Histochem Cell Biol (2008) 130:55–70 leading to an increased loss of solutes in the form of “leak- Xux diarrhoea”. Notably, the integrity of the intestinal bar- rier is not only impaired in patients with Crohn’s disease but also many Wrst-degree relatives of Crohn’s disease patients present with increased intestinal permeability in the absence of clinical symptoms (Hollander 1993; Peeters et al. 1997; Yacyshyn and Meddings 1995). From this observation it was concluded that barrier dysfunction in Crohn’s disease precedes the inXammatory process in con- trast to many other inXammatory diseases, probably arising from genetic defects or driven by environmental factors like intestinal luminal antigens or bacterial toxins. The epithelial barrier in the intestine is established by a single layer of epithelial cells. However, barrier dysfunc- tion alone does not to seem be suYcient to cause Crohn’s disease, since unaVected relatives of patients with Crohn’s disease comparably present increased permeability, but do not show the abnormal mucosal inXammatory response reported of patients with Crohn’s disease (Weber and Turner 2007). In healthy individuals, the intestinal muco- sal barrier is organised through tight junction strands con- necting the adjacent epithelial cells (Weber and Turner 2007). These TJs seal the paracellular space and an intact intestinal mucosa. TJ permeability is rate limiting for epi- thelial permeability and defects thereof are an established source for intestinal barrier defects as observed in Crohn’s disease. The basic understanding of TJ function we devel- oped is that they form an ion-selective and size-selective paracellular gate whose permeability varies throughout the gastrointestinal tract (see above). According to this, it is not surprising that the pattern of claudin isoforms expressed varies alongside the gastrointestinal tract (Nus- rat et al. 2000). Recent studies now show that the expres- sion pattern of characteristic claudins is altered in Crohn’s disease (Weber and Turner 2007) with a concomitant eVect on the integrity of TJ strands: Zeissig et al. (2007) showed by freeze–fracture electron microscopy that the overall number of TJ strands sealing the epithelial layer is reduced while concomitantly an increased number of strand breaks was noted in tissue from patiens with Crohn’s disease (Zeissig et al. 2007). The expression of 12 claudin isoforms in the intestinal epithelium was investi- gated in healthy individuals and patients with Crohn’s dis- ease, leading to the insight that the expression of the claudins-3, -5, and -8 was decreased in active disease. On the contrary, expression of barrier-reducing claudin-2 was increased in histological samples from patients, which was particularly observed in the crypt epithelium. This altered pattern of claudin isoform expression was thus concluded to be partly responsible for the observed mophological and functional disruption of TJs. However, claudin isoform expression patterns were unaltered in patients with inac- tive Crohn’s disease, rendering this observed change in 61 expression patterns rather a consequence than a cause of active disease. It is has been acknowledged for a long time that chronic inXammation in Crohn’s disease is associated with the overproduction of proinXammatory cytokines. Searching for the nature of these pro-inXammatory mediators eVecting the TJ disruption and dysfunction, investigators (Conyers et al. 1990; Heller et al. 2005; Prasad et al. 2005) had iden- tiWed IL-13, IFN and TNF as factors in patient’s serum lowering resistance and opening TJs. However, diVerential eVects of the diVerent cytokines crititical to IBD pathogenis have been reported from studies in cell culture models, indicating that the mechanisms by which IFN and TNF inrease paracelluar permeability diVer from those used by IL-13 (Prasad et al. 2005). IFN and TNF exposure of model cell lines led to a reduction in claudin-2 expression, while IL-13 exposure induced increased claudin-2 expres- sion. Those observed discrepancies, which might be based on the source of epithelial cell lines, the experimental design or the doses of cytokines applied are the focus of current investigation. Other lines of research are concen- trated on gaining more information on the source of pro- inXammatory cytokines in IBD and the mode how those cytokines may work together to modify claudin expression pattern, either in vitro or in vivo (Weber and Turner 2007). At the cell biological level, recent investigation demon- strated that IFN exposure promoted the endocytosis of occludin, JAM-1 and claudin-1 into early and recycling endosomes (Bruewer et al. 2005), an eVect which appears to be mediated by RhoA/Rho kinase, which further induced a myosin II-dependent formation of vacuoles in the apical cell moiety (Utech et al. 2005). At the gene expression level, other research groups could demonstrate that TNF induced an increase in Caco-2 TJ permeability mediated by activation of the pro-inXam- matory transcription factor NF B. NF B action leads to a downregulation of speciWcally ZO-1 gene expression and a redistribution of ZO-1 protein away from the intercellular junctions (Ma et al. 2004). A comparable eVect could be described in the nonintestinal model epithelial cell line, MDCK, and in the blood brain barrier model cell line cEND, where also disruption of TJs following exposure of epithelial and endothelial cells to TNF could be demon- strated (Förster et al. 2007; Poritz et al. 2004). Blood-brain barrier compromise in neuroinXammation–multiple sclerosis Homeostasis of the central nervous system (CNS) microen- vironment is essential for its normal function. It is main- tained by the blood-brain barrier (BBB) which regulates the transport of molecules from blood into brain and back- wards. The function of this highly specialised barrier is to 123