the form of chemical and building-related intolerance. Study II investigated psychological distress in the four forms of asthma and allergy. Psychological distress was in this study defined as stress, burnout, anxiety, depression and environmental health worries. Study III examined usage of problem and emotion focused coping strategies and perceived social support from the surrounding in high and low asthma/allergy severity. All studies were performed using data from the Västerbotten Environmental Health Study, a questionnaire-based survey with focus on various environmental hypersensitivities and asthma and allergy. The result showed that the co- and multimorbidity with the environmental intolerances in asthma/allergy was larger than what was statistically excepted. Those with allergic asthma and atopic dermatitis experienced more stress, burnout and anxiety than those with non-allergic asthma, allergic rhinitis and non-asthma/allergy. Moreover, the most common way of coping with asthma and allergy was found to be strategies such as avoiding environments that are believed to affect health, and trying to accept the situation, independent of asthma/allergy severity. Finally, in general, those with asthma and allergy reported receiving most support from their partner, other family members and health care, and least support was perceived by those with low asthma/allergy severity.The findings suggest that co- and multimorbidity with environmental intolerances is relatively common in asthma and allergy, and should therefore be included in the clinical anamnesis for this patient group. The elevated level of distress in allergic asthma and atopic dermatitis evokes the question of use of therapies such as mindfulness maybe beneficial in certain afflicted persons. The results on coping and social support provide a foundation for further research regarding informing the asthma/allergy patient and family members about effective coping strategies and the importance of adequate social support. A metaperspective is taken in which interrelations between important variables in the thesis are discussed.

Human immunodeficiency virus (HIV) infection has reached epidemic proportions in South Africa. The availability of highly active anti-retroviral therapy (HAART) prolongs life in HIV-infected persons, who may subsequently present with chronic manifestations of HIV-infection. The respiratory morbidity attendant to HIV-infection, even in the presence of HAART is high, the aftermath of which is lung tissue destruction and bronchiectasis. As a consequence of the political decision not to offer HAART to HIV-infected children, a number of children in South Africa have been left with severe consequences of uncontrolled HIV-infection. Bronchiectasis is one of those and because children with this devastating condition were numerous in the Pretoria region, the author and her colleagues began a Chronic Lung Disease Clinic in that region. This prompted the idea of investigating both the epidemiological profiles of these children and an attempt to intervene with both standard bronchiectasis guideline care and the use of a form of therapy commonly employed in other forms of bronchiectasis. This thesis explores those ideas. Important new and novel findings that were consequent were; that bronchiectasis is diagnosed late in HIV-infected children at a mean age of 6.9 years. The predominant organisms cultured from the airways are Haemophilus influenzae and parainfluenzae in 49% of samples. Pseudomonas aeruginosa (PA), common in cystic fibrosis (CF)-bronchiectasis is an uncommon pathogen in HIV-related bronchiectasis; isolated in only 2% of specimens. Tuberculosis (TB), at least as reported, is a significant antecedent of bronchiectasis, reported in 48.5%of children. A further 21.2% of the patients had received more than two courses of anti-TB treatment. However, proof of TB infection has been lacking. Respiratory morbidity is significant with the mean forced expiratory flow in one second (FEV1) of 53%, in this cohort at the time of presentation. Thirty-six percent of all children were exposed to environmental tobacco smoke, although this was not correlated with disease severity or HIVdisease progression. There is elevation of immunoglobulins in HIV-related bronchiectasis, with a mean IgE of 79 kU/l. This was not, though, associated with HIV disease progression as previously described in adult studies, nor with the presence of allergic bronchopulmonary aspergillosis (ABPA). The elevation in IgE was also not associated with an elevation of T helper-2 mediated cytokines, confirming the lack of association with atopy. The predominant cytokine, identified is interleukin (IL)-8, both systemically