Cell-matrix Adhesion Molecules Research Articles

Negative impact of DEP exposure on human airway epithelial cell adhesion, stiffness, and repair.

Epidemiological and experimental studies suggest that diesel exhaust particles (DEPs) may be associated with increased respiratory mortality and morbidity. Several recent studies have also shown that DEPs increase the production of inflammatory cytokines by human bronchial epithelium (HBE) cells in vitro. The present study investigates the effects of DEPs on the interaction of l-HBE cells (16HBE14o-) with the cell and matrix microenvironment based on evaluation of integrin-type cell/matrix ligand expression, cytoskeleton (CSK) stiffness, and matrix remodeling via matrix metalloproteinase (MMP)-1, MMP-2, and MMP-9 expression. The results showed that DEP exposure induced: 1) a net dose-dependent decrease in CSK stiffness through actin fibers, 2) a concomitant specific reduction of both alpha(3)- and beta(1)-integrin subunits extensively expressed on the HBE cell surface, 3) a decrease in the level of CD44, which is a major HBE cell-cell and HBE cell-matrix adhesion molecule; and 4) an isolated decrease in MMP-1 expression without any change in tissue inhibitor of matrix metalloproteinase (TIMP)-1 or TIMP-2 tissue inhibitors. Restrictive modulation of cell-matrix interaction, cell-cell connection, CSK stiffness, and fibrillary collagen remodeling results in a decreased wound closure capacity and an increased deadhesion capacity. In conclusion, on the basis of these results, we can propose that, in addition to their ability to increase the production of inflammatory cytokines, DEPs could also alter the links between actin CSK and the extracellular matrix, suggesting that they might facilitate HBE cell detachment in vivo.

Immunohistochemical analysis of neural cell adhesion molecule (N-CAM) and pan-cadherin in the small intestine of intrauterine growth-retarded newborn rats caused by maternal protein malnutrition

Cell-cell and cell-matrix adhesion molecules play an important role in morphogenesis, cell signaling and are involved in cell proliferation, cell death, cell polarization and differentiation. In the present study, we investigated N-CAM and pan-cadherin expression in small intestine of intrauterine growth-retarded (IUGR) newborn rats after maternal protein malnutrition during pregnancy. N-CAM and pan-cadherin immunostaining was increased in small intestine of IUGR newborn rats. This increase was evident in epithelial cells on villi, lamina propria, submucosa, muscularis mucosa and muscularis externa. The increase in numbers of villous N-CAM-positive and pan-cadherin-positive epithelial cells was statistically significant (p < 0.001). In most areas, crypts did not show any immunopositive epithelial cells or showed decreased expression of the adhesion molecules. Although the villous height was decreased in IUGR rats, the decrease was statistically not significant. Expression and recruitment of N-CAM and pan-cadherin in small intestine of newborn IUGR rats may indicate a direct or indirect involvement of adhesion mechanisms or signaling in the growth retardation process.

Cell Adhesion-Mediated Transformation of a Human SCLC Cell Line Is Associated with the Development of a Normal Phenotype

Small cell lung carcinoma (SCLC) is a highly metastatic disease with a poor prognosis due to its resistance to current modes of therapy. SCLC cells appear to arise by oncogenic transformation of self-renewing pulmonary neuroendocrine cells, which have the potential to differentiate into a variety of lung epithelial cell lineages. Epithelial–mesenchymal conversion involved in such cell type transitions leads to the acquisition of an invasive and metastatic phenotype and may be critical for neoplastic progression and its eventual resistance to therapy. In order to investigate mechanisms involved in such transitions, a SCLC cell line was exposed to 5-bromodeoxyuridine. This treatment induced a dramatic conversion from non-substrate-adherent aggregates to monolayers of cells exhibiting an epithelioid phenotype. The phenotypic transition was concomitant with downregulation of vimentin, upregulation of cytokeratins, and cell–cell and cell–matrix adhesion molecules as well as redistribution of the actin cytoskeleton. The changes in the levels and organization of cell–cell and cell–matrix adhesion molecules were correlated with an in vivo loss of tumorigenicity.

