O papel modulador do gene AIRE - capes

Promiscuous gene expression in murine FTOC14·74·74·74·73·14·7Chromosomal location of differentially expressedgenesThe genomic distribution of the 192 genes modulated(repressed or induced) during the 5 days of FTOC developmentallowed for the co-ordinated expression of organizingchromosomal clusters.Figure 4 shows the frequency distribution of therepressed and induced genes among chromosomes. Takingall the developmental phases together, the number ofrepressed genes (154) was greater than that of inducedgenes (38). All chromosomes, except Y, harboured differentiallyexpressed genes, with a slightly biased distributionon chromosomes 2, 5, 11 and 19 for repressed genes andon chromosomes 3, 4, 11, 15 and 19 for induced genes.Discussion9·53·1 1·63·16·314·711·1PGE in the thymus is a complex phenomenon observedin humans and mice, which is exhibited by TECs (mTECs)4·73·13·13·1CirculatoryCentral NervousDigestiveEpidermis/SkinEyesFat tissueGlandsIntestinesLocomotoryLymphoidMusclesPeripheral NervousReproductiveRespiratorySensory OrgansStem cellsUrinaryFigure 3. Representation of tissue/organ system-specific gene expressionin 20 days FTOC.Frequency (%)14 Repressed Induced1210864201 2 3 4 5 6 7 8 9 101112 13 14 15 16 17 18 19 X Y NFChromosomesFigure 4. Chromosomal distribution of the repressed and inducedgenes considering all FTOC development (15–20 days).NF, not found.and involves 5–10% of all known genes of these species.This process is a guarantee of self-representation ofmost parenchymal tissues and organs during the centraltolerance of T cells.Using PCR, Derbinski’s group previously demonstratedthat the expression of five tissue-specific genes, such asthyroglobulin, CRP, GAD67, insulin and albumin, wasdetectable only in mTECs purified from ex vivo thymictissue at embryonic day 15 (E15). 7Accordingly, the complexity of PGE increases in, fromcTECs to immature mTECs to mature CD80 hi mTECs.These different gene pools are not complementary, butadditive, that is, there is no apparent association betweenthe respective molecular/biological functions of the genesin parenchymal organs. The significance of PGE in thethymus is associated with the central tolerance of Tcells. 9–14While PGE by mTECs was well documented by theauthors cited above, many aspects of this phenomenonremain unexplored, for example, its evaluation in the thymusof autoimmune strains and/or knockout mice, itsmodulation by means of cytokines or other moleculesinterfering in gene expression, such as RNA interference,and its time–course during the ontogenetic developmentof the thymus.Molecular characterization of PGE in the FTOC modelsystem is a relevant approach in immunobiology, becausethe functional analysis of T-cell development has becomepossible after the introduction of techniques in which thethymic microenvironment is mimicked, such as FTOC.This method is based on the use of early fetal thymus tissue,which is composed of a homogeneous thymocytepopulation (double-negative cells).In this study, the occurrence of PGE in vitro in FTOCis described for the first time. To evaluate whether PGEin this model system is a development-dependent phenomenon,we regarded the differential gene expressionduring ontogeny by comparing days of gestation (p.c.), asthe most informative in the delineation of the gene pool.Use of the FTOC model system was chosen, rather thancompare the changes in expression profiles in thymustissue obtained at different gestational days, to approachthree important aspects simultaneously. Since FTOCreproduces the in vivo thymus development, this modelsystem represented a useful tool first, for the fine demarcationof PGE onset and, second, to demonstrate thatPGE is a phenomenon that can be reproduced in vitro.The third aspect was a beneficial possibility of the FTOCmodel system, comparing the same pool of thymus tissueat day 15 with later time-points.We demonstrated that PGE in FTOC, which is characterizedby the overexpression of parenchymal organ andtissue-specific antigen genes, emerges at 20 days p.c.(Fig. 1). Since this in vitro organ culture mimicked thethymus gestation in vivo, including the maturation of TÓ 2006 Blackwell Publishing Ltd, Immunology, 119, 369–375 373