and locally (in airway secretions). There was elevation of other T helper-1 driven cytokines, reflecting an ability to mediate adequate inflammatory responses, which was independent of the level of immunosuppression. With the presence of HAART, there was a decline in the pro-inflammatory cytokines over time, which may be attributed to the ongoing effect of HAART that ties in to, or goes beyond the restoration of T cell numbers. Soluble triggering receptor expressed on myeloid cells (sTREM), an innate immune marker, is elevated in children with HIV-related bronchiectasis when compared to a control group of children with cystic fibrosis-related bronchiectasis. sTREM is not associated with the presence of exacerbations and the level of immunosuppression. The use of an anti-inflammatory drug erythromycin also did not impact the sTREM values. There was also no relationship between sTREM and pro and antiinflammatory cytokines and chemokines. Fluorine-18-fluorodeoxyglucose positron emission tomography (18F-FDG PET) could not reliably predict the presence of pulmonary exacerbations. Its diagnostic value was limited to identifying disease activity in acute pneumonia. 18F-FDG PET also had no significant correlation with CRP, inflammatory cytokines or markers of HIV disease activity. In a randomised controlled trial of erythromycin, a cost-effective immunomodulatory drug, compared to placebo, erythromycin was ineffective in reducing the number of pulmonary exacerbations. Erythromycin also failed to demonstrate any effect on systemic and local pro- and anti-inflammatory cytokines/chemokines. With access to anti-retroviral therapy, airway clearance, nutritional rehabilitation and vigilant follow up there was an improvement in pulmonary function parameters and stability of the degree of bronchiectasis that we propose is probably in keeping with an organ system disease modifying effect that may be, an as yet, undefined and undescribed byproduct of HAART. / Thesis (PhD)--University of Pretoria, 2012. / Paediatrics and Child Health / unrestricted

Orientador: Luiz Henrique de Araújo Machado / Resumo: A dermatite atópica canina é uma importante alergopatia de ordem genética, inflamatória, pruriginosa e crônica. Os tratamentos existentes atualmente são sintomáticos, algumas vezes insatisfatórios no controle da doença e passíveis de efeitos colaterais. As células-tronco mesenquimais (CTM), pelas suas propriedades imunomoduladores e anti-inflamatórias, podem ser uma alternativa no tratamento da dermatite atópica. Foi realizado um estudo longitudinal, duplo-cego, com período inicial de tratamento placebo com três aplicações quinzenais de soro fisiológico, com posterior aplicação de CTM heterólogas, derivadas de tecido adiposo, em seis cães com dermatite atópica, totalizando três aplicações quinzenais na dose de 5x106 células por animal. A escala visual de prurido esclarecido (EVPE), o escore de lesões cutâneas (CADESI-4), a resposta inflamatória cutânea pela análise das citocinas IL4, IL6, IL10, IL31 e TNF-alfa e da proteína filagrina pela técnica de imunoistoquímica e a avaliação dos lipídeos epidérmicos pela coloração de Sudam III foram comparadas entre o tratamento placebo e com as CTM. O tratamento com CTM foi benéfico para a melhora das manifestações clínicas nos animais com dermatite atópica, diminuindo de forma significativa o escore CADESI-4 e EVPE, com redução consistente de mais de 50% destes dois parâmetros ao final do tratamento com CTM. A melhora clínica evidente nos animais com DA tratados com terapia celular aliadas à baixa frequência de efeitos colaterais, sina... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The atopic canine is an inflammatory allergic dermatitis frequent and important. The distinct treatment available is symptomatic, currently unsatisfactory in the control of the disease and susceptible to collateral effects. The mesenchymal Stem Cells (MSC) by their immunomodulators and anti-inflammatory characteristics can be an alternative in the treatment of the atopic dermatitis. A longitudinal study was performed, blind-double, with an initial period of placebo treatment within saline solution, after the application of 5x106 heterologous CTM, derived from adipose tissue, in six dogs with atopic dermatitis. Each treatment constituted of three applications in by-weekly intervals. The visual analog scale of pruritis, the score of skin lesions (CADESI-4), the skin inflammatory response and filaggrin through the immunohistochemistry technique and the evaluation of the skin lipids by the Sudam III coloration were compared between the placebo treatment and the CTM treatment. The treatment with CTM with the used protocol was beneficial to the improvement of the clinical responses of the animals with atopic dermatitis, decreasing significantly the CADESI-4 and EVDP score, with a significant reduction of more than 50% of these two parameters at the end of the treatment with CTM while compared to the placebo. The clinical improvement was evident in animals with DA treated with cellular therapy allied to the low frequency of the collateral effects, indicates that with CTM can be cons... (Complete abstract click electronic access below) / Doutor