Action of thyroid hormone in brain.

Among the most critical actions of thyroid hormone in man and other mammals are those exerted on brain development. Severe hypothyroidism during the neonatal period leads to structural alterations, including hypomyelination and defects of cell migration and differentiation, with long-lasting, irreversible effects on behavior and performance. A complex regulatory mechanism operates in brain involving regulation of the concentration of the active hormone, T3, and the control of gene expression. Most brain T3 is formed locally from its precursor, T4, by the action of type II deiodinase which is expressed in glial cells, tanycytes, and astrocytes. Type III deiodinase (DIII) is also involved in the regulation of T3 concentrations, especially during the embryonic and early post-natal periods. DIII is expressed in neurons and degrades T4 and T3 to inactive metabolites. The action of T3 is mediated through nuclear receptors, which are expressed mainly in neurons. The receptors are ligand-modulated transcription factors, and a number of genes have been identified as regulated by thyroid hormone in brain. The regulated genes encode proteins of myelin, mitochondria, neurotrophins and their receptors, cytoskeleton, transcription factors, splicing regulators, cell matrix proteins, adhesion molecules, and proteins involved in intracellular signaling pathways. The role of thyroid hormone is to accelerate changes of gene expression that take place during development. Surprisingly, null-mutant mice for the T3 receptors show almost no signs of central nervous system involvement, in contrast with the severe effects of hypothyroidism. The resolution of this paradox is essential to understand the role of thyroid hormone and its receptors in brain development and function.

Disturbance of endothelial barrier function by bacterial toxins and atherogenic mediators: a role for Rho/Rho kinase.

Disturbance of endothelial barrier function by bacterial toxins and atherogenic mediators: a role for Rho/Rho kinase.

PTP1B regulates neurite extension mediated by cell-cell and cell-matrix adhesion molecules.

N-cadherin and beta1-integrin adhesion and signaling play important roles in growth cone adhesion and guidance. Each of these adhesion receptor systems is composed of multiprotein complexes, and both adhesion and downstream signaling events are regulated through the interaction of protein tyrosine kinases and phosphatases with many of the proteins that make up these complex systems. Work from our laboratory reported that the nonreceptor protein tyrosine phosphatase PTP1B is localized to adherens junctions and focal adhesion complexes and regulates both N-cadherin- and beta1-integrin-mediated adhesion. PTP1B appears to modulate integrin-mediated adhesion through regulation of src activation and cadherin-mediated adhesion through dephosphorylation of beta-catenin. We have continued these studies and report that PTP1B is localized to the tips of growing neurites and that introduction of a noncatalytic mutant of PTP1B into PC12 cells results in inhibition of N-cadherin- and beta1-integrin-mediated neurite outgrowth but is without effect on neurite outgrowth on poly-L-lysine. Moreover, suppressing the level of PTP1B in primary embryonic chick neural retina cells using antisense oligonucleotides also inhibits N-cadherin- and beta1-integrin-mediated neurite outgrowth. Neither of these techniques reduces the levels of expression of either adhesion receptor. We conclude that PTP1B is a regulatory component of the molecular complex required for both N-cadherin and beta1-integrin-mediated axon growth.

