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J C Simon

Publications and source records attributed to J C Simon.

At least 73 records · Page 4Linked to original sources
PubMed1998

CD44 variant isoforms are essential for the function of epidermal Langerhans cells and dendritic cells.

Upon antigen encounter epidermal Langerhans cells (LC) and dendritic cells (DC) emigrate from peripheral organs and invade lymph nodes through the afferent lymphatic vessels and then assemble in the paracortical T cell zone and present antigen to T lymphocytes. Part of this process is mimicked by metastasizing tumor cells. Since splice variants of CD44 promote metastasis to lymph nodes we explored the expression of CD44 proteins on migrating LC and DC. We show that following antigen contact, LC and DC upregulate pan CD44 epitopes and epitopes encoded by variant exons v4, v5, v6 and v9. Antibodies against CD44 epitopes arrest LC in the epidermis, prevent the binding of activated LC and DC to the T cell zones of lymph nodes, and severely inhibit their capacity to induce a delayed type hypersensitivity reaction to a skin hapten in vivo. Our results demonstrate that CD44 splice variant expression is obligatory for the migration and function of LC and DC.

Cell Movement↗
PubMed1998

Possible role of coagulation factor XIII in the pathogenesis of venous leg ulcers.

BACKGROUND: Aim of this placebo-controlled clinical study was to examine the expression pattern of coagulation factor XIIIa in patients with chronic venous leg ulcers and the impact of a 10 day topical factor XIII treatment on ulcer healing, leg ulcer size and radius reduction. PATIENTS AND METHODS: 24 patients were stratified into two groups, each consisting of 12 patients, with leg ulcers > 1.000 mm2, or < 1.000 mm2. Four patients of each study group were assigned to the control group (n = 8). All leg ulcers were treated by topical application of non-adhering dressings and compression therapy. Patients of the treatment group (n = 16) were treated by additional topical treatment off factor XIII twice daily for ten days. Immunohistochemical staining of leg ulcer specimens before and after treatment (day 10) was performed in all patients. RESULTS: The immunohistochemical staining of factor XIIIa in all specimens before and after therapy showed no significant increase in the expression of factor XIIIa. Comparison of the leg ulcer size, radius and daily radius reduction in the treatment and control group showed no significant differences in values of patients with leg ulcers > 1.000 mm2. However, a decreased leg ulcer size and radius was found in patients of the treatment group with more acute leg ulcers < 1.000 mm2 in contrast to patients with larger leg ulcers (daily ulcer radius reduction from day 0-10; 0.31 mm versus 0.13 mm, p < 0.015). CONCLUSIONS: These results indicate that locally applied factor XIII promotes especially wound healing of more acute smaller venous leg ulcers. Since immunohistochemical staining of factor XIIIa showed no significant differences before and after therapy, we propose that factor XIII is inactivated rapidly after local application on venous leg ulcers.

Administration, Topical↗
PubMed1998

Further characterization of UVB radiation effects on Langerhans cells: altered expression of the costimulatory molecules B7-1 and B7-2.

We have reported previously that low-dose UVB radiation (UVBR, 50-200 J/m2) perturbs the antigen-presenting cell (APC) function of murine Langerhans cells (LC) by interfering with yet undefined costimulatory signals. In this study, we investigated (1) the effects of UVBR on the expression of the costimulatory molecules B7-1 and B7-2 on murine LC, (2) the functional consequences of defective B7-1 and B7-2 signalling on primary and secondary T-cell responses induced by LC and (3) the mechanism by which UVBR interferes with B7-1 and B7-2 expression. Ultraviolet-B radiation dose-dependently inhibited the culture-induced upregulation of B7-1 and B7-2 on LC from both UVB-susceptible (UVBs, C57BL/6) and UVB-resistant (UVBR, Balb/c) mice and abrogated their capacity to stimulate proliferation of naive alloreactive T cells and of the KLH (keyhole limpet hemocyanin)-specific T helper (Th)1 clone HDK-1. The UVBR-induced suppression of B7-1 and B7-2 on LC and their perturbed APC function were related, because exogenous triggering of the B7/CD28 pathway with a stimulatory monoclonal antibody (mAb) for CD28 to UVB-irradiated LC partially restored T-cell proliferation. Such reconstitution was not observed when the mAb was added to killed LC, indicating that the UVBR-induced suppression of APC function was not due to lethal effects on LC. Conditioned supernatants from UVB-irradiated epidermal cells did not inhibit the functional upregulation of B7-1 and B7-2, suggesting that UVBR inhibits B7-1 and B7-2 upregulation by acting directly on LC and not by altering LC costimulatory function via release of soluble immunosuppressive factors. In conclusion, UVBR distorts the functional expression of B7-1 and B7-2 on LC from both UVBS and UVBR mice, thereby contributing to the failure of UVB-irradiated LC to stimulate resting alloreactive T cells or KLH-specific Th1 cells.