Introdução: O estudo dos fatores clínicos associados ao prognóstico da rinossinusite crônica (rsc), seja associada à polipose nasossinusal (RSCcPN) ou não (RSCsPN), ainda é pouco abordado a longo prazo. Objetivo: Avaliar pacientes submetidos à ESS (cirurgia endoscópica nasal, do inglês endoscopic sinus surgery) para o tratamento de RSC no Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo, entre 1996 e 2006, e correlacionar a recidiva em longo prazo com parâmetros como a extensão da doença, atopia, tabagismo, asma, eosinofilia e doença respiratória exacerbada pela aspirina (DREA). Métodos: Duzentos e um pacientes foram seguidos por um período médio de 12 anos. Os dados clínicos foram levantados, assim como exames de endoscopia nasal, Tomografia Computadorizada (TC), exames séricos, prick test e prova de função pulmonar. O tempo de seguimento pós-operatório foi analisado, sendo considerado fator de mau prognóstico a indicação de novo procedimento cirúrgico. Foi realizada comparação entre os fatores pela curva de Kaplan-Meyer, e pós-teste de Log-rank. Resultados e Discussão: Pacientes com RSCcPN tiveram chance de nova cirurgia três vezes maior do que aqueles sem pólipos nasais, no período seguido. Entre os pacientes com RSCsPN, apenas a asma foi um fator de pior prognóstico significativo, levando à chance de cirurgia 5,5 vezes maior do que os não-asmáticos. Já entre os pacientes com RSCcPN, aqueles com recidiva apresentaram maior extensão da doença à TC antes da primeira cirurgia. Foram ainda considerados fatores significativamente de pior prognóstico nos pacientes com RSCcPN: asma (odds ratio [OR] de 3,2); atopia a fungos (OR de 1,9); eosinofilia periférica (considerada como >500/µL, levando a OR de 1,9); e intolerância ao Ácido Acetil Salicílico (AAS) (DREA, apresentando OR de 2,5). Conclusões: Concluiu-se que a presença de pólipos per se é fator de pior prognóstico, aumentando em três vezes a chance de recorrência cirúrgica. Entre os pacientes com RSCsPN, apenas a asma influenciou o prognóstico. Já naqueles com RSCcPN, a asma, eosinofilia periférica, atopia a fungos e DREA aumentaram significativamente a probabilidade de nova intervenção cirúrgica. / Introduction: The analysis of prognostic factors associated with the recurrence of chronic rhinosinusitis (CRS), either with nasal polyps (CRSwNP) or without (CRSsNP), is still poorly discussed in the literature. Objective: To evaluate the patients that underwent endoscopic sinus surgery (ESS) due to CRS in Clinics Hospital of Ribeirão Preto Medical School, University of São Paulo, between 1996 and 2006, and to correlate the long-term recurrence to clinical factors, such as extensiveness of the disease, atopy, smoking habits, eosinophilia, and Aspirinexacerbated respiratory disease (AERD). Methods: We collected data of 201 patients, who were followed during an average period of 12 years. Clinical data collected were: extensiveness of the disease at endoscopy and at CT scans, prick test, blood exams, and pulmonary function. The follow-up period after surgery was assessed, and the indication of a new surgical procedure was considered as a poor prognostic factor. Comparison between factors was performed by Kaplan-Meyer curve, with Log-rank post-test. Results and discussion: CRSwNP patients were 3 times more likely to need a revisional surgery than CRSsNP during the follow-up period. Only asthma was a significant prognostic factor in patients with CRSsNP, leading to 5.5 times higher chance of recurrence than non-asthmatic patients. Among patients with CRSwNP, patients with recurrence presented, prior to surgery, higher CT scan extension of the disease. Other factors that influenced the prognosis on CRSwNP were: asthma (odds ratio [OR]: 3.2); atopy for fungi (OR: 1.9); peripheral eosinophilia (considered as >500/?L, leading to an OR: 1.9); and ASA intolerance (AERD; OR: 2.5). Conclusions: The presence of polyps were related to poor prognosis per se, leading to a higher chance of surgical recurrence. Among patients with CRSsNP, only asthma influenced the prognosis. Among the patients with CRSwNP, asthma, peripheral eosinophilia, fungi atopy, and AERD significantly increased the likelihood of further surgical intervention.