Suppression of epithelial syndecan-1 expression by tumour necrosis factor-a

Background: Syndecan-I, a transmembrane heparan sulphate proteoglycan, is expressed on the basolateral surface of columnar epithelium where it functions as a cell-cell, cell-matrix adhesion molecule. Syndecan-I binds to a variety of matrix and heparin-binding growth factor molecules and is thought to play an important role during wound repair, where its expression is usually upregulated, by facilitating increased growth factor binding. In inflammatory bowel disease (ffiD) syndecan-l expression is reduced in areas of ulcerated mucosa, particularly in reparative epithelium. The mechanism causing reduced syndecan-l expression in ffiD is unknown. Aim: To investigate the regulatory effect of the pro-inflammatory cytokine tumour necrosis factor-a (TNF-a) on syndecan-I expression in the HT29 colonic epithelial cell line. Methods: Confluent monolayers of HT29 cells were stimulated with TNF-a (0.625, 0.125, 2.5, 5.0, 10, 25, 50 ng/ml) for 24 hours. Flow cytometry (FACS) and immunofluorescent microscopy using indirect immunostaining procedures were used to analyze syndecan-l protein expression. The mean fluorescent intensity (MFI) of syndecan-I staining in viable antibody labeled treated cells was compared with that of untreated control cells. All experiments were performed in triplicate. Modulation of syndecan-I expression at the RNA level was determined using RT-PCR. Results: Stimulation of HT29 monolayers with TNF-a resulted in down-regulation of syndecan-I at both the protein and RNA levels as revealed by FACS analysis and RT-PCR. Reduction of MFI ranged from 10% at 0.625 ng/ml to 64% at 50 ng/ml. Time course studies revealed that cells treated with 5 ng/ml TNF-a had a 2% reduction in MFI at 3-5 hours and a maximum reduction (-35%) at 13 hours. Immunofluorescence microscopy revealed a visible progressive reduction in membrane staining with increasing concentrations of TNF-a. No increase in cytoplasmic staining was observed at any concentration of TNF-a. Conclusions: Reduced syndecan-l expression is likely to impair mucosal healing due to diminished anti-ulcerogenic growth factor binding. These data show that TNF-a, a pro-inflammatory cytokine thought to have an etiological role in Crohn's disease, has a strong effect on the downregulation of syndecan-l expression. Such an effect may account for the apparently unique reduction of syndecan-I expression in ffiD.

Immunohistochemical analysis of cell-matrix adhesion molecules and their ligands in the portal tracts of primary biliary cirrhosis.

Intraepithelial migration of lymphoid cells (epitheliotropism) through the basement membrane of the bile duct is a key event in the development of chronic non-suppurative destructive cholangitis (CNSDC) and eventual immune-mediated bile duct loss in primary biliary cirrhosis (PBC). Cell-to-cell and cell-to-extracellular matrix proteins may play an important role in the development of CNSDC. To address the events of epitheliotropism in CNSDC, the expression of cell-matrix adhesion molecules such as integrins alpha1, alpha3, alpha4, alpha5, and alpha6 and the distribution of fibronectin, laminin, and collagen type IV were studied immunohistochemically, with emphasis on both infiltrating lymphocytes and the bile ducts, in frozen sections from 15 PBC cases and 34 controls (chronic viral hepatitis, extrahepatic biliary obstruction, and normal liver). In PBC and chronic viral hepatitis, most of the infiltrating lymphoid cells expressed integrin alpha4, while such expression was less common in extrahepatic biliary obstruction and normal liver. A biliary basement membrane-like structure was delineated by immunostaining of collagen type IV and laminin in PBC and controls. On the basement membrane of CNSDC, fibronectin, a ligand of integrin alpha4, was strongly and frequently expressed in PBC, while such expression on the biliary basement membrane was rare in other controls. These results suggest that increased fibronectin expression on the biliary basement membrane and integrin alpha4-fibronectin interaction facilitate adhesion and the penetration of infiltrating alpha4-expressing lymphocytes into the biliary epithelial layer in PBC.

Integrins and E‐cadherin cooperate with IGF‐I to induce migration of epithelial colonic cells

Although the detailed mechanisms of cell migration remain largely unknown, it is now clear that growth factors and cell adhesion molecules are crucial for this process. We have shown that type I insulin-like growth factor (IGF-I) promotes migration of human colonic tumour cells. Since morphological analysis suggested an involvement of adhesion molecules, we have now examined the role of integrins (cell-matrix adhesion molecules) and E-cadherin/catenins complex (cell-cell adhesion molecules) in the IGF-I-induced migration. Using a monolayer wounding assay, we have determined that, except for α2β1, all of the integrins expressed in HT29-D4 cells are involved in the induced cell migration. Immunofluorescence studies revealed that upon IGF-I stimulation the integrins reorganized at the leading edge of migrating cells. We also demonstrate that E-cadherin is involved in cell migration. A rapid tyrosine phosphorylation of E-cadherin and β-catenin was detected upon IGF-I stimulation. Tyrosine phosphorylation was associated with reduced membranous expression of E-cadherin and promotion of cell motility, suggesting a regulation of the E-cadherin/catenins complex. This effect can be reversed by incubating cells with tyrosine kinase inhibitors. Taken together, our results suggest that IGF-I promotes colonic cell migration through reorganization of integrin receptors and through modulation of E-cadherin/catenins complex function. Int. J. Cancer 83: 497–505, 1999. © 1999 Wiley-Liss, Inc.

