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Vitiligo is the most common depigmenting disorder resulting from the loss of melanocytes from the basal epidermal layer. The pathogenesis of the disease is likely multifactorial and involves autoimmune causes, as well as oxidative and mechanical stress. It is important to identify early events in vitiligo to clarify pathogenesis, improve diagnosis, and inform therapy. Here, we show that E-cadherin (Ecad), which mediates the adhesion between melanocytes and keratinocytes in the epidermis, is absent from or discontinuously distributed across melanocyte membranes of vitiligo patients long before clinical lesions appear. This abnormality is associated with the detachment of the melanocytes from the basal to the suprabasal layers in the epidermis. Using human epidermal reconstructed skin and mouse models with normal or defective Ecad expression in melanocytes, we demonstrated that Ecad is required for melanocyte adhesiveness to the basal layer under oxidative and mechanical stress, establishing a link between silent/preclinical, cell-autonomous defects in vitiligo melanocytes and known environmental stressors accelerating disease expression. Our results implicate a primary predisposing skin defect affecting melanocyte adhesiveness that, under stress conditions, leads to disappearance of melanocytes and clinical vitiligo. Melanocyte adhesiveness is thus a potential target for therapy aiming at disease stabilization.

Allograft pathology, antibody-tissue interaction as demonstrated by C4d deposition and serological evidence of donor-specific antibodies (DSA) are the cardinal diagnostic features of antibody-mediated lesions (AML) in kidney transplantation. However, discrepancy between histological and serological findings is common, and more reliable diagnostic tools are called for. Here, we asked whether the in situ detection of DSA could serve as marker for AML. To that end, we applied the anti-HLA single antigen flow bead assay to eluates from 51 needle core graft biopsies performed for cause. Intragraft antibody profiles were correlated to serum DSA (sDSA), histological data and transplant outcome. The prevalence and the mean number of intragraft DSA (gDSA) were lower than that of sDSA (15/51 gDSA+ vs. 37/51 sDSA+ patients; 1.64 gDSA vs. 2.24 sDSA per patient). DSA were detected in all anti-HLA antibody-positive biopsies (15/15). The presence of gDSA was significantly associated with (1) microcirculation lesions taken individually (g, cg) and analyzed in functional clusters (ptc + g + cg > 0, cg + mm > 0), (2) C4d positivity and (3) a worse short-term transplant outcome (p = 0.05). These associations were not found for patients presenting only sDSA. Taken together, these results indicate that gDSA is a severity marker of antibody-mediated pathogenic process., (© Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Infantile digital fibromatosis or inclusion body fibromatosis is a rare, benign fibroproliferative lesion with recurrent potential that occurs on the digits of infants. A highly characteristic morphologic finding is the presence of paranuclear inclusion within the tumoral cells. We report here a case occurring in an 8-month-old infant with 2 asynchronous lesions of the toes., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Waldenström macroglobulinemia is defined by a bone marrow lymphoplasmacytic infiltration associated with serum IgM monoclonal gammopathy. Specific properties of the IgM gammopathy induce the main clinical manifestations revealing the disease: hyperviscosity syndrome, autoimmune peripheral neuropathy, cryoglobulinemia or hemolysis, and exceptional skin deposit such as macroglobulinosis cutis that we here report. Physicians should be aware of these clinical manifestations to avoid diagnostic delay., (Copyright © 2010 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

Matrix metalloproteinase (MMP)-3 is a protease involved in cancer progression and tissue remodeling. Using immunofluorescence and immunoelectron microscopy, we identified nuclear localization of MMP-3 in several cultured cell types and in human liver tissue sections. Western blot analysis of nuclear extracts revealed two immunoreactive forms of MMP-3 at 35 and 45 kd, with the 35-kd form exhibiting caseinolytic activity. By transient transfection, we expressed active MMP-3 fused to the enhanced green fluorescent protein (EGFP/aMMP-3) in Chinese hamster ovary cells. We showed that EGFP/aMMP-3 translocates into the nucleus. A functional nuclear localization signal was demonstrated by the loss of nuclear translocation after site-directed mutagenesis of a putative nuclear localization signal and by the ability of the MMP-3 nuclear localization signal to drive a heterologous protein into the nucleus. Finally, expression by Chinese hamster ovary cells of EGFP/aMMP-3 induced a twofold increase of apoptosis rate, compared with EGFP/pro-MMP-3, which does not translocate to the nucleus. Increased apoptosis was abolished by site-directed mutagenesis of the catalytic site of MMP-3 or by using the MMP inhibitor GM6001. This study elucidates for the first time the mechanisms of nuclear localization of a MMP and shows that nuclear MMP-3 can induce apoptosis via its catalytic activity.