<p>The objective of the dissertation was to study the cabin environment, and identify personal and environmental risk factors, associated with symptoms, and perception of cabin air quality. Another objective was to study if ban of smoking, and increased relative air humidity on intercontinental flights, could have a beneficial health effect. The studies were performed among Scandinavian cabin crew in one Airline Company. Office workers from the same company served as controls. Exposure differed between cruise and non-cruise conditions. Air humidity was very low during intercontinental flights (3-8%). Concentration of moulds, bacteria, formaldehyde, and ozone was low. Tobacco smoking increased respirable particles in the cabin air, from 3 to 49 mg/m3, and increased cotinine in urine. The ETS-exposure was highest in the aft part of the cabin. Symptoms and environmental complaints were more common among flight crew than office workers. We could identify personal factors of importance, and certain conditions that could be improved, to achieve a better cabin environment. There was an association between symptoms and environmental perceptions and work stress, lack of influence on working condition, and a history of atopy. After ban on smoking in aircraft, there was a decrease of ocular and general symptoms, and increased tear-film stability in aircrew. Air humidification reduced headache and ocular, nasal, and dermal dryness symptoms, increased tear-film stability, and increased nasal patency. Our result indicates that ETS and low air humidity are important environmental factors in aircraft, and that atopy, and work stress could be significant risk factors for symptoms and environmental perceptions.</p>

The objective of the dissertation was to study the cabin environment, and identify personal and environmental risk factors, associated with symptoms, and perception of cabin air quality. Another objective was to study if ban of smoking, and increased relative air humidity on intercontinental flights, could have a beneficial health effect. The studies were performed among Scandinavian cabin crew in one Airline Company. Office workers from the same company served as controls. Exposure differed between cruise and non-cruise conditions. Air humidity was very low during intercontinental flights (3-8%). Concentration of moulds, bacteria, formaldehyde, and ozone was low. Tobacco smoking increased respirable particles in the cabin air, from 3 to 49 mg/m3, and increased cotinine in urine. The ETS-exposure was highest in the aft part of the cabin. Symptoms and environmental complaints were more common among flight crew than office workers. We could identify personal factors of importance, and certain conditions that could be improved, to achieve a better cabin environment. There was an association between symptoms and environmental perceptions and work stress, lack of influence on working condition, and a history of atopy. After ban on smoking in aircraft, there was a decrease of ocular and general symptoms, and increased tear-film stability in aircrew. Air humidification reduced headache and ocular, nasal, and dermal dryness symptoms, increased tear-film stability, and increased nasal patency. Our result indicates that ETS and low air humidity are important environmental factors in aircraft, and that atopy, and work stress could be significant risk factors for symptoms and environmental perceptions.

