PubMed Health⌕ Search

Biomedical subjects

Stefania Jablonska

Publications and source records attributed to Stefania Jablonska.

At least 19 recordsLinked to original sources
PubMed2006

Gene profiling of scleroderma skin reveals robust signatures of disease that are imperfectly reflected in the transcript profiles of explanted fibroblasts.

OBJECTIVE: To determine whether biopsy specimens obtained from systemic sclerosis (SSc) lesions show a distinctive gene profile, whether that gene profile is maintained in fibroblasts cultured from SSc skin biopsy specimens, and whether results from tissue obtained from multiple clinical centers can be combined to yield useful observations in this rare disease. METHODS: Biopsy samples and passaged fibroblasts were stored in RNAlater solution prior to processing for RNA. RNA from SSc and control skin biopsy specimens, as well as SSc and control explanted passage 4 fibroblasts, from 9 patients and 9 controls was hybridized to Affymetrix HG-U133A arrays. Data were analyzed using the BRB ArrayTools system. When appropriate, findings were followed up with immunohistochemical analysis or TaqMan studies. RESULTS: Biopsy samples obtained from patients with SSc had a robust and distinctive gene profile, with approximately 1,800 qualifiers distinguishing normal skin from SSc skin at a significant level. The SSc phenotype was the major driver of sample clusters, independent of origin. Alterations in transforming growth factor beta and Wnt pathways, extracellular matrix proteins, and the CCN family were prominent. Explanted fibroblasts from SSc biopsy samples showed a far smaller subset of changes that were relatively variable between samples, suggesting that either nonfibroblast cell types or other aspects of the dermal milieu are required for full expression of the SSc phenotype. CONCLUSION: SSc has a distinct gene profile that is not confounded by geographic location, indicating that extended multicenter studies may be worthwhile to identify distinct subsets of disease by transcript profiling. Explanted SSc fibroblasts show an incomplete reflection of the SSc phenotype.

Adult↗
PubMed2005

Imiquimod is a strong inhibitor of tumor cell-induced angiogenesis.

BACKGROUND: Imiquimod, a potent immunomodulator, not having a direct antiproliferative activity, was found to be effective in genital and cutaneous premalignancies and malignancies. As tumor development depends on blood vessel supply, the inhibition of angiogenesis could be responsible for the antitumor activity. OBJECTIVE: To find in a murine model whether imiquimod has antiangiogenic activity and whether this activity is mediated by locally induced cytokines. METHODS: The study was performed in two cell lines: Skv human keratinocytes containing multiple integrated copies of HPV16 derived from bowenoid papulosis, and murine L1 lung sarcoma cells of Balb/c mice. The murine model of cutaneous angiogenesis was used to assess and count the new blood vessel formation. The mice were immunosuppressed by a total body X-ray irradiation and treated with 5% or 2.5% imiquimod cream before or after induction of angiogenesis with intradermally injected tumor cell suspension. In some experiments the mice were, in addition, treated intraperitoneally with monoclonal antibodies against murine IFNalpha, TNFgamma or IL-18. RESULTS: Topical application of imiquimod on the murine skin resulted in reduction of angiogenesis (P < 0.001) induced by intradermal injection of both human and mouse tumor cells, more pronounced when 5% cream was applied on three consecutive days. Antibodies against murine IFNgamma, TNFalpha and IL-18 completely abolished the inhibitory effect of imiquimod on angiogenesis induced by murine L1 sacroma cells. When human Skv cells were used in angiogenesis assay, the effect of imiquimod was abolished by antibodies against IL-18 but not against TNFalpha, which may be due to overproduction of TNFalpha by Skv cells. CONCLUSIONS: Antiangiogenic effect of imiquimod was found to be mediated by IL-18, probably through promoting production of INFgamma, the most important inhibitor of angiogenesis.

Adjuvants, Immunologic↗
PubMed2005

Circulating soluble tumour necrosis factor receptors in patients with epidermodysplasia verruciformis as compared to patients with cutaneous tumours in the general population.

Soluble tumour necrosis factor receptors type I and II (sTNF-RI and II) were evaluated in sera from patients with epidermodysplasia verruciformis and patients with cutaneous warts, actinic keratoses, squamous cell carcinomas or basal cell carcinomas by specific enzyme-linked immunobiological assays. In patients with widespread epidermodysplasia verruciformis lesions, the levels of both sTNF-Rs were in normal range. Both types of sTNF-Rs were significantly increased in patients with warts. The levels of sTNF-RI were significantly increased in patients with multiple actinic keratoses, squamous cell carcinoma and basal cell carcinoma. Increased levels of circulating sTNF-Rs may facilitate development of cutaneous tumours. Normal levels of sTNF-Rs in patients with epidermodysplasia verruciformis might, at least partially, contribute to a slow growth and low metastatic potential of cancers in these patients.