Fibrosis, defined as the excessive deposition of extracellular matrix in an organ, is the main complication of chronic liver damage. Its endpoint is cirrhosis, which is responsible for significant morbidity and mortality. The accumulation of extracellular matrix observed in fibrosis and cirrhosis is due to the activation of fibroblasts, which acquire a myofibroblastic phenotype. Myofibroblasts are absent from normal liver. They are produced by the activation of precursor cells, such as hepatic stellate cells and portal fibroblasts. These fibrogenic cells are distributed differently in the hepatic lobule: the hepatic stellate cells resemble pericytes and are located along the sinusoids, in the Disse space between the endothelium and the hepatocytes, whereas the portal fibroblasts are embedded in the portal tract connective tissue around portal structures (vessels and biliary structures). Differences have been reported between these two fibrogenic cell populations, in the mechanisms leading to myofibroblastic differentiation, activation and "deactivation", but confirmation is required. Second-layer cells surrounding centrolobular veins, fibroblasts present in the Glisson capsule surrounding the liver, and vascular smooth muscle cells may also express a myofibroblastic phenotype and may be involved in fibrogenesis. It is now widely accepted that the various types of lesion (e.g., lesions caused by alcohol abuse and viral hepatitis) leading to liver fibrosis involve specific fibrogenic cell subpopulations. The biological and biochemical characterisation of these cells is thus essential if we are to understand the mechanisms underlying the progressive development of excessive scarring in the liver. These cells also differ in proliferative and apoptotic capacity, at least in vitro. All this information is required for the development of treatments specifically and efficiently targeting the cells responsible for the development of fibrosis/cirrhosis.

Background/aims: Hepatic undifferentiated (embryonal) sarcoma (HUS) is an exceptional hepatic malignant tumor in adults. Genetic studies were never reported in adult cases., Methods: In this study concerning three cases of HUS occurring in adult, we studied the three classical ways of carcinogenesis i.e. the TP53 (p53), Wnt (CTNNB1/beta-catenin and AXIN1) and telomerase (hTERT) pathways. We studied the expression of p53, beta-catenin and telomerase catalytic subunit hTERT by immunohistochemistry in the three cases; we determined TP53 gene mutation in two cases and the genome-wide allelotype, AXIN1, and CTNNB1/beta-catenin gene mutation in one case., Results: Immunohistochemistry showed an overexpression of p53 in more than 80% of tumoral cells; furthermore, mutations of TP53 were observed in two cases, involving the sequence-specific DNA binding domain. In contrast, no mutation was found in CTNNB1/beta-catenin and AXIN1 genes. Tumoral cells did not show hTERT staining nor nuclear expression of beta-catenin. In addition, allelotype analysis in one case showed loss of heterozygosity of chromosome 7p, 11p, 17p, 22q, and allelic imbalance of 1p, 8p, 20q., Conclusions: In this report of HUS in three adult patients, we emphasize the role of TP53 pathway in carcinogenesis of this rare tumor. This point could be of interest for therapeutic strategies.

Background/aims: Cellular retinol-binding protein-1 (CRBP-1) which is involved in vitamin A metabolism is highly expressed in liver cells, particularly in hepatic stellate cells (HSCs). In this work, the CRBP-1 expression was studied by immunohistochemistry in the different liver cell populations, including HSCs and portal fibroblasts, of normal liver and of fibrotic and cirrhotic liver., Methods: Normal liver, fibrotic liver in different stages and cirrhotic liver sections were studied. Immunohistochemistry was performed using antibodies against CRBP-1, alpha-smooth muscle actin (SMA), CD 68 and CD 34., Results: In normal liver, quiescent HSCs expressed CRBP-1, while portal fibroblasts did not. In fibrotic or cirrhotic liver, activated HSCs co-expressed CRBP-1 and alpha-SMA; a variable proportion of portal and septal (myo)fibroblasts, more important in cirrhosis, neo-expressed both CRBP-1 and alpha-SMA. Biliary epithelial cells both in normal and pathological situations expressed CRBP-1. Neither Kupffer cells, nor endothelial cells showed CRBP-1 expression., Conclusions: Our study demonstrates that CRBP-1 is a good marker to identify HSC in normal human liver. Furthermore, in fibrotic or cirrhotic liver, the different patterns of expression for CRBP-1 and alpha-SMA allow the distinction of different subsets of fibroblastic cells involved in fibrogenesis and septa formation.