Submitted by Geandra Rodrigues (geandrar@gmail.com) on 2018-10-10T13:46:10Z No. of bitstreams: 1 ingridpimentelcunhamagalhaesdesouzalima.pdf: 1571962 bytes, checksum: 521511b66ed89adf27b01a59f98c7cfc (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2018-10-16T13:34:14Z (GMT) No. of bitstreams: 1 ingridpimentelcunhamagalhaesdesouzalima.pdf: 1571962 bytes, checksum: 521511b66ed89adf27b01a59f98c7cfc (MD5) / Made available in DSpace on 2018-10-16T13:34:14Z (GMT). No. of bitstreams: 1 ingridpimentelcunhamagalhaesdesouzalima.pdf: 1571962 bytes, checksum: 521511b66ed89adf27b01a59f98c7cfc (MD5) Previous issue date: 2018-08-24 / O objetivo do presente estudo é avaliar a positividade do teste cutâneo de contato alérgico de leitura tardia para Dermatophagoides pteronyssinus, Dermatophagoides farinae e Blomia tropicalis em pacientes com doenças respiratórias como rinite alérgica e/ou asma com ou sem dermatite atópica. A maioria dos trabalhos existentes nessa área de pesquisa se refere ao emprego desse método diagnóstico na dermatite atópica, mas, neste estudo, a amostra é composta, principalmente, de pacientes com doenças respiratórias. Blomia tropicalis é um ácaro muito incidente no Brasil e só há dois trabalhos que envolvem o emprego deste ácaro da poeira domiciliar típico de países de clima tropical. Os pacientes foram selecionados pela história clínica e foram divididos em dois grupos: I- pacientes com doenças respiratórias, como asma e/ou rinite alérgica, com dermatite atópica e II- pacientes somente com doenças respiratórias. Foi realizado teste cutâneo de leitura imediata e teste de cutâneo de contato alérgico de leitura tardia para os três ácaros no mesmo dia. O teste de contato alérgico foi retirado em 48 horas. A análise estatísitica foi realizada em porcentagens e a tabela 1 apresenta as variáveis por sexo e por grupo estudado. Setenta e quatro pacientes, com idades de 2 a 60 anos, foram incluídos neste estudo; 16 no grupo I e 58 no grupo II. Considerando o teste cutâneo de leitura imediata, o ácaro mais prevalente foi o Dermatophagoides pteronyssinus, seguido pelo Dermatophagoides farinae e Blomia tropicalis. Em relação ao teste cutâneo de contato alérgico de leitura tardia, o ácaro que induziu maior positividade foi o Dermatophagoides farinae (78,4%), seguido pelo Dermatophagoides pteronyssinus (77%) e Blomia tropicalis (52,7%). Comparando o teste cutâneo de leitura imediata com o teste cutâneo de contato alérgico de leitura tardia, 53 pacientes (71,6%) foram positivos para ambos os testes, e 30 (56,6%) foram positivos ao mesmo ácaro. Foram identificados seis pacientes (8%) que tinham história clinica positiva para alergia e só apresentavam positividade no teste cutâneo de contato alérgico de leitura tardia. Estes resultados sugerem que o teste cutâneo de contato alérgico de leitura tardia é relevante e deve ser considerado como um teste diagnóstico adicional, em pacientes com história clínica positiva para doenças respiratórias, com teste cutâneo de leitura imediata negativa. / The aim of this study is to evaluate the positivity rates of atopy patch tests for Dermatophagoides pteronyssinus, Dermatophagoides farinae and Blomia tropicalis in patients with respiratory diseases such as asthma and allergic rhinitis with or without atopic dermatitis. Most studies have been performed with atopic dermatitis patients, but in our study, most of the patients had respiratory conditions. Blomia tropicalis is a mite that is prevalent in tropical areas, such as Brazil, and only two publications include these three mites, which are present in Brazil. The patients’ clinical histories were collected, and the patients were subjected to skin prick and patch tests with the three different house dust mites on the same day. The patch tests were examined 48 hours later, and then, the patients were divided into two groups: I- patients with respiratory diseases, such as asthma and/or rhinitis, and atopic dermatitis and