Metagenomics, or genomic sequence of the community of microbiota (bacteria, fungi, virus), enables an investigation of the full complement of genetic material, including virulence, antibiotic resistance, and strain differentiating markers. The granularity to distinguish between closely related strains is important as within one species, these strains possess distinct functions and relationships to a host. To analyze metagenomic samples, I developed a reference-based approach that utilizes both single nucleotide variants and genetic content to assign species and strain-level designations. After refining this approach with complex simulated communities, I utilized it to analyze the microbial communities present in skin samples from healthy and diseased individuals. First, to investigate strain-level heterogeneity in healthy adults, I focused on the common skin commensals Propionibacterium acnes and Staphylococcus epidermidis with well-documented sequence variation. Results indicated that an individual’s strains of P. acnes are shared across multiple sites of his or her body, and that those strains are more similar within than between individuals. For S. epidermidis, in addition to individual site similarities, there were also site-specific strains. Overall these results emphasize that both individuality and site specificity shape our bodies’ microbial communities. Based on longitudinal data, an individual’s strain signatures remain stable for up to a year despite external, environmental perturbations. I then used metagenomic data to explore microbial temporal dynamics in atopic dermatitis (AD; eczema), an inflammatory skin disease commonly associated with Staphylococcal species. Species-level investigation of AD flares demonstrated a microbial dichotomy in which S. aureus predominated on more severely affected patients while S. epidermidis predominated on less severely affected patients. Strain-level analysis determined that S. aureus-predominant patients were monocolonized with distinct S. aureus strains, while all patients had heterogeneous S. epidermidis strain communities. To assess the host immunologic effects of these species, I topically applied patient-derived strains to mice. AD strains of S. aureus were sufficient to elicit a skin immune response, characteristic of AD patients. This suggests a model whereby staphylococcal strains contribute to AD progression through activation of the host immune system. Overall, this strain-level analysis of healthy and disease communities provides previously unexplored resolution of human skin microbiome. / 2018-03-24T00:00:00Z

The prevalence of childhood allergic diseases has been increasing in Taiwan. In Taipei area, according to the surveillance of Hsieh KH, the prevalence rate of childhood asthma increased from 1.3% in 1974 to 10.79% in 1994. The other allergic diseases, such as allergic rhinitis, atopic dermatitis and urticaria , have been also increasing in Taipei, Taichung and Tainan city by a serious studies in Western Taiwan. There is no any report of childhood allergic diseases in Eastern Taiwan till now. So, we want to analyze the prevalence of childhood allergic diseases and the common allergens in Eastern Taiwan. From Nov. 2002 to Oct. 2004, all of the primary school children in Yu-Li town in Hualien county were included in this study. (total 2058 children of 12 school). All of them were surveyed with pediatric allergic diseases questionnaire (asthma, allergic rhinitis, atopic dermatitis and urticaria). After the survey, the suspected allergic cases were analyzed for their hypersensitivity to the common allergens by allergen screening test and specific IgE exam of Pharmacia CAP system. 1816 children completed the questionnaire (completive rate 88.24%) and 688 (37.88%) children were suspected to have allergic diseases. 151 (8.87%) asthma¡F448 (24.67%) allergic rhinitis¡F70 (3.85%) atopic dermatitis¡F65 (3.58%) urticaria. A total of 623 suspected allergic cases were analyzed for their hypersensitivity to the common allergens. The common allergens were also analyzed. 87.7% allergic to D. pteronyssinus (Dp) ; 83.9% Blomia tropicalis (Bt) ; 35.0% German cockroach; 16.0% Dog dander; 7.5% Cat dander; 8.0% Candida albicans; 11.2% Bermuda grass; 38.6% shrimp; 33.1% crab; 26.6% milk; 14.3% egg white; 6.7% peanuts; 6.1% Cod fish; 5.4% Wheat; 4.7% Soya bean. The prevalence of childhood allergic diseases in Eastern Taiwan is lower than Western Taiwan. The different envelopment and living type may be the major reasons. From this study, we also suggest that Blomia tropicalis (Bt) should be included in the common aeroallergy analysis in Eastern Taiwan.