Integrins and E-cadherin cooperate with IGF-I to induce migration of epithelial colonic cells.

Although the detailed mechanisms of cell migration remain largely unknown, it is now clear that growth factors and cell adhesion molecules are crucial for this process. We have shown that type I insulin-like growth factor (IGF-I) promotes migration of human colonic tumour cells. Since morphological analysis suggested an involvement of adhesion molecules, we have now examined the role of integrins (cell-matrix adhesion molecules) and E-cadherin/catenins complex (cell-cell adhesion molecules) in the IGF-I-induced migration. Using a monolayer wounding assay, we have determined that, except for alpha2beta1, all of the integrins expressed in HT29-D4 cells are involved in the induced cell migration. Immunofluorescence studies revealed that upon IGF-I stimulation the integrins reorganized at the leading edge of migrating cells. We also demonstrate that E-cadherin is involved in cell migration. A rapid tyrosine phosphorylation of E-cadherin and beta-catenin was detected upon IGF-I stimulation. Tyrosine phosphorylation was associated with reduced membranous expression of E-cadherin and promotion of cell motility, suggesting a regulation of the E-cadherin/catenins complex. This effect can be reversed by incubating cells with tyrosine kinase inhibitors. Taken together, our results suggest that IGF-I promotes colonic cell migration through reorganization of integrin receptors and through modulation of E-cadherin/catenins complex function.

BP180/type XVII collagen: its role in acquired and inherited disorders or the dermal-epidermal junction.

BP180 is a member of the collagen protein family and is also referred to as type XVII collagen or BP antigen 2. It is a transmembrane protein constituent of the dermal-epidermal anchoring complex. The long-held hypothesis that BP180 functions as a cell-matrix adhesion molecule has been supported by recent investigations of human disorders of the dermal-epidermal junction in which BP180 is either genetically defective or targeted by the immune system. In generalized atrophic benign epidermolysis bullosa, mutations of BP180 result in an inherited subepidermal blistering disease. In bullous pemphigoid, herpes/pemphigoid gestationis, cicatricial pemphigoid, lichen planus pemphigoides and linear IgA disease, autoantibodies are directed to different epitopes on the BP180 ectodomain. Recent molecular investigations have provided new insights, not only into the mechanism of autoantibody-mediated subepidermal blistering, but also into the biochemical structure and cell biological functions of BP180 and other components of the dermal-epidermal anchoring complex. These findings have suggested new directions for the development of diagnostic and therapeutic tools for these autoimmune and genetic diseases.

The internal and external protein scaffold of the T-tubular system in cardiomyocytes.

The transverse tubule system of the cardiomyocyte remains undeformed despite the extreme forces it undergoes during the contraction-relaxation cycle, but the morphological basis for its stability remains unclear. Therefore, we have investigated the architecture and subcellular protein scaffold of the cardiac T-tubules and compared it with that of the costameres and of the free sarcolemma. Tissue samples from normal rat and monkey hearts, and left ventricular tissue from normal and cardiomyopathic human hearts obtained at transplantation surgery were investigated using immunocytochemistry and confocal microscopy and by electron microscopy. In addition, we used a re-differentiation model of isolated, cultured adult rat cardiomyocytes. The cell membrane of the cardiac T-tubules was found to contain the cell-matrix focal adhesion molecules (FAMs) vinculin, talin, the alpha5beta1 integrin and the membrane-associated proteins (MAPs) dystrophin and spectrin. FAMs and MAPs were localized in the T-tubular membrane in a similar pattern: in longitudinally oriented myocytes as transverse punctate lines at the Z-level; in transversally cut myocytes a radial tubular network was found to extend throughout the interior of the cell. Immunolabeling for basement membrane components including collagen IV, fibronectin and laminin showed a colocalization with FAMs and MAPs parallel to the transverse T-tubules. The costameres of the sarcolemma showed a protein composition resembling that of the T-tubules but the intervening segments of free sarcolemma showed absence of FAMs and presence of MAPs. For the first time, we demonstrate the existence and protein composition of the T-tubular scaffold in the human heart. Furthermore, we show that cardiomyocytes from human failing hearts have less abundant but more dilated T-tubules than do experimental animals. These results indicate that the cardiac T-tubular system contains a subcellular scaffold closely resembling that of the costameres. It consists of FAMs, MAPs and basal lamina proteins that confer structural integrity to the cardiac T-tubular membrane during contraction/relaxation cycles.