II-patients with only respiratory diseases. The statistical analysis results are presented as percentages, and Table 1 presents the variables by gender and groups studied. A total of 74 patients ranging in age from 2 to 60 years old were included in this study; 16 patients were included in group I and 58 were included in group II. In the skin prick tests, the most prevalent mite that evoked a reaction was Dermatophagoides pterronyssinus, followed by Dermatophagoides farinae and Blomia tropicalis. Regarding the atopy patch tests, the mite that most frequently induced a positive reaction was Dermatophagoides farinae (78.4%), followed by Dermatophagoides pteronyssinus (77%) and Blomia tropicalis (52.7%). A comparison between the skin prick and atopy patch tests revealed that 53 patients (71.6%) were positive on both tests, and 30 (56.6%) patients were positivite for the same mite. We found six patients (8%) who had a positive clinical history of allergy and only exhibited positivity on the atopy patch test. These results suggest that the mite atopy patch test is relevant and should be considered as an additional test for patients with clinical histories of allergic respiratory disease who have negative prick test results.

Peptiderge Mediatoren sind neben ihrer Funktion bei der Aufrechterhaltung der körpereigenen Homöostase unter physiologischen Bedingungen auch bei der Regulation pathopysiologischer und pathobiochemischer Prozesse chronisch-entzündlicher Erkrankungen maßgeblich beteiligt. In der vorliegenden Arbeit wurde diese Rolle durch Untersuchung des Expressionsprofils peptiderger Mediatoren und ihrer Rezeptoren unter normalen Bedingungen charakterisiert und auf dieser Grundlage Veränderungen des Mediatorstoffwechsels bei entzündlichen Erkrankungen erfasst. Aufgrund der geringen Kenntnisse bezüglich der Rolle anti-inflammatorischer Mediatoren wurde dabei insbesondere die Expression und Genregulation des Mediators VIP und seiner Rezeptoren untersucht. Dabei wurden molekularbiologische Methoden verwandt, um definierte Rezeptoren für VIP und verwandte Mediatoren in den Atemwegen und der Haut zu identifizieren. Im Anschluss daran wurde anhand verschiedener entzündlicher Erkrankungen der oberen Atemwege nachgewiesen, dass sich das peptiderge Mediatorprofil krankheitsspezifisch ändert und diese Subgruppen-spezifischen Änderungen nicht als ein universelles Epiphänomen der Entzündungsreaktion zu sehen sind. Ebenso konnte die Veränderung der Genexpression von Rezeptoren für peptiderge Mediatoren untersucht werden, wobei am Beispiel der Hypoxie die Induktion eines in den Atemwegen exprimierten Rezeptors nachgewiesen wurde. Am Beispiel der atopischen Dermatitis konnte darüber hinaus bewiesen werden, dass die Expression von VIP-Rezeptoren im Rahmen einer allergischen Erkrankung vermindert sein kann. Letztlich wurden ebenfalls mit VIP interferierende Transduktionsmechanismen untersucht, wobei die genauen Interaktionen peptiderger Mediatoren mit diesen intrazellulären Molekülen im Rahmen entzündlicher Erkrankungen noch aufzuschlüsseln sind. Die Ergebnisse der vorliegenden kumulativen Arbeit weisen in ihrer Gesamtheit auf eine wesentliche Bedeutung neurogener Mediatoren für pathophysiologische Mechanismen allergisch-entzündlicher Erkrankungen der Atemwege und Haut hin und lassen zukünftige therapeutische Ansätze auf Basis neuro-immunmodulierender Mechanismen sinnvoll erscheinen. / Peptidergic mediators participate next to their physiological role for numerous aspects of systemic and local homeostasis also in the regulation of pathophysiological and pathobiochemical processes in chronic inflammatory diseases. In the present study this role was investigated by assessing the expression profiles of peptidergic mediators and their receptors under physiological conditions. Basing on these findings differences of the mediator expression in inflammatory diseases were examined. Due to the relatively little knowledge on