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PubMed1996

Alpha 6 beta 4 integrin and newly deposited laminin-1 and laminin-5 form the adhesion mechanism of gastric carcinoma. Continuous expression of laminins but not that of collagen VII is preserved in invasive parts of the carcinomas: implications for acquisition of the invading phenotype.

We studied the expression and distribution of different laminin chains, the alpha 6 beta 4 integrin and type VII collagen, i.e., components of the epithelial adhesion complex, in gastric carcinomas and in suggested preneoplastic stages of this malignancy. Intestinal-type gastric carcinomas showed strong reactivity for laminin alpha 1, alpha 3, beta 1, and beta 3 chains, the components of laminin-1 and -5, at the interface between malignant cells and tumor stroma. The reactivities were continuous throughout the carcinomas, even in structures invading through the smooth muscle layers of the gastric wall. The expression of different laminin chains was accompanied by strong polarized reactivity for the alpha 6 beta 4 integrin, which is a receptor for both laminin-1 and laminin-5. Collagen type VII was only occasionally present at sites showing reactivity for laminin-5 and was totally absent from the cell islands invading through the gastric wall. Intestinalized gastric epithelium showed a similar expression pattern of laminins and the alpha 6 beta 4 integrin as the gastric carcinomas. Our results suggest that gastric carcinomas use the alpha 6 beta 4 integrin and newly deposited laminin-1 and -5, accompanied by the disappearance of type VII collagen, as their mechanism of adhesion during the invasion through surrounding tissues. Unlike in previous studies, the reactivity for the laminin-5 protein was not restricted to the invading cells but surrounded the malignant glandular structures throughout the tumor. Our results also show that both intestinal-type gastric carcinoma, and intestinal metaplasia mimic the gastric surface epithelium in the expression pattern of laminins and the beta 4 integrin subunit. This supports previous studies proposing a pathogenetic sequence from intestinal metaplasia to gastric carcinoma.

Antigens, Surface↗
PubMed1997

Type XVII collagen (BP 180) in the developing avian cornea.

PURPOSE: Previous sequence analyses of hemidesmosomal BP 180/collagen XVII cDNA from human skin and of a similar chicken corneal cDNA showed some similarities, but major differences as well. The authors examined whether, in one species, the same mRNA is present in cornea and skin. They also studied the developmental expression of the molecule and compared it to the transmembrane hemidesmosome component, alpha 6 beta 4 integrin, and to the formation of hemidesmosomes themselves. METHODS: Cornea and skin BP 180/collagen XVII cDNAs were cloned by reverse transcription-polymerase chain reaction (RT-PCR) and sequenced. Developmental expression was evaluated by quantitative RT-PCR, immunoblotting, and immunofluorescence microscopy. alpha 6 beta 4 integrin was evaluated by immunofluorescence microscopy, and hemidesmosome formation was assessed by electron microscopy. RESULTS: The same alpha 1 (XVII) collagen/BP 180 mRNA is present in cornea and skin. The appearance of alpha 1 (XVII) collagen mRNA and protein shows similar temporal patterns of expression, with changes in the mRNA preceding those of the protein by approximately 2 days. The appearance of mature hemidesmosomes lags still further. Immunofluorescence histochemistry of alpha 1 (XVII) collagen and alpha 6 beta 4 integrin shows that their developmental appearance is regulated closely. CONCLUSIONS: The differences between human BP 180/collagen XVII and the chicken corneal molecule represent species divergence. The appearance of alpha 1 (XVII) collagen mRNA and protein is regulated closely, with the protein lagging. Mature hemidesmosomes, once present, have a low turnover rate. The developmental appearance of alpha 1 (XVII) collagen and alpha 6 beta 4 integrin are regulated closely. However, the component responsible for initiating hemidesmosome formation remains unknown.

Animals↗
PubMed1997

The basement membrane zone in lichen sclerosus: an immunohistochemical study.