Cellular and molecular partners involved in gut morphogenesis and differentiation.

The intestinal mucosa represents an interesting model to study the cellular and molecular basis of epithelial-mesenchymal cross-talk participating in the development and maintenance of the digestive function. This cross-talk involves extracellular matrix molecules, cell-cell and cell-matrix adhesion molecules as well as paracrine factors and their receptors. The cellular and molecular unit is additionally regulated by hormonal, immune and neural inputs. Such integrated cell interactions are involved in pattern formation, in proximodistal regionalization, in maintenance of a gradient of epithelial proliferation and differentiation, and in epithelial cell migration. We focus predominantly on two aspects of these integrated interactions in this paper: (i) the role of basement membrane molecules, namely laminins, in the developmental and spatial epithelial behaviour; and (ii) the importance of the mesenchymal cell compartment in these processes.

T-cadherin and signal-transducing molecules co-localize in caveolin-rich membrane domains of vascular smooth muscle cells

Cadherins are a family of cellular adhesion proteins mediating homotypic cell-cell binding. In contrast to classical cadherins, T-cadherin does not possess the transmembrane and cytosolic domains known to be essential for tight mechanical coupling of cells, and is instead attached to the cell membrane by a glycosylphosphatidylinositol (GPI) anchor. This study explores the hypothesis that T-cadherin might function as a signal-transducing protein. Membranes from human and rat vascular smooth muscle cells were fractionated using Triton X-100 solubilization and density gradient centrifugation techniques. We demonstrate that T-cadherin is enriched in a minor detergent-insoluble low-density membrane domain and co-distributes with caveolin, a marker of caveolae. This domain was enriched in other GPI-anchored proteins (CD-59, uPA receptor) and signal-transducing molecules (Gαs protein and Src-family kinases), but completely excluded cell-cell and cell-matrix adhesion molecules (N-cadherin and β1-integrin). Coupling of T-cadherin with signalling molecules within caveolae might enable cellular signal transduction.

Cleavage of BP180, a 180-kDa Bullous Pemphigoid Antigen, Yields a 120-kDa Collagenous Extracellular Polypeptide

The hemidesmosome (HD) is a cell-to-substrate adhesion apparatus found in stratified and complex epithelia. One of the putative cell-matrix adhesion molecules present in the HD is the 180-kDa bullous pemphigoid antigen (BP180), also termed type XVII collagen. In our previous study, using a monoclonal antibody (mAb) 1337, we have detected a 120-kDa collagenase-sensitive polypeptide in the HD fraction (Uematsu, J. and Owaribe, K. (1993) Cell Struct. Funct. 18, 588 (abstr.)). The present study was undertaken to assess the relation of the 120-kDa polypeptide to this BP180. Immunofluorescence microscopy of bovine skin revealed the basement membrane zone of skin to be stained clearly with mAb 1337, whereas the lateral surfaces of basal cells, which were decorated by typical antibodies against BP180, were not. The antibody did not detect HDs in cultured cells but rather in the culture medium. These results indicate a localization of mAb 1337 antigen distinct from BP180. However, the same polypeptide was also recognized by monoclonal antibodies to the extracellular but not the cytoplasmic part of BP180, and found to react with a polyclonal antibody against the non-collagenous 16A domain of BP180. Therefore, the polypeptide was identified as an extracellular fragment of BP180. mAb 1337 immunoprecipitated the 120-kDa fragment from the medium, but not the 180-kDa molecule of BP180 extracted from cultured cells, indicating that the antibody specifically recognizes the fragment. The mAb 1337 apparently recognizes a unique epitope that is exposed or formed by the cleavage. Hence, the staining pattern observed for bovine skin demonstrated the presence of the 120-kDa extracellular fragment. Rotary shadow electron microscopy of affinity-purified 120-kDa fragments demonstrated that they have the unique molecular shape consisting of a central rod and a flexible tail, without the globular head that is present in the BP180 molecule. From these results, we conclude that mAb 1337 shows unique epitope specificity, recognizing only the 120-kDa extracellular fragment of BP180, which is constitutively cleaved on the cell surface as a 120-kDa fragment both in in vivo and in vitro.