the role of potentially anti-inflammatory mediators the expression and gene regulation of the mediator VIP und its receptors were analysed. In this respect molecular techniques were used to assess distinct receptors for VIP and related mediators in the airways and skin. IN a next Step inflammatory diseases of the upper respiratory tract were examined and it was shown that the peptidergic mediators profile changes in relation to the disease entity and that this disease subtype-specific change is not a universal epiphenomenon of the ongoing inflammation. Also, alterations in the gene expression of peptidergic mediator receptors were analysed. Using hypoxia as an example the gene induction of airway-expressed receptors was demonstrated in relation to this stimulus. In further studies involving atopic dermatitis tissues a down-regulation of VIP receptor expression was demonstrated for allergic inflammatory conditions. In a last step VIP interfering signal transduction mechanisms were examined and future studies need to be carried out to fully assess the regulation of these interactions in relation to chronic inflammatory processes. The present results demonstrate an important role of neurogenic mediators in the pathophysiology of allergic inflammatory diseases of the airways and the skin and point to a potential use of neuro-immunomodulation in the future therapy of these diseases.

Durch Immunregulation und -modulation sorgt das Immunsystem dafür, daß von außen in den Organismus gelangende Agentien nicht zu dauerhaften Schäden führen. Wesentliche Funktionen des Immunsystems stützen sich dabei auf die zelluläre Immunität. Gerät dieses komplizierte Regelwerk aus dem Gleichgewicht, können schwere Erkrankungen autoimmuner oder atopischer Genese resultieren. Der erste Teil der Arbeit befaßt sich mit zwei Aspekten der zellulären Immunantwort. Allergische Immunantworten sind durch die Typ 2 T Zellantwort charakterisiert. Für die Induktion einer Typ 2 Antwort wird Interleukin-4 benötigt, dessen Herkunft nicht geklärt ist. NK1.1 positive T Zellen als Quelle des initialen IL-4 konnten durch in vivo und in vitro Messung von allergie-spezifischen Parametern ausgeschlossen werden. Der MHC-Komplex präsentiert T Zellen Antigene in Form von Peptiden. Pathologische T Zellantworten können durch fortwährende Antigenpräsentation unterhalten werden. Durch Untersuchungen zur molekularen Charakteristik der MHC - Peptid Interaktion ließen sich Bindungsmotive so verfeinern, daß Peptide mit sehr starker Bindung an den MHC ohne gleichzeitige Erkennungssequenz für den T Zellrezeptor entwickelt werden konnten. Peptide dieser Art könnten zur Blockierung einer pathologischen T Zellantwort genutzt werden. Für viele immunologische Erkrankungen ist die Beteiligung genetischer Faktoren beschrieben worden. Der zweite Teil der Arbeit befaßt sich mit der Bedeutung genetischer Disposition bei Allergien im Mausmodell. Homozygote Inzuchtstämme konnten als High- und Low-Responder für den Phänotyp "allergische Soforttypreaktion der Haut" gegenüber Birkenpollenextrakt definiert werden. Die Phänotypisierung der F1 Generation wies auf dominante Vererbung hin, die informative Rückkreuzung auf die Beteiligung von mindestens zwei Genen für die Ausprägung des Merkmals. Wie die Analyse MHC congener Mäuse zeigte, entspricht einer dieser Loci dem MHC Komplex. Durch eine genomweite Kartierung mit Mikrosatelliten wurde als weiterer Kandidat der IL-5 Rezeptor identifiziert. Die detaillierte Analyse des Gens in High-und Low-Respondern weist auf eine Anzahl funktionell bedeutsamer Polymorphismen hin. Dabei imponiert das Low-Responder Allel als Suszeptibilitätsallel. Die Unterschiede haben Auswirkung auf Transkription/Translation und Spleißvorgänge, die zu quantitativer Differenz der Genprodukte führt. Die Daten weisen damit auf einen regulatorischen Mechanismus hin, da die Proteinstruktur des Rezeptors bei High- und Low-Respondern identisch ist. / Immune deviations