This thesis presents genetic studies of atopic dermatitis (AD) and IgA deficiency in dogs. AD is a chronic inflammatory and pruritic skin disorder caused by allergic reactions against environmental allergens. Both genetic and environmental factors are involved in the development of Canine AD (CAD) and human AD. In Paper I, we performed genome-wide association studies (GWAS) and identified a locus on chromosome 27 significantly associated with CAD in German shepherd dogs (GSDs). The locus contains several genes and fine-mapping indicated strongest association close to the candidate gene PKP2. In Paper II, we performed additional fine-mapping and identified four highly associated SNPs located in regions with transcriptional regulatory potential in epithelial and immune cells. The risk alleles were associated with increased transcriptional activity and the effect on expression was cell-type dependent. These data indicate that multiple cell-type specific enhancers regulate the expression of PKP2, and/or the neighboring genes YARS2, DNM1L and FGD4, and predispose GSDs to CAD. IgA deficiency is the most common primary immune deficiency disorder in both humans and dogs, characterized by a higher risk of recurrent mucosal tract infections, allergic and other immune-mediated diseases. In Paper III, we performed the widest screening (to date) of serum IgA levels in dog breeds (Ndogs=1267, Nbreeds=22) and defined eight breeds as predisposed to low IgA levels. In Paper IV, we performed GWAS in four of the breeds defined as prone to low IgA levels. We used a novel percentile groups-approach to establish breed-specific cut-offs to perform analyses in a close to continuous manner. In total, 35 genomic loci were suggestively associated (p<0.0005) to IgA levels, and three genomic regions (including the genes KIRREL3 and SERPINA9) were genome-wide significantly associated with IgA levels in GSDs. A ~20kb long haplotype on chromosome 28, significantly associated to IgA levels in Shar-Pei dogs, was positioned within the first intron of the gene SLIT1 overlapping with a possible dog domestication sweep. This thesis suggests novel candidate genes involved in two immune-mediated disorders in the dog. Hopefully, these results will become an important resource for the genetic research of the corresponding human diseases.

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 5 uppsatser.

Tez (Tıpta Uzmanlık) - Süleyman Demirel Üniversitesi, Tıp Fakültesi, Dermatoloji Anabilim Dalı, 2003. / Bibliyografya var.

Thesis (Ph.D.)--Flinders University, Dept. of Medicine-Biotechnology. / Typescript bound. Includes bibliographical references: (leaves 267-307) Also available online.