The alteration in expression of basement membrane zone (BMZ) components in lichen sclerosus was investigated by immunohistochemical staining of skin biopsies from seven patients with histologically confirmed disease compared with controls. Monoclonal antibodies and polyclonal sera directed against proteins of the hemidesmosomes, anchoring fibrils, lamina lucida, lamina densa and BMZ collagens were used. Characteristic histological appearances at the dermo-epidermal junction were reflected in widespread alterations in antigen expression in the epidermal basement membrane and the papillary dermis. Expression of the proteins which constitute the structural scaffold (collagen IV and VII) were increased in lichen sclerosus. Expression of hemidesmosomal proteins which mediate adhesion and cell to matrix interaction (alpha 6 beta 4 and bullous pemphigoid antigen) and expression of anchoring filament components were markedly reduced, suggesting that the epidermal cells are exposed to selective damage.

Antibodies, Monoclonal↗
PubMed1997

Physicochemical characterization and differentiation of the components of the cutaneous basement membrane zone.

Many of the techniques used in the diagnosis and characterization of the acquired blistering diseases of the skin and of their target antigens require the use of tissue that has been modified by heat, chemicals, or by proteolytic digestion. The effect these treatments may have on the blistering disease antigens is poorly understood and has seldom been taken into account in the interpretation of the results. Likewise, their effect on the immunodetection and expression of the ubiquitous proteins of the basement membrane zone and extracellular matrix has rarely been investigated. We have addressed this problem by probing tissue split after heat, chemical treatment and proteolytic digestion with an extensive panel of antibodies to the hemidesmosome-plasma membrane-anchoring filament complex, the extracellular matrix and the anchoring fibrils. The results showed that chemical modification by sodium chloride, calcium chloride and ethylenediaminetetraacetic acid, and incubation in 0.15 mol/L NaCl at 56 degrees C for 1 min did not adversely affect the expression of the alpha 6 beta 4 integrin, laminin-5, the LH39 antigen, laminin-1, collagen type IV or collagen type VII. The methods that involved proteolytic digestion had the greatest detrimental effect on these basement membrane components, with pepsin having a damaging effect on the greatest number of antigens, and the LH39 antigen being the most sensitive to proteolytic degradation. This project has highlighted the susceptibility of the basement membrane zone and extracellular matrix proteins to proteolytic hydrolysis. It has demonstrated a way of differentiating between specific proteins, and has shown its potential for the differential diagnosis of the autoimmune blistering disease antigens.

Antigens, Surface↗
PubMed1998

Prognostic value of alpha 6 beta 4 integrin expression in breast carcinomas is affected by laminin production from tumor cells.

Immunocytochemical analysis of breast carcinoma specimens for alpha 6 beta 4 integrin expression and other different pathobiological markers revealed beta 4 integrin subunit expression in 36 of 80 cases analyzed and a significant association only with alpha 6 integrin subunit expression (P < 0.01) and laminin production (P = 0.01) by tumor cells. Survival analysis indicated that beta 4 and alpha 6 expression are associated with poor prognosis (P = 0.02), whereas laminin production showed only borderline association (P = 0.06). However, analysis of disease outcome in relation to expression of both alpha 6 beta 4 and laminin indicated best outcomes for patients with tumors producing laminin but not expressing alpha 6 beta 4 integrin, whereas worst outcomes were observed for alpha 6 beta 4- and laminin-positive tumors, indicating that alpha 6 beta 4 expression was associated with prognosis, mainly in the laminin-producing tumor subset. These data indicate that the prognostic value of alpha 6 beta 4 integrin expression is affected by laminin production from tumor cells and suggest that interaction between these two molecules mediates distinct signals that are important for tumor progression.

Antigens, Surface↗
PubMed1998

Topical retinoic acid reduces skin papilloma formation but resistant papillomas are at high risk for malignant conversion.