Background/aims: Liver adenomatosis is characterized by the presence of multiple adenomas of various sizes in the liver. The aim of this study was to characterize the morphology of small nodules which can be difficult to identify., Methods: Seven patients included in this study underwent surgery for the removal of one or several nodules. All, but one, were females. Three out of seven presented with acute bleeding. Five had six or more nodules at presentation, and two only one, who developed nodules later on during follow-up., Results: All of the large nodules that were >2 cm, except one, were typical adenomas with or without hemorrhagic areas. Smaller nodules (1-2 cm), some of which discovered on the resected specimen were either typical adenomas or non-typical nodules. These non-typical nodules were characterized by a polylobulated aspect with steatotic zones, and in between, bands of non-steatotic hepatocytes with portal tracts-like structures containing occasional cytokeratin 7 and less often cytokeratin 19 positive biliary cells. Numerous steatotic foci were also seen in four cases. They were isolated or grouped forming microadenomas or non-typical micronodules (<1 cm) containing biliary elements. Our findings lead to the following hypothesis: adenomatosis is characterized by the simultaneous occurrence of multiple adenomas; if several adenomatous foci expand at the same time in the same area, they will form one polylobulated nodule containing non-adenomatous tissue with portal tracts in between areas of adenomatous tissue (non-typical micronodule). Such a small micronodule may in turn expand and join another micronodule to form a bigger one by the same process (non-typical nodule). As nodules grow, their non-adenomatous components including hepatocytic plates and portal tracts constituents will progressively disappear to end up with the classical aspect of an adenoma., Conclusions: This hypothesis supports the concept that non-typical nodules/micronodules are adenomas precursors. However, they can be difficult to classify since they resemble focal nodular hyperplasia precursor.

Background: Eccrine squamous syringometaplasia has been reported in some cases as an Herpeviridae complication. We report a case of eccrine squamous syringometaplasia associated with a severe cytomegalovirus infection in an immunocompromised patient, and we discuss about potential viral or drug triggering factors., Methods: A 22 years-old man was hospitalized in an intensive care unit for rejection of a renal graft associated with a disseminated cytomegalovirus infection. A papular and papulopustular eruption appeared on the trunk and the limbs., Results: Histological examination of a skin sample showed eccrine squamous syringometaplasia, with evidence of cytomegalovirus genomic sequences using PCR. Two weeks later, the patient developed toxic epidermal necrolysis, with fatal issue., Conclusions: Eccrine squamous syringometaplasia is a rare condition, without specific clinical features. Numerous local affections have been reported to induce eccrine syringometaplasia (ulcer, scar, pyoderma gangrenosum, drug injection.), drugs (cytotoxic agents, non steroidal anti inflammatory therapies) and in cases of infection due to cytomegalovirus or herpes simplex virus. The potential implication of cytomegalovirus or foscarnet as triggering factors in our case is discussed. This observation and other similar reported cases lead to the conclusion that eccrine squamous syringometaplasia may be an underestimated complication of cytomegalovirus infections in immunocompromised patients.

Background: The expression and the distribution of fibrillin-1 and elastin were studied in normal and pathological human liver samples., Methods: As controls, histologically normal/subnormal liver samples (n = 24) were used. Pathological samples corresponded to seven cirrhosis and eight hepatocellular carcinomas (HCC) developed on cirrhotic (four) or noncirrhotic (four) liver., Results: In normal liver, fibrillin-1 and elastin co-localized in vessel walls and portal tract connective tissue. Fibrillin-1 alone was detected along sinusoids and in portal spaces at the interface with the limiting hepatocytic plates and close to the basement membrane of bile ducts. By transmission electron microscopy, typical bundles of microfibrils were detected both in Disse space and in portal zones. Cirrhotic nodules were usually rich in fibrillin-1 along sinusoids; fibrillin-1 and elastin were co-localized in fibrotic septa surrounding nodules. In HCC, fibrillin-1 was present between tumoral hepatocytes; stromal reaction around the tumors contained both fibrillin-1 and elastin., Conclusions: Fibrillin-1 was associated with elastin in portal mesenchyme and vessel walls of normal liver, in fibrotic septa around cirrhotic nodules and stromal reaction around HCC, but was expressed alone in the perisinusoidal space. The functional roles for fibrillin-1 in non-elastic tissues, such as the liver, remain to be elucidated.