Adult↗
PubMed2004

An increased transforming growth factor beta receptor type I:type II ratio contributes to elevated collagen protein synthesis that is resistant to inhibition via a kinase-deficient transforming growth factor beta receptor type II in scleroderma.

OBJECTIVE: Aberrant transforming growth factor beta (TGFbeta) signaling has been implicated in the pathogenesis of scleroderma (systemic sclerosis [SSc]), but the contribution of specific components in this pathway to SSc fibroblast phenotype remains unclear. This study was undertaken to delineate the role of TGFbeta receptor type I (TGFbetaRI) and TGFbetaRII in collagen overexpression by SSc fibroblasts. METHODS: Primary dermal fibroblasts from SSc patients and healthy adults were studied (n = 10 matched pairs). Adenoviral vectors were generated for TGFbetaRI (AdTGFbetaRI), TGFbetaRII (AdTGFbetaRII), and kinase-deficient TGFbetaRII (AdDeltakRII). TGFbetaRI basal protein levels were analyzed by (35)S-methionine labeling/immunoprecipitation and immunohistochemistry. Type I collagen and TGFbetaRII basal protein levels were analyzed by Western blot and newly secreted collagen by (3)H-proline incorporation assay. RESULTS: Analysis of endogenous TGFbetaRI and TGFbetaRII protein levels revealed that SSc TGFbetaRI levels were increased 1.7-fold (P = 0.008; n = 7) compared with levels in healthy controls, while TGFbetaRII levels were decreased by 30% (P = 0.03; n = 7). This increased TGFbetaRI:TGFbetaRII ratio correlated with SSc collagen overexpression. To determine the consequences of altered TGFbetaRI:TGFbetaRII ratio on collagen expression, healthy fibroblasts were transduced with AdTGFbetaRI or AdTGFbetaRII. Forced expression of TGFbetaRI in the range corresponding to elevated SSc TGFbetaRI levels increased basal collagen expression in a dose-dependent manner, while similar TGFbetaRII overexpression had no effect, although transduction of fibroblasts at higher multiplicities of infection led to a marked reduction of basal collagen levels. Blockade of TGFbeta signaling via AdDeltakRII resulted in approximately 50% inhibition of basal collagen levels in healthy fibroblasts and in 5 of 9 SSc cell lines. A subset of SSc fibroblasts (4 of 9 cell lines) was resistant to this treatment. SSc fibroblasts with the highest levels of TGFbetaRI were the least responsive to collagen inhibition via DeltakRII. CONCLUSION: This study indicates that an increased TGFbetaRI:TGFbetaRII ratio may underlie aberrant TGFbeta signaling in SSc and contribute to elevated basal collagen production, which is insensitive to TGFbeta signaling blockade via DeltakRII.

Activin Receptors, Type I↗
PubMed2004

Natural cell-mediated cytotoxicity of peripheral blood lymphocytes against target cells transfected with epidermodysplasia verruciformis-specific human papillomavirus type 8 L1 DNA sequences.

The aim of the present study was to characterise natural cell-mediated cytotoxicity against COS-7 cells transfected with potentially oncogenic HPV-8 L1 DNA sequences cloned in sense and antisense orientation and to evaluate their lysis by peripheral blood lymphocytes (PBL) from patients with epidermodysplasia verruciformis (EV), a rare disease associated with life-long infection by specific HPV types. COS-7 cells were transfected with HPV-8 Hinc II restriction fragment (nucleotide positions 5434-7654) cloned in sense (COS-L1S) and antisense (COS-L1A) orientation into pCB6 expression vector. Cytotoxic activity of isolated PBL against COS cell lines as well as K562 erythroleukaemic cells was evaluated by 51Cr-release assay. We found that lymphocytes responsible for natural lysis of COS and K562 cells are CD3-negative CD56-positive natural killer (NK) cells. Analysis of NK cell cytotoxic activity against different COS cell lines has revealed that lymphocytes from healthy subjects killed COS-L1S cells significantly more efficiently than wild COS-7 and COS-L1A cells. Significantly more efficient lysis of COS-L1S cells was also observed in EV patients. Thus, expression of HPV L1 renders target cells more susceptible to NK-mediated cytotoxicity that may enable more effective elimination of transformed cells.

Adult↗
PubMed2003

High prevalence of epidermodysplasia verruciformis-associated human papillomavirus DNA in actinic keratoses of the immunocompetent population.