Retinoic acid (RA) was topically applied to the skin of Sencar mice during the promotion phase of specific tumor induction protocols that produce papillomas at low (12-O-tetradecanoylphorbol-13-acetate promoted, TPA) or high (mezerein-promoted) risk for premalignant progression and malignant conversion. RA consistently reduced the yield of papillomas and carcinomas in both protocols, but the frequency of malignant conversion in papillomas that emerged during RA treatment was not reduced. When TPA was reapplied after cessation of RA treatment, the number of papillomas increased 2-fold, suggesting that RA had not eliminated initiated cells. In vitro, RA prevented the emergence of transformed keratinocytes in an assay that mimics malignant conversion, suggesting that RA can suppress conversion if applied during the stage of premalignant progression. Examination of tumor markers at weeks 14 and 22 of the tumor-induction experiments in vivo indicated that papillomas evolving during RA treatment exhibited a phenotype of high progression risk, even in the TPA-promoted groups. In the majority of these tumors, the alpha6beta4 integrin and retinoid X receptor alpha transcripts were detected suprabasally, indicating an advanced state of premalignant progression. RA-treated tumors also expressed higher levels of transcripts for transforming growth factor (TGF)-beta1 and localized TGF-beta1 peptide in the basal portions of the tumor fronds. Because up-regulated expression of TGF-beta1 suppresses papilloma formation, these studies suggest a mechanism whereby RA can prevent papilloma eruption via a TGF-beta intermediate, but papillomas resistant to RA may have altered TGF-beta signaling and progress to carcinomas at an increased frequency.

Administration, Topical↗
PubMed1996

Differential regulation of integrins and extracellular matrix binding in epidermal differentiation and squamous tumor progression.

Cell surface receptors of the integrin family regulate physiological and pathological processes in skin, including proliferation, differentiation, and malignant transformation. In skin, integrins are compartmentalized. While alpha 6 beta 4 is restricted to the basal surface of basal cells, beta 1 integrins are expressed in basal and suprabasal layers. In vivo and in Ca(2+)-induced differentiation of mouse keratinocytes in vitro, the loss of attachment to laminin via alpha 6 beta 4 integrin is an early event associated with initiation of spinous differentiation. The restricted expression of alpha 6 beta 4 to the basal cells in normal skin is disrupted early in the development of squamous cancer, where benign papillomas at high risk for malignant progression express alpha 6 beta 4 suprabasally in an expanded proliferative compartment. The aberrant suprabasal alpha 6 beta 4 is associated with reduced keratin 1 expression and upregulation of keratin 13, keratin 8, and gamma-glutamyltranspeptidase. During malignant conversion, the increase in alpha 6 beta 4 protein and mRNA is associated with novel expression of an alternatively spliced form of the alpha 6 subunit, alpha 6B. The induction of alpha 6B both in vivo and in vitro is particularly high in malignant cells produced by transduction of both v-fos and v-rasHa oncogenes into normal keratinocytes where it was associated with increased attachment to laminin. Furthermore, binding to laminin is increased by introduction of alpha 6B into a papilloma cell line. These results establish a link between squamous tumor progression and the upregulation of the alpha 6 beta 4 integrin and suggest that expression of alpha 6B could be functionally relevant to interaction of tumor cells with the laminin matrix during malignant conversion.

Animals↗
PubMed1998

Thymocyte contact or monoclonal antibody-mediated clustering of 3beta1 or 6beta4 integrins activate interleukin-6 (IL-6) transcription factors (NF-kappaB and NF-IL6) and IL-6 production in human thymic epithelial cells.

T-cell precursors develop within the thymus in contact with multiple supportive elements, among which thymic epithelial cells (TEC) are known to exert a dominant role in their homing, survival, and functional differentiation. All these functions are supported by cell-cell contacts and cytokine release. Signaling events triggered in lymphoid cells by adhesion to TEC are well characterized, but little is known about the opposite phenomenon. To address this issue, we derived cultures of TEC from human normal thymus. TEC monolayers were cocultured with thymocytes and immunostained with monoclonal antibodies (MoAbs) to integrin (2, 3, 4, and 6) and beta (beta1 and beta4) chains. Optical and confocal analysis showed that integrins were polarized on TEC at discrete surface locations: 6beta4 lined the basal surface of TEC monolayers, whereas 3beta1 was found mostly at TEC-TEC contacts; it is noteworthy that both 3beta1 and 6beta4 became highly enriched also at the boundaries with adherent thymocytes. Functional studies performed with MoAbs anti-beta1 and -beta4 integrins showed that beta1, and, to a much lower extent, beta4 heterodimers are involved in the TEC-thymocyte adhesion. Thymocyte contact or MoAb-mediated ligation of 3, 6, beta1, and beta4 integrins was investigated as a potential inducer of intracellular signaling in TEC. Thymocyte adhesion or cross-linking of MoAbs bound to integrins clustered at the TEC/thymocyte contact sites led to activation of interleukin-6 (IL-6) gene transcription factors, namely NF-IL6 serine phosphorylation and NF-kappaB nuclear targeting, as well as to increased IL-6 secretion. We propose that integrin clustering occurring during TEC-thymocyte contacts modulates in TEC the gene expression of a cytokine involved in thymocyte growth and functional differentiation.