Dermatite atópica (DA) é uma dermatose inflamatória, de caráter crônico e recidivante, com alta prevalência mundial, caracterizada por eczema localizado ou generalizado, xerose cutânea e prurido intenso, mais comum em crianças, porém podendo acometer adultos, muitas vezes prejudicando de forma considerável a qualidade de vida dos pacientes e seus familiares. O diagnóstico de alergia inclui testes in vivo (testes cutâneos de hipersensibilidade imediata ou prick test) e testes in vitro com mensuração de anticorpos IgE no sangue. Está disponível método para detecção de alergia baseado no princípio de diagnóstico por componentes, o ImmunoCAP Immunosorbent Allergen CHIP (ImmunoCAP-ISAC) que marca a transição para o diagnóstico molecular de alergia. No presente estudo, tivemos por objetivos determinar o perfil de resposta IgE a alérgenos purificados, naturais ou recombinantes, em pacientes adultos com DA e comparar o valor do diagnóstico de alergia por componentes com métodos diagnósticos existentes. Foram selecionados 39 pacientes adultos com DA dentre aqueles Atendidos nos Ambulatórios de Alergia e Dermatologia do HCFMRP-USP. A idade dos pacientes variou de 14-66 anos (média ± DP 34,3 ± 2.1 anos), 64% mulheres. O tempo médio de doença foi de 16 anos. SCORAD médio foi de 36,6 (2-90). Média geométrica (MG) de IgE total foi 1,963 kU/L (24-63,000 kU/L). Alérgenos de ácaros foram dominantes, com sensibilização a Der p1 e a Der f1, Der p2 e Der f2 em 82% e 85% dos pacientes, com MG 27,6; 50; 39,2; 45,4 ISU-E respectivamente, seguidos de gato (38%), cachorro (36%) e pólen de gramíneas (36%). IgE para alérgenos de baratas, fungos, pólen de árvores, látex e veneno de insetos foi encontrada em menos de 20% dos pacientes em baixos níveis. Sensibilização para castanhas (33%) e camarão (31%) foram os alérgenos mais prevalentes entre os alimentos, enquanto a reatividade IgE para leite e ovo esteve presente em 10% ou menos dos pacientes, com baixos níveis de anticorpos IgE na maioria dos casos. Apenas 6 pacientes (15,4%) apresentaram IgE para o panalérgeno tropomiosina, e 3/39 (7,7%) foram negativos para todos os 112 componentes de alérgenos testados no ImmunoCAP-ISAC, com níveis de IgE total de 24, 38,7 e 156 kU/L. Concluímos que o perfil de sensibilização IgE entre os pacientes adultos com dermatite atópica difere daquele entre os pacientes com alergiarespiratória, apresentando menos sensibilização para baratas e para o panalérgeno tropomiosina, e difere ainda do perfil presente em crianças com DA, com predomínio de sensibilização IgE a castanhas e camarão, e baixa taxa de sensibilização a alérgenos de leite de vaca e ovo. / Atopic dermatitis (AD) is an inflammatory, chronic, relapsing dermatosis with a high global prevalence characterized by localized or generalized eczema, cutaneous xerosis and intense pruritus, more common in children, but it can affect adults, often causing considerable damage to the quality of life of patients and their families. The diagnosis of allergy includes in vivo tests (skin tests of immediate hypersensitivity or prick test) and in vitro tests with measurement of IgE antibodies in the blood. An allergy detection method based on the principle of component diagnosis is available, ImmunoCAP Immunosorbent Allergen CHIP (ImmunoCAP-ISAC), and marks the transition to the molecular diagnosis of allergy. In the present study, we aimed to determine the IgE response profile to purified, natural or recombinant allergens in adult patients with AD and to compare the value of component allergy diagnosis with existing diagnostic methods. Thirty-nine adult patients with AD were selected from among those attending the Outpatient Clinic of Allergy and Dermatology at HCFMRP-USP. The age of the patients ranged from 14-66 years (mean ± SD 34,3 ± 2.1 years), 64% women. The mean duration of illness was 16 years. SCORAD mean was 36,6 (2- 90). Geometric mean (GM) of total IgE was 1,963 kU / L (24-63,000 kU / L). Mite allergens were dominant, with sensitization to Der p1 and Der f1, Der p2 and Der f2 in 82% and 85% of the patients, with GM 27,6; 50; 39.2; 45.4 ISU-E respectively, followed by cat (38%), dog (36%) and grass pollen (36%). IgE for cockroach, fungus, tree pollen, latex and insect venom allergens was found in less than 20% of patients at low levels. Sensitization to nuts (33%) and shrimp (31%) were the most prevalent allergens among foods, while IgE reactivity to milk and egg was present in 10% or less of the patients, with low levels of IgE antibodies in most cases. Only 6 patients (15.4%) presented IgE for the pan-allergen tropomyosin, and 3/39 (7.7%) were negative for all 112 allergen components tested on ImmunoCAP-ISAC, with total IgE levels of 24; 38,7 and 156 kU / L. We concluded that the IgE sensitization profile among adult patients with atopic dermatitis differs from that among patients with respiratory allergy, presenting less sensitization to cockroaches and to the pan-allergen tropomyosin, andalso differs from the profile present in children with AD, with a predominance of IgE sensitization to nuts and shrimp, and low sensitization rate to cow\'s milk and egg allergens.