Skin cancers in both immunosuppressed and immunocompetent populations are associated with epidermodysplasia verruciformis human papillomavirus (EV-HPV) DNA. However, little is known about the prevalence of EV-HPVs in actinic keratoses in immunocompetent individuals. Actinic keratoses from 114 patients were classified as low-grade ( n=76) or high-grade ( n=38) according to the extent of histological atypia. HPV DNA was amplified from 54 frozen and 60 paraffin-embedded biopsy specimens by nested polymerase chain reaction (PCR) with several consensus and type-specific primers. PCR products were sequenced for typing. These results were compared with HPV detection in skin cancers ( n=20) and Bowen's disease ( n=18). A broad spectrum of EV-HPV types including oncogenic HPV5 and HPV8 and partially characterized sequences were detected in actinic keratoses and cutaneous cancers. In actinic keratoses a higher prevalence of EV-HPV DNA was found in frozen tissues than in formalin-fixed tissues (85% vs 67%). There was no difference between the low- and high-grade actinic keratoses either in terms of EV-HPV DNA prevalence or the results of serological study using HPV8 virus-like particles. The detection rate of EV-HPVs was lower in skin cancers and Bowen's disease. This would suggest involvement of EV-HPVs in the early stages of cutaneous oncogenesis.

Antibodies, Viral↗
PubMed2003

Persistent down-regulation of Fli1, a suppressor of collagen transcription, in fibrotic scleroderma skin.

The molecular and cellular mechanisms that maintain proper collagen homeostasis in healthy human skin and are responsible for the dysregulated collagen synthesis in scleroderma remain primarily unknown. This study demonstrates that Fli1 is a physiological negative regulator of collagen gene expression in dermal fibroblasts in vitro and in human skin in vivo. This conclusion is supported by the analyses of mouse embryonic fibroblasts from Fli1(-/-), Fli1(+/-), and Fli1(+/+) mice. In cultured human and mouse fibroblasts Fli1 expression levels are inversely correlated with the collagen type I expression levels. These in vitro observations were validated in vivo. In healthy human skin Fli1 protein is expressed in fibroblasts and endothelial cells. Significantly, absence of Fli1 expression in individual fibroblasts correlates with elevated collagen synthesis. In contrast to healthy skin, Fli1 protein is consistently absent from fibroblasts and significantly reduced in endothelial cells in clinically involved scleroderma skin, which correlates with enhanced collagen synthesis in systemic sclerosis skin. This study supports the role of Fli1 as a suppressor of collagen transcription in human skin in vivo. Persistent down-regulation of Fli1 in scleroderma fibroblasts in vivo may directly contribute to uncontrolled matrix deposition in scleroderma skin.

Adult↗
PubMed2003

Possible involvement of epidermodysplasia verruciformis human papillomaviruses in the immunopathogenesis of psoriasis: a proposed hypothesis.

We have shown previously in psoriasis a very high prevalence of epidermodysplasia verruciforms-associated human papillomavirus 5 (EVHPV5) DNA and antibodies to human papillomavirus 5 (HPV5) virus-like particle (VLP) L1, and we suggested that this benign hyperproliferative disorder could be a reservoir for EVHPVs. Here we provide new data confirming the expression of EVHPVs in psoriasis and present our hypothesis on their possible involvement in the immunopathogenesis of the disorder. The new important finding was detection by radioimmunoprecipitation assay of a very high prevalence of antibodies to E6/E7 HPV5 oncoproteins, known to enhance keratinocyte proliferation. More recently, EV genes were identified, EVER1 and EVER2, whose mutations are responsible for epidermodysplasia verruciformis. Eidermodysplasia verruciforms-associated human papillomaviruses are harmless to the general population as a result of genetic restriction, which in psoriasis appears to be partly alleviated, and this may allow the viral gene expression. We hypothesize that induction of keratinocyte proliferation in psoriasis by various stimuli initiates the EVHPV life cycle with expression of early (E6/E7) and late (L1) viral proteins. The early proteins may, in turn, enhance the keratinocyte proliferation, and the late proteins could serve as target for specific-B- and T-cell-mediated responses. Immune responses against the viral antigens in the epidermis may result in the chemoattraction of leukocytes and Munro abscess formation, as well as in production of the psoriatic process. The novel immunomodulatory therapies could also inhibit immune responses against EVHPV proteins, leading to decreased cytokine production, keratinocyte proliferation and EVHPV expression. Thus the beneficial effect of these therapies is not discordant with the propose hypothesis of possible involvement of EVHPVs in the immunopathogenesis of psoriasis.

Cell Division↗
PubMed2003

Progressive facial hemiatrophy: central nervous system involvement and relationship with scleroderma en coup de sabre.