Antibodies, Monoclonal↗
PubMed2000

The functions of exogenous and endogenous laminin-5 on corneal epithelial cells.

Recent evidence suggests that the basement membrane not only separates basal cells from Bowman's layer, but also has a crucial role in the proliferation, differentiation and migration of corneal epithelial cells. The basement membrane is composed of a mixture of matrix components including collagens, laminins and heparan sulfate proteoglycans. In these extracellular matrixes, laminin is a major component of the basement membrane. Of 11 laminin isoformes, laminin-5 is a variant, composed of three nonidentical subunits alpha3, beta3, gamma2 and is a major component of the corneal basement membrane. However, little is known about the interactions of laminin-5 with corneal epithelial cells. In this study, we investigated the functions of laminin-5 on SV-40 transfected human corneal epithelial cells (HCE cells). We also revealed different functions between exogenous and endogenous laminin-5 on HCE cells. Laminin-5 is synthesized initially as a 490 kDa molecule that undergoes specific processing to cleavaged isoforms after being secreted. The alpha3 subunit is processed from 200-190 kDa to 160 kDa/145 kDa. The gamma2 subunit is processed from 150 kDa to 105 kDa/80 kDa. The beta3 subunit (140 kDa) is not processed. Exogenously added laminin-5 (soluble form) in this study was purified from a serum-free, conditioned medium of a human gastric carcinoma cell line STKM-I. This soluble laminin is a processed isoform containing alpha3 (160 kDa), beta3 (140 kDa) and gamma2 (105 kDa) chains. On the other hand, immunocytochemical analysis showed that HCE cells themselves secreted laminin-5 endogenously. Western blotting analysis revealed that HCE cells initially produced unprocessed isoform containing 190 kDa alpha3, 140 kDa beta3 and 150 kDa gamma2 chains and that after being secreted, the alpha3 chain was processed to 160 kDa/145 kDa and the gamma2 chain was processed to 105 kDa. Initially we investigated the functions of exogenous (processed) laminin-5 on HCE cells. Exogenously added laminin-5 strongly promoted cell adhesion via alpha3beta1 integrin, cell spreading, assembly of hemidesmosomes and mildly inhibited cell migration. Next we estimated the effect of endogenous (unprocessed) laminin-5 on HCE cells. Using an anti laminin-5 monoclonal antibody (mAb) or anti integrin alpha3beta1 mAbs, the blocking of the interaction between endogenously secreted laminin-5 and HCE cells caused strong inhibition of cell migration. Integrin alpha3beta1 and alpha6beta4 were expressed in HCE cells. These integrins are receptors of laminin-5. But, anti integrin alpha6beta4 mAbs did not have any blocking ability against cell migration. These results indicated that endogenous (unprocessed) laminin-5 has a crucial role in cell migration on HCE cells via alpha3beta1 integrin. In conclusion, structural differences between exogenous (processed) and endogenous (unprocessed) laminin-5 regulated their functions on HCE cells. Exogenously added laminin-5 strongly promoted cell adhesion, cell spreading and assembly of hemidesmosomes. Endogenously secreted laminin-5 had a crucial role in cell migration. In the future, processed soluble laminin-5 could be a useful drug for the prevention of recurrent corneal erosion, and unprocessed soluble laminin-5 could be applied for the treatment of prolonged corneal epithelial defects.

Blotting, Western↗
PubMed1998

Endothelial cells assemble two distinct alpha6beta4-containing vimentin-associated structures: roles for ligand binding and the beta4 cytoplasmic tail.