Bakgrund: Atopisk dermatit (AD) är en vanlig kronisk inflammatorisk hudsjukdom som kännetecknas av eksematösa vätskande sår och intensiv klåda. AD är dels en T-hjälparcell (TH) - 2 driven sjukdom vilket innefattar den akuta fasen av sjukdomen där TH2-cellerna blir aktiverade och börjar producera cytokinerna interleuin (IL)-4, IL-5 samt IL13. I den kroniska fasen ses i stället en dominans av TH1-celler som i stället främst uttrycker cytokiner som γ-interferon (IFN- γ) och IL-12 vilket bidrar till en kronisk inflammation. Personer som har milda symtom kan ofta kontrollera sjukdomen med enbart topikala medel. För personer som har svårare symtom kan fototerapi eller systemisk behandling behövas. Abrocitinib/Upadacitinib är selektiva janus-kinas (JAK)1-hämmare och hämmar signalvägen som annars resulterar i produktion av proinflammatoriska cytokiner och tillväxtfaktorer. Behandlingen resulterar i minskad inflammation i huden. Dupilumab är en monoklonal antikropp som hämmar IL-4 och IL-13 vilket också resulterar i minskad inflammation.  Syfte: Syftet medstudien var att kritiskt granska utfallet i publicerade studier vad gäller abrocitinib/upadacatinib och dubilumab samt att jämföra skillnaden i effekt och säkerhet för att bedöma hur stor betydelse den nya behandlingen kan ha för patienter med måttlig till svår AD.  Metod: Arbetet är en litteraturstudie som är baserad på sex vetenskapliga artiklar som är hämtade via databasen PubMed. Studier inkluderades som innefattade monoterapi samt om dess primära utfallsvariabel var EASI75 eller IGA.  Resultat: Två studier uppvisade signifikant förbättrad effekt av abrocitinib i två styrkor mot placebo. Studien som jämförde upadacitinib i två styrkor mot placebo visade på signifikant förbättrad effekt mot placebo. Jämförelse av 300 mg dupilumab mot placebo uppvisade också signifikant förbättrad effekt. I en studie där 30 mg upadacitinib jämfördes mot 300 mg dupilumab visade upadacitinib på signifikant förbättrad effekt mot dupilumab. I en annan studie där 100 mg respektive 200 mg abrocitinib jämfördes mot dupilumab och placebo uppvisade abrocitinib förbättrad effekt mot både dupilumad och placebo, dock ej statistiskt signifikant. Biverkningar rapporterades i högre grad för 200 mg-gruppen samt 30 mg upadacitinib-gruppen jämfört med dupilumab. Samtliga studier är sponsrade av läkemedelsföretag som har utvecklat respektive studieläkemedel vilket kan öka risk för bias då företagen vill att deras produkt ska visa på så god effekt som möjligt.  Slutsats: Abrocitinib/upadacitinib anses vara bra behandlingsalternativ för patienter med måttlig till svår AD då det visar på god effekt jämfört med placebo. Dupilumab visar likaså på bra effekt jämfört med placebo. Jämförande studier mellan abrocitinib/upadacitinib mot dupilumab visar på bättre effekt av andelen patienter som uppnådde det primära effektmåttet. Dock är resultatet mellan studieläkemedlena inte markant överlägset någon annan även om abrocitinib/upadacitinib visar på bättre effekt än dupilumab i båda jämförande studierna där resultatet i studie är statistiskt signifikant. / Atopic dermatitis (AD) is a common well-known chronic inflammatory skin disease characterized by eczematous exuding wounds and intense itching. AD is partly a disease driven by the t-helper (TH) 2-cells and involves activation of the acute phase of the disease that starts to produce cytokines interleukin (IL) – 4, IL-5 and IL-13. TH1-cells stands mainly for the expression of cytokines as g-interferon (IFN-g) and IL-12 which contribute to the chronic inflammation. For people with mild symptoms it is usually enough to treat with topical steroids but people who suffer from more severe symptoms, systemic treatment may be needed. Abrocitinib/Upadacitinib is a new selective JAK-1 inhibitor that inhibit the pathway which otherwise results in production of proinflammatory cytokines and growth factors. That results in less inflammation in skin. Dupilumab, that is an inhibitor of IL-4 and IL-13 also results in less inflammation in skin, has been the only approved biological treatment against moderate to severe AD until abrocitinib and upadacitinb was discovered. There is a need of more alternative and safe systemic therapies. This study aims to critically examine the results in different published articles to criticize which treatment of the comparable drugs is the best for patients considering both effect and safety with patients suffering from moderate to severe AD.  This study is based on six scientific articles from PubMed. Studies included if the patients was treated with monotherapy and if the primary outcome was EASI75 and IGA. Two studies presented significantly improved effect of abrocitinib in two different strengths against placebo. One study that compared upadacitinib in two strengths against placebo also showed on significantly improved effect. Comparison of dupilumab 300 mg against placebo showed on significantly improved effect. One study that compared 30 mg upadacitinib against 300 mg dupilumab showed significantly improved effect against dupilumab. The last study that compared 100 mg respectively 200 mg abrocitinib against 300 mg dupilumab showed improved effect of abrocitinib against dupilumab, although it was not significant. Side effects were reported most frequently in the 200 mg abrocitinib study group and also in the 30 mg upadacitinib study group comparable to dupilumab. All of the studies are funded by pharmaceutical companies that also have developed the different study-drugs that is investigated which may increase the risk of bias.   In summary, abrocitinib/upadacitinib is considered a good treatment option for patients suffering from moderate to severe AD comparable with placebo. Treatment with dupilumab also shows on a good treatment comparable to placebo. Studies comparing abrocitinib/upadacitinib with dupilumab shows on more effect of the amount of patients that achieved primary outcome. However, the results between the drugs are not remarkable superior to any other even though abrocitinib/upadacitinib shows on a better effect than dupilumab in both comparative studies.

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