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• W2149796053 abstract "Atopic eczema (AE) is a chronic inflammatory skin disease characterised by pruritic (itchy) skin lesions. The pathogenic mechanisms underlying AE are still unclear, although several factors such as genetic predisposition, a dysfunctional skin barrier, exposure to environmental allergens and skin colonisation with microorganisms appear to be of importance. Malassezia sympodialis is a yeast which is part of our normal cutaneous flora. Approximately 50% of adult AE patients have serum IgE specific for M. sympodialis allergens or display immediate-type skin reactions against crude extracts of this yeast, while such reactivity is rarely observed in other allergic diseases, indicating that sensitization to this yeast is associated with AE. Ten allergens from M. sympodialis have been cloned to date, designated Mala s 1 and Mala s 5-13. Six of these exhibit sequence homology to known proteins whereas four do not. The aim of this thesis has been to gain knowledge of host-microbe interactions of allergens from M. sympodialis in the pathogenic mechanisms of AE and in healthy individuals. This has been accomplished by studying structural properties and cellular interactions, with a special focus on the two allergens Mala s 1 and Mala s 11. Mala s 1 is a major allergen mainly localized in the yeast cell wall and exposed on the cell surface. Interestingly, Mala s 1 does not exhibit any significant sequence homology to known proteins. We have solved the crystal structure of Mala s 1 by singlewavelength anomalous dispersion techniques using selenomethionine-substituted Mala s 1. Mala s 1 folds into a six-fold β-propeller, a novel fold among allergens. The putative active site of Mala s 1 overlaps structurally with putative active sites in potential homologues, Q4P4P8 and Tri 14, from the plant parasites Ustilago maydis and Gibberella zeae, respectively. This resemblance suggests that Mala s 1 and the parasite proteins may have similar functions. In addition, we demonstrate that Mala s 1 binds to phosphatidylinositol (PtdIns) (3)-phosphate (P), PtdIns(4)P, and PtdIns(5)P, lipids possibly playing a role in the localization of Mala s 1 to the cell surface. Mala s 11 displays a high degree of sequence homology to human manganese superoxide dismutase (hMnSOD). In AE patients sensitized to M. sympodialis, hMnSOD can elicit positive skin prick tests or atopy patch tests along with binding IgE, suggesting an autoimmune response. We report that Mala s 11 is able to inhibit IgE-binding to hMnSOD and vice versa, indicating that these two homologues share common IgE epitopes. We have also identified residues possibly involved in such cross-reactivity. In addition, we compared the influence of Mala s 11 and hMnSOD on human dendritic antigen presenting cells. Whereas rhMnSOD did not affect the phenotype of monocytederived dendritic cells (DCs), rMala s 11 up-regulated maturation markers and induced significantly higher levels of inflammatory cytokines in the culture supernatants. This suggests that DCs from healthy individuals possess the ability to distinguish between Mala s 11 and hMnSOD despite their high homology. Whether this is also the case for DCs in AE patients remains to be clarified. In summary, we have determined a novel three dimensional structure not previously demonstrated among allergens. We demonstrate the ability of DCs to distinguish between proteins with high sequence homology and we provide a structural basis underlying the autoimmune response to hMnSOD in AE based on IgE-mediated cross-reactivity. Thesis summary in Swedish – Svensk sammanfattning av avhandlingen Strukturell och funktionell analys av allergen fran jastsvampen Malassezia sympodialis Atopiskt eksem (AE) ar en kronisk hudsjukdom dar torr hud och klada ar typiska symptom. Exakt vad som ligger bakom denna sjukdom ar annu inte kant, men faktorer som patientens genetiska bakgrund, en bristfallig hudbarriar, mikroorganismer pa hudytan samt allergi anses ha en betydande roll. Vid en allergisk sjukdom reagerar kroppen pa ofarliga proteiner i omgivningen genom att producera IgE-antikroppar. Dessa antikroppar kan binda till proteinerna, som da kallas allergen, och denna bindning ligger bakom de allergiska symptomen. Jastsvampen Malassezia sympodialis tillhor den normala hudfloran. Omkring 50% av vuxna AE patienter har IgE-antikroppar mot allergen fran M. sympodialis eller positivt pricktest mot M. sympodialis extrakt. Dessa symptom ses sallan hos individer med andra allergiska