The alpha6beta4 laminin binding integrin functions in the assembly of type I hemidesmosomes, which are specialized cell-matrix adhesion sites found in stratified epithelial cells. Although endothelial cells do not express all the components of type I hemidesmosomes, endothelial cells can express the alpha6beta4 integrin. Because endothelial cells lose expression of alpha6beta4 in culture, we expressed recombinant alpha6beta4 in the dermal microvascular endothelial cell line, HMEC-1, to test whether endothelial cells can assemble adhesion structures containing alpha6beta4. Using immunofluorescence microscopy, we found that recombinant alpha6beta4 concentrates specifically in a novel fibrillar structure on the basal surface of endothelial cells in the absence of an exogenous laminin substrate. This localization is regulated by an intracellular mechanism, because the beta4 cytoplasmic domain is sufficient to direct a reporter domain (IL-2R) to the fibrillar structures independently of recombinant alpha6beta4. In addition, this IL-2R-beta4 chimera is sufficient to recruit the intermediate filament-associated protein HD1/plectin to these fibrillar structures and this also occurs in the absence of recombinant alpha6beta4. The fibrillar localization pattern, as well as the recruitment of HD1/plectin, requires the first and second fibronectin type III repeats and the connecting segment of the beta4 tail. In addition, when endothelial cells are provided a laminin 5-rich matrix, recombinant alpha6beta4 redistributes from the fibrillar structure to type I hemidesmosome-like structures. The beta4 cytoplasmic domain can also direct a reporter domain to these type I hemidesmosome-like structures; however, this process is dependent upon the expression of recombinant alpha6beta4 Biochemical analysis indicates that both the fibrillar and the type I hemidesmosome-like structures are associated with the vimentin intermediate filament cytoskeleton. Thus, the results illustrate that endothelial cells have the essential components necessary to assemble at least two distinct alpha6beta4-containing and vimentin-associated structures on their basal surface and that the alpha6beta4 cytoplasmic tail and the availability of specific alph6beta4 ligands regulate receptor localization to these structures.

Antigens, Surface↗
PubMed2001

Rapid loss of microvascular integrin expression during focal brain ischemia reflects neuron injury.

The integrity of cerebral microvessels requires the close apposition of the endothelium to the astrocyte endfeet. Integrins alpha1beta1 and alpha6beta4 are cellular matrix receptors that may contribute to cerebral microvascular integrity. It has been hypothesized that focal ischemia alters integrin expression in a characteristic time-dependent manner consistent with neuron injury. The effects of middle cerebral artery occlusion (MCAO) and various periods of reperfusion on microvasclar integrin alpha1beta1 and alpha6beta4 expression were examined in the basal ganglia of 17 primates. Integrin subunits alpha1 and beta1 colocalized with the endothelial cell antigen CD31 in nonischemic microvessels and with glial fibrillary acidic protein on astrocyte fibers. Rapid, simultaneous, and significant disappearance of both integrin alpha1 and beta1 subunits and integrin alpha6beta4 occurred by 2 hours MCAO, which was greatest in the region of neuron injury (ischemic core, Ic), and progressively less in the peripheral (Ip) and nonischemic regions (N). Transcription of subunit beta1 mRNA on microvessels increased significantly in the Ic/Ip border and in multiple circular subregions within Ic. Microvascular integrin alpha1beta1 and integrin alpha6beta4 expression are rapidly and coordinately lost in Ic after MCAO. With loss of integrin alpha1beta1, multiple regions of microvascular beta1 mRNA up-regulation within Ic suggest that microvessel responses to focal ischemia are dynamic, and that multiple cores, not a single core, are generated. These changes imply that microvascular integrity is modified in a heterogeneous, but ordered pattern.

Animals↗
PubMed2005

Targeted deletion of the integrin beta4 signaling domain suppresses laminin-5-dependent nuclear entry of mitogen-activated protein kinases and NF-kappaB, causing defects in epidermal growth and migration.

