Introduction 2008 2003 2003a 1998 2004 1999 2000 Structure of the tight junction 1963 1 1973 2003 2 1973 1978 Fig. 1 Molecular composition of tight junctions. The transmembrane proteins occludin, the claudin(s) and junctional adhesion molecule-1 (JAM-1) constitute the barrier formed by TJs sealing the paracellular space. They appear to be interacting in a homophilic manner, and occludin seems to co-polymerase into claudin-based TJ strands. Claudins adhere with each other in a homotypic as well as a heterotypic manner. ZO-1, -2, and -3 bind the cytoplasmic tail of occludin and link the TJ to the actin cytoskeleton. Proteins of the ZO family can shuttle to the nucleus to influence transcriptional processes in cellular proliferation and differentiation. The ZO-proteins have also been shown to interact with claudins and provide molecular scaffolds for TJ assembly. Cingulin is a 140 kDa TJ plaque protein which assoicates with the actomyosin cytoskeleton. Its putative function is transduction of the mechanical force generated by the actomyosin cytoskeleton important for cellular differentiation. The Ras target AF-6 interacts with ZO-1 and serves as a. peripheral component of tight junctions in epithelial cells. Symplekin is a 126 kDa protein that occurs and probably functions in the nucleus as well as in the TJ plaques. Tyrosine phosphorylated Par3 regulates tight junction assembly and promotes cellular polarity by intracellular signalling. Localization of 7H6 TJ-associated antigen along the cell border of vascular endothelial cells has been shown to correlate with paracellular barrier function. Additional proteins have been localised to the TJs but a function has presently not been assigned. Moreover diverse signaling proteins are detected at the apical junctional complex but they are not uniquely confined to the TJ  Fig. 2 1989 Bar  Occludin 1993 1996 3 1996 1996 1998 1998b 1999 1996 Fig. 3 a triangles orange-red green cream 1996 b blue orange c pink blue yellow 2000 black  The claudins 1998a 3 1999 2001 Summarizing existing data, there is clear evidence that the claudins constitute the backbone of TJ strands, while occludin, which itself cannot reconstitute such TJ strands, seems to play a permeability regulating role by incorporating itself into the claudin-based strands, a process, the mechanism of which however is not yet understood. The function(s) of occludin thus still remain to be elucidated. Junction-associated adhesion molecules (JAMs) 3 2008 2004 2002 2000 3 2000 2002 2001 1998 2001 2000 TJ plaque proteins and the coordination of signaling at the TJ 2008 2003 2004 1986 2004 TJs as permeability barrier 2006 2004 1988 3 1993 2000 Role of claudin proteins in formation of a TJ permeability barrier K i 3 2001 2 2 2003b 2003 Role of occludin in formation of a TJ permeability barrier 1996 2001 1999 2+ 1997 1997 2005 2007 TJs and human disease Modulation of barrier function by cytokines 2001 2001 1999 1 Table 1 Modulation of TJ barrier function in human disease Classification Tight junction protein affected Reference Cancer  Breast cancer: invasive ductal cancer Claudin-1, ZO-1 2003  Prostate cancer: prostatic adenocarcinomas Claudins-1, -3, -4 and claudin-7 2007  Thyroid neoplasma, follicular adenoma Occludin and claudin-1, -4 and -7 2007  Gastroesophageal reflux disease: Barrett’s  esophagus (dysplasia) Claudin-18 2007  Lung cancer: Basaloid squamous carcinoma Ultrastructural junctional dedifferentiation 1998 Inflammation  Inflammatory bowel disease: Morbus Crohn Claudins-2,-3, -5, and -8, ZO-1 2007  Collagenous collitis Occludin, claudin-2 and -4 2002  Multiple sclerosis Occludin, claudin-5 2007 Hereditary diseases  Hereditäry deafness Claudin-14 2003  Familial hypomagnesemia Claudin-16 1999  cystic fibrosis Occludin, claudin-1, -4, JAM, ZO-1 2002 Vision loss  Diabetic eye disease: diabetic retinopathy Occludin, ZO-1 2005 Viral infection  Reoviral infection (hydrocephalus, encephalitis) JAM-1 2003 Bacterial toxins  Clostridium perfringens Claudin-3 and -4 2001 Inflammatory bowel disease: Crohn’s disease 1993 1997 1995 2007 2007 2000 2007 2007 2007 1990 2005 2005 2005 2007 2005 2005 2004 2007 2004 Blood-brain barrier compromise in neuroinflammation–multiple sclerosis 1999 2 2007 2002 1992 1998 2007 1996 1995 2001 2000 2006 2006 2000 2001 2005 1990 2007 2008 2007 2006 1993 1984 1993 2006 2002 2005 2006 2002 Hereditäry diseases Hereditäry deafness: nonsyndromic recessive deafness DFNB29 + + + + 1998 1989 2005 CLDN14 2001 2003 + + + + + 1986 CLDN14 2005 CLDN14 Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) 2+ 2+ 1999 2+ 2+ 2006 2+ 2+ 1999 2+ 2+ 2006 1999 2+ 2+ + 2+ 2006 + 2+ 2005 2+ 2+ 1999 2+ 2+ 2005 2006 2006 2+ 2+ 2006 CLDN16 CLDN16 2006 CLDN19 CLDN19, 2008 Vascular system Diabetic retinopathy The barrier between the vascular lumen and neural layers in the retina and the brain parenchyme maintains a characteristic microenvironment and is essential for proper neuronal function. This blood-retinal barrier (BRB) consists of two anatomical entities: an inner BRB formed by junctions between endothelial cells of the retinal capillaries, and an outer BRB composed of TJs between retinal pigment epithelial cells. Clinical evidence from fluorescein angiography has demonstrated that the inner BRB appears to be the primary site of vascular leakage leading to macular edema. 1998 2001 1995 2005 2005 2005 2005 1998 2006 2006 2001 2005 Multiple sclerosis See above. Tight junction alterations in cancer Decreased expression of claudin-1 correlates with malignant potential in breast cancer 2001 2002 2007 2005 2000 1998 1999 1983 2002 Drosophila 1991 1999 1998 The molecular pathways leading toward the loss of claudin-1 expression however, remain to be explained. Bacterial toxins Clostridium perfringens enterotoxin 2001 2001 1999 2001 2001 2007 2007 Clostridium histolyticum Bacillus thuringiensis 2008 2008 Conclusion and perspectives The discovery of the existence of occludin- and claudin-based TJs constituting a permeability barrier in epithelial and endothelial cells has paved the way for the elucidation of the molecular background of diverse human diseases the pathogenesis of which had been unclear before. It became clear that the presence of TJs is indispensable for tissue compartmentalisation and cellular homeostasis. Disturbances in TJ function are reflected in many diseases, but on the other hand, awareness of their involvement has facilitated therapy enormously. For instance, antiinflammatory or antimetastatic drugs could be developed based on their ability to repair broken barrier function. These strategies have become indispensable in the treatment of disease like MS, inflammatory bowel disease or diabetic retinopathy. Following the strategy of pathogenic agents, which use TJ proteins as a docking station to invade cells, even strategies for drug delivery techniques could be implemented. Future attempts will have to address the role of occludin and the exact contribution of the diverse claudins to the formation of ion selective pores, which are still open questions. A more thorough understanding will greatly facilitate diagnosis and the development of specific treatment regimens for diseases originating from impaired TJ function.