can lead to serious autoimmune or atopic disorders. Two possible candidates for such pathological immune responses have been investigated: (i) the MHC class I allele HLA-B27, which is strongly linked to ankylosing spondylitis and reactive arthritis. Its presentation of potentially pathogenic peptides and therapeutical modifications of peptidic ligands have been studied. (ii) Interleukin-4 (IL-4), which is the key player in the induction and maintenance of allergic immune responses. A subpopulation of natural killer (NK1.1) cells have been discussed as a source of initial IL-4. Through experiments with NK1.1 deficient mice we could demonstrate, that such immune resonses are not dependent on the presence of NK1.1 cells. Both, autoimmunity and atopy belong to the large group of multifactorial diseases, i. e. genetic and environmental factors influence the expression of the various phenotypes. To dissect the genetics of allergic diseases systematically, a mouse model of immmediate cutaneous hypersensitivity (ICHS) upon birch pollen sensitization has been etablished. Phenotyping of the F1 progeny of high- and low-responder mice revealed ICHS as a dominant trait with incomplete penetrance. Mice from a backcross to the low-responder strain did split into the three classes of high-, intermediate and low-response. Genotyping of these mice revealed a strong candidate gene on chromosome 6: the interleukin-5 receptor (IL-5R). Analysis of the IL-5R gene resulted in the detection of genetic variance of the high- and low-responder allele in non-coding regions with functional relevance. Additional regulatory variance is implicated through differential alternative splicing of the three receptor isoforms. A second gene cluster contributes to the expression of the allergic phenotype: MHC class II alleles, as has been demonstrated for other immunologic disorders in mice and humans.

A Imunodeficiência Comum Variável (ICV) e a Deficiência Seletiva de Imunoglobulina A (DIgA) são as imunodeficiências primárias humorais de maior freqüência na população mundial. Ambas as doenças são caracterizadas pela ausência ou redução significativa de imunoglobulinas no soro. Embora diversas anormalidades imunológicas tenham sido associadas a estas doenças, nenhuma hipótese unificadora a respeito das bases moleculares das mesmas foi proposta até o presente momento, sendo que o único defeito comum a todos os pacientes é a falha na diferenciação de células B em plasmócitos e conseqüente secreção de anticorpos. Devido à alta incidência de auto-imunidade e alergia em pacientes com ICV e DIgA, no presente trabalho, visamos analisar por citometria de fluxo a população de linfócitos CD4+ com potencial regulador nesses pacientes, para avaliar se possíveis defeitos quantitativos ou funcionais nesta população reguladora poderiam explicar a alta incidência de doenças auto-imunes ou alérgicas associadas a estas imunodeficiências. / Common Variable Immunodeficiency (CVID) and Selective Immunoglobulin A deficiency (IgAD) are the humoral primary immunodeficiencies with the highest incidence in the population. Both diseases are characterized by the absence or significant reduction of serum immunoglobulins. Although several immunological abnormalities have been associated with these diseases, no unifying hypothesis regarding the molecular basis of CVID and IgAD have been proposed to date, and the only defect common to all patients is the failure in differentiation of B cells into plasma cells and consequent secretion of antibodies. Due to the high incidence of autoimmunity and allergy in patients with CVID and IgAD, in the present work we analyzed by flow cytometry the population of CD4+ lymphocytes with regulatory potential in these patients to assess whether possible quantitative or functional defects in this regulatory population could explain the high incidence of autoimmune diseases or allergic reactions associated with these immunodeficiencies.