The alpha6beta4 integrin-a laminin-5 receptor-mediates assembly of hemidesmosomes and recruitment of Shc and phosphoinositide 3-kinase through the unique cytoplasmic extension of beta4. Mice carrying a targeted deletion of the signaling domain of beta4 develop normally and do not display signs of skin fragility. The epidermis of these mice contains well-structured hemidesmosomes and adheres stably to the basement membrane. However, it is hypoplastic due to reduced proliferation of basal keratinocytes and undergoes wound repair at a reduced rate. Keratinocytes from beta4 mutant mice undergo extensive spreading but fail to proliferate and migrate in response to epidermal growth factor (EGF) on laminin-5. EGF causes significant phosphorylation of extracellular signal-regulated kinase (ERK) and Jun N-terminal protein kinase (JNK) and phosphorylation and degradation of IkappaB in beta4 mutant cells adhering to laminin-5. Unexpectedly, however, ERK, JNK, and NF-kappaB remain in the cytoplasm in beta4 mutant cells on laminin-5, whereas they enter effectively into the nucleus in the same cells on fibronectin or in wild-type cells on both matrix proteins. Inhibitor studies indicate that alpha6beta4 promotes keratinocyte proliferation and migration through its effect on NF-kappaB and P-JNK. These findings provide evidence that beta4 signaling promotes epidermal growth and wound healing through a previously unrecognized effect on nuclear translocation of NF-kappaB and mitogen-activated protein kinases.

Active Transport, Cell Nucleus↗
PubMed2001

Integrin laminin receptors and breast carcinoma progression.

This review explores the mechanistic basis of breast carcinoma progression by focusing on the contribution of integrins. Integrins are essential for progression not only for their ability to mediate physical interactions with extracellular matrices but also for their ability to regulate signaling pathways that control actin dynamics and cell movement, as well as for growth and survival. Our comments center on the alpha6 integrins (alpha6beta1 and alpha6beta4), which are receptors for the laminin family of basement membrane components. Numerous studies have implicated these integrins in breast cancer progression and have provided a rationale for studying the mechanistic basis of their contribution to aggressive disease. Recent work by our group and others on mechanisms of breast carcinoma invasion and survival that are influenced by the alpha6 integrins are discussed.

Antigens, Neoplasm↗
PubMed2005

Integrins adhesion molecules and some of their ligands in laryngeal cancer.

In this review data regarding the regular expression and distribution of integrins adhesion molecules as well as some of their ligands in cases of squamous cell carcinoma of the larynx (LSCC) are discussed. Cancer of the larynx is one of the most common malignancies of the head and neck. Upon neoplastic transformation several alterations of the integrins adhesion molecules and extracellular matrix (ECM) components are observed, i.e. the loss of the normal architecture especially depolarization of some integrins, like alpha6beta4, alpha3beta1, alpha2beta1 as well as the presence of alpha6beta1 integrin in neoplastic epithelium. Furthermore, the upregulation of alpha5beta1 integrin is a negative prognostic factor. In cases of laryngeal cancer, disorganization of the basal membrane components (laminins 1 and 5, type IV collagen, tenascin, fibronectin isoforms) which represent integrins ligands, is found. This is due to partial or complete destruction of the basal membrane, thus, permitting extravasation and migration of cancer cells. These phenomena are observed in a greater degree in tumors showing poor prognosis. It seems that damage of these adhesion complexes is important in the neoplastic process. So, further studies are necessary to establish the importance of these markers to early larynx cancer diagnosis and reach the decision on appropriate therapeutic strategies in the management of those patients.

Animals↗
PubMedDate not supplied

Altered expression of integrins and basement membrane proteins in malignant and pre-malignant lesions of oral mucosa.