Expression of cell adhesion molecules by microvascular endothelial cells in the cortical and subcortical regions of the normal human brain: an immunohistochemical analysis

We studied the repertoire of junctional, cell-matrix and leucocyte-endothelial adhesion molecules normally expressed by cortical and subcortical brain microvessels, as compared with large intracranial vessels. An indirect immunoperoxidase method was applied to acetone-fixed cryostat sections of normal brain tissue obtained from 10 adult patients during surgical resections for intracranial aneurysms or at autopsy. Like large intracranial vessels, brain microvessels expressed the two endothelial-specific junctional cell adhesion molecules VE-cadherin and platelet-cell adhesion molecule-1. We verified that they also expressed the molecular components of adherens-type junctions, including catenins, plakoglobin, vinculin and alpha-actinin. Brain microvessels expressed a large repertoire of integrin molecules of the beta 1, beta 3 and beta 4 subfamilies. However, they displayed apparently lower levels of alpha 2, alpha 5, alpha V and beta 3 integrin chains than large intracranial vessels. Brain microvessels constitutively expressed large amounts of the leucocyte-endothelial adhesion molecules, intercellular adhesion molecule (ICAM)-2 and CD34 and very low amounts of ICAM-1 and lymphocyte function-associated antigen-3. In contrast to large intracranial vessels, brain microvessels presented no constitutive expression of P-selectin. Our study shows that, in contrast to their highly specific structural and functional characteristics, brain microvascular endothelial cells present a repertoire of cell adhesion molecules very similar to that of most other capillary vessels in the body.

Fibrolamellar carcinoma of the liver: composition of the extracellular matrix and expression of cell-matrix and cell-cell adhesion molecules.

We have analyzed the composition of the tumor stroma and the expression of cell-matrix and cell-cell adhesion molecules in 11 cases of fibrolamellar carcinoma of the liver (FLC), in comparison with 34 cases of hepatocellular carcinoma and 8 cases of focal nodular hyperplasia. Fibrolamellar carcinoma was characterized by the presence of large amounts of tenascin in tumor stroma and by the scarce expression of basement membrane components at the contact of neoplastic clusters. Like normal hepatocytes, neoplastic cells constantly expressed the alpha1 integrin chain, lacked the beta4 integrin chain, and coexpressed E-cadherin and the hepatocyte N-related cadherin. Abnormalities in the expression of cell adhesion molecules, including altered cadherin expression, alphaV integrin chain induction, and CD44 expression, were detected in the majority of cases. The composition of the tumor stroma and the pattern of expression of cell adhesion molecules in fibrolamellar carcinoma were reminiscent of those observed in grade III and grade IV hepatocellular carcinomas. Our results therefore show that, despite its slow local growth and good prognosis, fibrolamellar carcinoma expresses many characteristics usually associated with clinically aggressive malignancies. Further studies are needed to identify the factors responsible for the apparent dissociation between clinical behavior and biological characteristics in this tumor.

