Gene expression and genetic association studies in eczema.

Eczema is an itching relapsing and often chronic inflammatory skin disorder associated with cutaneous hyper reactivity to environmental triggers that are innocuous to normal individuals. The differentiation of epidermal keratinocytes leads to the formation of a physical barrier and together with appropriate innate immune responses produce a functional epidermal barrier protecting us against a number of detrimental factors in the external environment. Epidermal barrier dysfunction is an important factor in eczema development but is still poorly understood. The overall aim with the studies in this thesis was to improve our understanding of barrier dysfunction in eczema, mainly through the use of gene expression and genetic association studies. In study I we showed that antigen presenting dendritic cells (DCs) from eczema affected individuals responds differently to allergen (Malassezia sympodialis) stimulation compared to DCs from healthy individuals. Our results indicate a diverse response among the eczema patients, where some exhibited an exaggerated inflammatory response towards the allergen on the DC level. In study II we used a mouse model for eczema to search for new differentially expressed genes, related to barrier function, in eczema. We found a reduction in the expression of the cornulin (CRNN) gene, a marker of late epidermal differentiation, in eczema-like skin in mice and this finding was then validated in eczema patients. We then tested whether genetic variability at the CRNN locus was associated with eczema susceptibility. Although association with atopic eczema was found, the effect of linkage disequilibrium with filaggrin (FLG) variants could not be excluded as a possible explanation for the association. In study III we confirmed that the previously identified FLG gene is a major susceptibility gene in atopic eczema and present data supporting that FLG variants play a role in determining disease severity and progression into associated allergic phenotypes. Finally, in study IV we showed that the transglutaminase 1 (TGM1) gene is differentially expressed and potentially represents a new susceptibility gene in the development of atopic eczema. In summary, the studies in this thesis have identified new differentially expressed genes associated with eczema. Furthermore, we confirmed the FLG gene as a susceptibility gene in eczema and identified the TGM1 gene as a new potential susceptibility gene. LIST OF PUBLICATIONS I. Susanne Gabrielsson, Eva Buentke, Agne Lieden, Margit Schmidt, Mauro D’Amato, Maria Tengvall-Linder and Annika Scheynius. Malassezia sympodialis Stimulation Differently Affects Gene Expression in Dendritic Cells from Atopic Dermatitis Patients and Healthy Individuals. Acta Derm Venereol, 2004, 84, 339-45. II. Agne Lieden, Elisabeth Ekelund, I-Chun Kuo, Ingrid Kockum, Chiung-Hui Huang, Lotus Mallbris, Simon P. Lee, Lim Kar Seng, Giam Yoke Chin, CarlFredrik Wahlgren, Colin N. A. Palmer, Bengt Bjorksten, Mona Stahle, Magnus Nordenskold, Maria Bradley, Kaw Yan Chua and Mauro D’Amato. Cornulin, a marker of late epidermal differentiation, is down regulated in eczema. Submitted for publication III. Agne Lieden*, Elisabeth Ekelund*, Jenny Link, Simon P. Lee, Mauro D’Amato, Colin N.A. Palmer, Ingrid Kockum and Maria Bradley. Loss-of-function Variants of the Filaggrin Gene are Associated with Atopic Eczema and Associated Phenotypes in Swedish Families. Acta Derm Venereol (in press) IV. Agne Lieden, Annika Saaf, Elisabeth Ekelund, Ingrid Kockum and Maria Bradley. Increased expression and genetic association links the transglutaminase 1 gene to atopic eczema. Submitted for publication, under revision for Allergy *Authors contributed equally