Integrins are transmembrane receptors that regulate cell-cell and cell-extracellular matrix (ECM) contact. In epithelial tissues, they interact with ECM components of the basement membrane (BM) to maintain the homeostasis and the architecture of the tissue. This interaction controls several cell functions such as adhesion, migration, proliferation, differentiation, and therefore has a key role in cancer development and metastasis. We studied the expression of integrins and ECM components of the BM by immunohistochemistry in frozen specimens of malignant squamous cell carcinoma (SCC), pre-malignant lesions of the oral mucosa (leucoplakia) and oral lichen planus. In invasive SCC, we observed altered polarity and distribution of alpha2beta1, alpha6beta4 and alpha3beta1 integrins, whereas in the in situ carcinoma alpha6beta4 and alpha3beta1 patterns only were altered. Immunostaining for ECM components such as Laminin-1 (Ln-1), Ln-5, and Collagen IV (Coll IV) was discontinuous and interrupted in invasive SCC, whereas it was normal in the in situ carcinoma. In both pre-malignant lesions and lichen planus specimens, integrins were expressed in a polarized manner in the presence of a normal BM, whereas were abnormally distributed in those tissues with altered staining patterns of the ECM components. In conclusion, we suggest that abnormal re-distribution of alpha3beta1 and alpha6beta4 integrins and expression of ECM components such as Ln-5 could play an important role in SCC invasion and metastasis.

Antigens, Surface↗
PubMed1997

A homozygous mutation in the integrin alpha6 gene in junctional epidermolysis bullosa with pyloric atresia.

The alpha6 integrin subunit participates in the formation of both alpha6beta1 and alpha6beta4 laminin receptors, which have been reported to play an important role in cell adhesion and migration and in morphogenesis. In squamous epithelia, the alpha6beta4 heterodimer is the crucial component for the assembly and stability of hemidesmosomes. These anchoring structures are ultrastructurally abnormal in patients affected with junctional epidermolysis bullosa with pyloric atresia (PA-JEB), a recessively inherited blistering disease of skin and mucosae characterized by an altered immunoreactivity with antibodies specific to integrin alpha6beta4. In this report, we describe the first mutation in the alpha6 integrin gene in a PA-JEB patient presenting with generalized skin blistering, aplasia cutis, and defective expression of integrin alpha6beta4. The mutation (791delC) is a homozygous deletion of a single base (C) leading to a frameshift and a premature termination codon that results in a complete absence of alpha6 polypeptide. We also describe the DNA-based prenatal exclusion of the disease in this family at risk for recurrence of PA-JEB. Our results demonstrate that, despite the widespread distribution of the alpha6 integrin subunit, lack of expression of the alpha6 integrin chain is compatible with fetal development, and results in a phenotype indistinguishable from that caused by mutations in the beta4 chain, which is expressed in a more limited number of tissues.

Antigens, Surface↗
PubMed2002

Phenotypic study of a case with successful transplantation of ex vivo expanded human limbal epithelium for unilateral total limbal stem cell deficiency.

OBJECTIVE: To minimize the risk to the donor eye when a conjunctival limbal autograft is performed for unilateral total limbal stem cell deficiency (LSCD), a new approach has been reported of expanding limbal epithelial progenitor cells from a small limbal biopsy cultured on amniotic membrane (AM). Herein, we present for the first time the morphologic and phenotypic outcome of one such patient. DESIGN: Interventional case report. METHODS: A 31-year-old male with a severe acid burn to his left eye received AM transplantation at the acute stage and a keratolimbal allograft (KLAL) at the chronic stage for total LSCD. As an alternative to combat the failed KLAL, the above-mentioned new surgical procedure was performed. The corneal button, obtained after a penetrating keratoplasty performed 5.5 months later, and a normal corneal button as a control were submitted to hematoxylin-eosin and immunofluorescence staining for keratin K3, connexin 43, goblet-cell mucin MUC 5AC, laminin 5, and integrins alpha3beta1 and alpha6beta4. MAIN OUTCOME MEASURES: Clinical and immunohistologic features. RESULTS: The resultant epithelium was stratified with five to six cell layers and anchored to laminin 5 of the amniotic basement membrane via integrins alpha3beta1 and alpha6beta4 in a manner similar to the normal corneal epithelium. Intriguingly, the epithelial phenotype was limbal and not corneal, based on the negative expression of keratin K3 and connexin 43 of the basal epithelium. CONCLUSIONS: The technique described ensures the preservation of amniotic basement membrane, which allows formation of adhesion complexes and maintains normal corneal architecture. The preservation of a limbal epithelial phenotype on the reconstructed corneal surface indicates that AM provides a unique stromal environment conducive to the preservation and expansion of limbal epithelial progenitor cells.

Adult↗