Fibrolamellar carcinoma of the liver: Composition of the extracellular matrix and expression of cell-matrix and cell-cell adhesion molecules

We have analyzed the composition of the tumor stroma and the expression of cell-matrix and cell-cell adhesion molecules in 11 cases of fibrolamellar carcinoma of the liver (FLC), in comparison with 34 cases of hepatocellular carcinoma and 8 cases of focal nodular hyperplasia. Fibrolamellar carcinoma was characterized by the presence of large amounts of tenascin in tumor stroma and by the scarce expression of basement membrane components at the contact of neoplastic clusters. Like normal hepatocytes, neoplastic cells constantly expressed the alpha1 integrin chain, lacked the beta4 integrin chain, and coexpressed E-cadherin and the hepatocyte N-related cadherin. Abnormalities in the expression of cell adhesion molecules, including altered cadherin expression, alphaV integrin chain induction, and CD44 expression, were detected in the majority of cases. The composition of the tumor stroma and the pattern of expression of cell adhesion molecules in fibrolamellar carcinoma were reminiscent of those observed in grade III and grade IV hepatocellular carcinomas. Our results therefore show that, despite its slow local growth and good prognosis, fibrolamellar carcinoma expresses many characteristics usually associated with clinically aggressive malignancies. Further studies are needed to identify the factors responsible for the apparent dissociation between clinical behavior and biological characteristics in this tumor. (Hepatology 1996 Nov;24(5):1128-36)

Cellular adhesion molecules and components of the extracellular matrix as target structures of autoimmunity

Cell-cell and cell-matrix adhesion molecules as well as extracellular matrix components are target structures of antibody-mediated autoimmunity that have recently been well characterized at the molecular biological level. Pathogenic autoantibodies against these molecules are causally related to disturbances of cell and tissue adhesion that become apparent as various (muco-)cutaneous blistering diseases. Desmosomal cadherins (desmogleins and desmocollins) mediate epidermal intercellular adhesion. Among these, desmoglein 1 and desmoglein 3 are the autoantigens of pemphigus foliaceus and pemphigus vulgaris, respectively, exhibiting intraepidermal blistering. The pathogenic relevance of autoantibodies against desmocollins. (IgA pemphigus) and desmoplakins (paraneoplastic pemphigus) still remains unclear. Hemidesmosomes contain the plaque protein BPAG1 and the partly collagen-like transmembrane protein BPAG2, representing the autoantigens of bullous pemphigoid and pemphigoid gestationis with subepidermal blistering. A certain subtype of cicatricial (benign mucous membrane) pemphigoid is characterized by autoantibodies against laminin 5 present in the subhemidesmosomal anchoring filaments, while epidermolysis bullosa acquisita and bullous SLE exhibit autoantibodies against collagen type VII constituting the anchoring fibrils. In addition, autoantibodies against a particular collagen type IV chain of the glomerular basement membrane are responsible for the manifestation of Goodpasture's syndrome. These recent molecular biological findings might be the basis for the development of novel therapeutic strategies.

Focal nodular hyperplasia of the liver: Composition of the extracellular matrix and expression of cell-cell and cell-matrix adhesion molecules

We studied by immunohistochemistry 25 cases of focal nodular hyperplasia (FNH) to evaluate the composition of the extracellular matrix and the expression and distribution of endothelial cell-cell adhesion molecules and integrin receptors. The extracellular matrix of FNH retained the overall organization of that of normal liver. The matrix of central scars resembled that of portal tracts. The main difference was the presence of large vitronectin deposits, which might indicate the existence of local hemodynamic disturbances. The matrix lining the sinusoid-like vessels running in the hyperplastic parenchyma retained characteristic features of the normal perisinusoidal matrix, such as the presence of tenascin. In the zone surrounding the central scars, it contained large amounts of laminin, von Willebrand factor, and thrombospondin, suggesting the development of perisinusoidal fibrosis. Laminin deposition was accompanied by the induction of cell-cell adhesion molecules on adjacent endothelial cells and by the up-regulation of specific integrin receptors on both hepatocytes and sinusoidal endothelial cells. In conclusion, our study: (1) reinforces the hypothesis that FNH is merely a hyperplastic response of liver parenchyma to local vascular abnormalities, and (2) shows that the lesions of perisinusoidal fibrosis associated with FNH are accompanied by the induction of integrin receptors on hepatocytes and sinusoidal endothelial cells.