sjukdomar, vilket tyder pa att allergi mot M. sympodialis har en speciell koppling till AE. Hittills har tio allergen fran M. sympodialis identifierats. Sex av dessa har likheter i DNA-sekvensen med tidigare kanda protein, medan ovriga fyra saknar detta. Malet med denna avhandling har varit att oka forstaelsen kring interaktionen mellan M. sympodialis allergen och manniska samt denna jastsvamps roll vid AE. Detta har gjorts genom att karakterisera den tredimensionella (3D) strukturen hos M. sympodialis allergen samt att studera hur dessa allergen paverkar celler i det manskliga immunforsvaret. De tva allergen som denna avhandling fokuserar pa ar Mala s 1 och Mala s 11. Allergenet Mala s 1 ar lokaliserat i jastens cellvagg och ar exponerat pa dess cellyta. Detta allergen har ingen likhet i DNA-sekvens med nagot protein med kand funktion, och foljaktligen ar aven funktionen hos Mala s 1 okand. Vi har lost 3D strukturen for Mala s 1 och funnit en struktur som aldrig tidigare observerats hos ett allergen. Likheten mellan den del av strukturen som troligtvis innehaller aminosyror av storst vikt for funktionen av Mala s 1 och motsvarande omrade hos proteiner fran vaxtparasiterna Ustilago maydis och Gibberella zeae tyder pa att Mala s 1 och dessa proteiner har liknande funktion. Vi fann aven att Mala s 1 binder till fosfatidylinositol, en lipid som kan ha en roll i att transportera Mala s 1 till cellytan. Allergenet Mala s 11 har hog likhet i DNA-sekvens med det manskliga enzymet mangansuperoxiddismutas (hMnSOD). Vi har visat att Mala s 11 kan hamma bindning av IgE-antikroppar till hMnSOD och vise versa, vilket tyder pa att dessa tva proteiner har strukturer som kan binda samma IgE-antikropp. Vi har aven identifierat vilka aminosyror som skulle kunna vara inblandade i en sadan sa kallad korsreaktivitet. Dessa resultat ger pa molekylar niva en trolig forklaring till den autoimmuna reaktionen mot hMnSOD som observerats hos AE patienter allergiska mot M. sympodialis. Vi har aven jamfort effekten av Mala s 11 och hMnSOD pa antigenpresenterande dendritiska celler (DCs), celler i immunforsvaret som tar upp frammande amnen och sedan visar upp dem for andra celler i immunforsvaret. Vara resultat tyder pa att DCs hos friska individer har formagan att skilja mellan Mala s 11 och det kroppsegna hMnSOD trots den stora likheten mellan dessa proteiner. Det aterstar att visa om DCs hos AE patienter har forlorat denna formaga. Sammanfattningsvis har dessa studier okat kunskapen om strukturen hos M. sympodialis allergen. Resultaten har pa molekylar niva givit en forklaring till mekanismerna bakom en autoimmun reaktion pa en kroppsegen substans med hog likhet med ett allergen samt pavisat formagan hos DCs att skilja pa proteiner med stor likhet i sekvens. LIST OF PUBLICATIONS This thesis is based on the following articles, which will be referred to in the text by their roman numerals: I. Monica Vilhelmsson*, B. Martin Hallberg*, Omid Rasool, Arezou Zargari, Annika Scheynius and Adnane Achour. Crystallization and preliminary crystallographic study of the Malassezia sympodialis allergen Mala s 1. Acta Cryst. 2006, F62:97-99. *These authors contributed equally to this work. II. Monica Vilhelmsson, Arezou Zargari, Reto Crameri, Omid Rasool, Adnane Achour, Annika Scheynius* and B. Martin Hallberg*. Crystal structure of the major Malassezia sympodialis allergen Mala s 1 reveals a β-propeller fold: A novel fold among allergens. J Mol Biol. 2007, 369:1079-1086. *Shared last authorship III. Monica Vilhelmsson, Catharina Johansson, Gunilla Jacobsson-Ekman, Reto Crameri, Arezou Zargari and Annika Scheynius. The Malassezia sympodialis allergen Mala s 11 induces human dendritic cell maturation, in contrast to its human homologue manganese superoxide dismutase. Int Arch Allergy Immunol. 2007, 143:155-162. IV. Monica Vilhelmsson, Andreas G Glaser, Daniel Badia Martinez, Margit Schmidt, Catharina Johansson, Claudio Rhyner, Kurt D. Berndt, Annika Scheynius, Reto Crameri, Adnane Achour* and Arezou Zargari*. Mutational analysis of amino acid residues involved in IgE-mediated cross-reactivity between the Malassezia sympodialis allergen Mala s 11 and its human homologue manganese superoxide dismutase." @default.
• W2149796053 created "2016-06-24" @default.
• W2149796053 creator A5070336118 @default.
• W2149796053 date "2008-03-21" @default.
• W2149796053 modified "2023-09-22" @default.
• W2149796053 title "Structural and functional studies of Malassezia sympodialis-derived allergens" @default.
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