Histochem Cell Biol (2008) 130:55–70 DOI 10.1007/s00418-008-0424-9 R E V I E W Carola Förster Tight junctions and the modulation of barrier function in disease Accepted: 18 March 2008 / Published online: 16 April 2008 © Springer-Verlag 2008 Abstract Tight junctions create a paracellular barrier in epithelial and endothelial cells protecting them from the external environment. Two diVerent classes of integral membrane proteins constitute the tight junction strands in epithelial cells and endothelial cells, occludin and members of the claudin protein family. In addition, cytoplasmic scaVolding molecules associated with these junctions regu- late diverse physiological processes like proliferation, cell polarity and regulated diVusion. In many diseases, disrup- tion of this regulated barrier occurs. This review will brieXy describe the molecular composition of the tight junctions and then present evidence of the link between tight junction dysfunction and disease. Keywords Tight junction · Occludin · Claudin · Cancer · InXammation · Toxin · Hereditary · Vascular Introduction Tight junctions (TJ) (zonulae occludentes) form a continu- ous, circumferential, beltlike structure at the boundary between the apical and the basolateral membrane domains in epithelial and endothelial cells. By constituting a regu- lated diVusion barrier for the paracellular pathway, TJs establish separate compartments in multicellular organisms and are also crucial for the exchange of substances between the internal and external cellular environment by the expression of tissue-speciWc transport proteins and chan- C. Förster (&) Institute of Anatomy and Cell Biology, University of Würzburg, Koellikerstrasse 6, 97070 Würzburg, Germany e-mail: carola.foerster@mail.uni-wuerzburg.de nels. The transmembrane proteins constituting the TJs are attached to the cytoskeleton, thereby linking cell–cell and cell–substratum adhesion sites. In addition, cytoplasmic plaque proteins constitute scaVolds for TJ assembly or are involved in the regulation of processes like transcription, proliferation and diVerentiation into a tissue-speciWc regu- lated diVusion barrier in physiology and development. Many excellent reviews have summarised data regarding the molecular composition and function of TJs (Ebnet 2008; Gonzalez-Mariscal et al. 2003; Matter and Balda 2003a; Mitic and Anderson 1998; Schneeberger and Lynch 2004; Tsukita and Furuse 1999; Zahraoui et al. 2000), so that the scope of the current review is focused on distur- bances of TJ function in human diseases. Structure of the tight junction As the apicalmost part of the junctional complex (Farquhar and Palade 1963), the TJ forms a continuous, circumferen- tial belt separating apical and basolateral plasma membrane domains, working as a barrier within the intercellular space and as a fence within the plasma membrane. In recent years, information on the molecular composition of TJs, in particular their transmembrane molecules, has accumu- lated, forming the basis of our current understanding of the structure and function of TJs in molecular terms (Fig. 1). The morphology of TJs has been intensively analysed by freeze–fracture electron microscopy (Staehelin 1973; Wol- burg et al. 2003), where they appear as a set of continuous, anastomosing transmembraneous particle strands on the inner leaXet of the plasma membrane (P-face) with comple- mentary vacant grooves on the outer leaXet (E-face) (Fig. 2). The number and complexity of ramiWcation of the network of TJ strands depends on the cell type, in sum 123