OBJECTIVE: To investigate the relationship of progressive facial hemiatrophy (PFH) and scleroderma en coup de sabre by establishing the presence and type of central nervous system (CNS) involvement in both diseases and the possible coexistence of PFH with scleroderma in other body sites. METHODS: We divided 19 cases of PFH into 2 groups: group 1 in which atrophies were preceded by cutaneous indurations (n = 10) and group 2 with no precedent indurations (n = 9). The third group consisted of 7 cases of scleroderma en coup de sabre with no PFH features. Clinical and laboratory investigations included indirect immunofluorescence for antinuclear antibodies, and routine neurological examination involved electroencephalography, magnetic resonance imaging (MRI) before and after contrast application to evaluate the integrity of blood-brain barrier, angio-MRI to evaluate intracranial blood vessel anomalies, and 99mTc-HM-PAO-SPECT to evaluate regional cerebral blood flow (CBF). RESULTS: We found similar anomalies in all 3 groups. MRI did not show abnormality in 2 out of 9 PFH cases preceded by indurations, in 5 out of 9 cases not preceded by indurations, and in all 7 cases of scleroderma en coup de sabre, including 5 patients, in whom the CBF was found to be diminished. In single cases of groups 1 and 2, SPECT was normal despite some MRI abnormalities. Angio-MRI was not contributory since the same abnormalities of Willis circle were found in normal controls. In single cases of both PFH groups, MRI with contrast disclosed some damage of the blood-brain barrier. CONCLUSION: Our results suggest frequent CNS involvement in PFH cases, regardless of the time of presentation of cutaneous indurations, with or without coexistent plaques of localized scleroderma in other locations. This indicates a close relationship between PFH and scleroderma en coup de sabre. The detection of abnormal SPECT by normal MRI in some cases of PFH and scleroderma en coup de sabre is of practical importance. This indicates the usefulness of SPECT in studying both PFH and scleroderma en coup de sabre.

Adult↗
PubMed2002

Do epidermodysplasia verruciformis human papillomaviruses contribute to malignant and benign epidermal proliferations?

The aim of this review is to present new data on epidermodysplasia verruciformis (EV) and EV human papillomaviruses (HPVs), regarded previously as specific to the disease. Recently introduced highly sensitive molecular methods for virologic studies allow detection of EV HPVs in non-EV populations. In this article, we present the most recent findings on EV and EV HPVs, which shed new light on a possible contribution of EV viruses to malignant and benign epidermal proliferation. We discuss the significance of EV HPV DNA detection in premalignant cutaneous lesions and nonmelanoma skin cancers; however, direct evidence for the causative role of EV HPV is still not available. In psoriasis, a high frequency of EV HPV-5 and other EV HPVs in the skin and the presence of specific HPV-5 antibodies strongly suggest expression of EV HPV proteins in this extensive epidermal proliferation. Epidermodysplasia verruciformis HPV-5 may also be transiently expressed in epidermal repair processes, whereas in psoriasis there is a continuous epidermal proliferation that could result in persistent viral expression. A potential contribution of EV HPVs to the pathogenesis of psoriasis is also supported by the recently disclosed co-localization of susceptibility loci for psoriasis and EV in the same region of chromosome arm 17qter; however, specific genes for both conditions are still not identified.

Epidermodysplasia Verruciformis↗
PubMed2002

A nonfatal case and 2 fatal cases of paraneoplastic pemphigus: can a complement indirect immunofluorescent test help to identify fatal "group A" paraneoplastic pemphigus cases?

We studied 3 recent cases of paraneoplastic pemphigus (PNP) in detail. Two patients died despite concerted management efforts. One patient received no treatment after the appearance of PNP and recovered completely from both PNP and lymphoma. Multiple serum studies of these 3 patients plus 9 other proven PNP cases revealed that 8 of 9 fatal PNP cases (referred to here as "group A") had distinctive cell surface antibodies detected by complement indirect immunofluorescent (CIIF) tests on monkey esophagus sections. By contrast, none of the sera from 3 patients with PNP who experienced long-term survival (referred to here as "group B") and none of 20 pemphigus vulgaris or 10 pemphigus foliaceus control sera revealed similar beaded cell surface CIIF reaction patterns, a difference that is statistically significant (P <.0001). Cell surface CIIF reaction patterns of group A PNP antibodies resemble the pattern of pemphigus antibody reactions in indirect immunofluorescent tests on the same substrate; however, the latter tend to be thinner and more linear, whereas the cell surface CIIF pattern tends to be more beaded, suggesting possible desmosomal reactions. We believe this test is useful in identifying an aggressive group A form of PNP.

Antibodies, Antinuclear↗