Animals↗
PubMed1998

Susceptibility to effects of UVB irradiation on induction of contact sensitivity, relevance of number and function of Langerhans cells and epidermal macrophages.

Sensitization on skin exposed to acute low-dose UVB irradiation separates normal humans into two phenotypically distinct groups: One group, following sensitization on UVB-irradiated skin, develops contact sensitivity, designated UVB resistant (UVB-R) and the second group, following sensitization on UVB-irradiated skin, fails to develop contact sensitivity, designated UVB susceptible (UVB-S). To investigate whether UVB susceptibility in humans in related to antigen-presenting activity in the skin we studied the effect of UVB irradiation on the number and function of the epidermal antigen-presenting cells in volunteers identified as UVB-R and UVB-S. Single cell suspensions of epidermal cells from control skin and skin exposed to 3 minimal erythema doses (MED) of UVB 3 days previously were stained for Langerhans cells (CD1a+HLA-DR+) and epidermal macrophages (CD1a-HLA-DR+). The UVB exposure of the skin significantly decreased the percentage of Langerhans cells (UVB-R: n = 7, P < 0.02, UVB-S: n = 6, P < 0.03) and increased the percentage of epidermal macrophages (UVB-R: n = 7, P < 0.03, UVB-S: n = 6, P < 0.03) however to the same degree in both the UVB-R and the UVB-S group. To study the effect on Langerhans cell alloreactivity, epidermal cells were harvested immediately after UVB irradiation. However, in both UVB-R and UVB-S subjects the Langerhans cell alloreactivity was blocked to the same degree immediately after UVB irradiation compared to nonirradiated epidermal cells. To determine the effect of UVB irradiation on epidermal macrophages, epidermal cells were harvested 3 days after UVB irradiation. Irradiated epidermal cells from both UVB-R and UVB-S subjects demonstrated a strong antigen-presenting capacity compared to epidermal cells from control skin leading to activation of T cells that mainly secrete interferon (IFN)-gamma and not interleukin (IL)-4. In conclusion we found that UVB susceptibility was not correlated with the number of Langerhans cells or epidermal macrophages in the skin at the same time of sensitization. Neither was it correlated with the capacity of Langerhans cells nor UVB-induced epidermal macrophages to activate T cells in vitro.

Adult↗
PubMed1997

An essential role for CD44 variant isoforms in epidermal Langerhans cell and blood dendritic cell function.

Upon antigen contact, epidermal Langerhans cells (LC) and dendritic cells (DC) leave peripheral organs and home to lymph nodes via the afferent lymphatic vessels and then assemble in the paracortical T cell zone and present antigen to T lymphocytes. Since splice variants of CD44 promote metastasis of certain tumors to lymph nodes, we explored the expression of CD44 proteins on migrating LC and DC. We show that upon antigen contact, LC and DC upregulate pan CD44 epitopes and epitopes encoded by variant exons v4, v5, v6, and v9. Antibodies against CD44 epitopes inhibit the emigration of LC from the epidermis, prevent binding of activated LC and DC to the T cell zones of lymph nodes, and severely inhibit their capacity to induce a delayed type hypersensitivity reaction to a skin hapten in vivo. Our results demonstrate that CD44 splice variant expression is obligatory for the migration and function of LC and DC.

Animals↗
PubMed1997

In situ expression of B7 and CD28 receptor families in skin lesions of patients with lupus erythematosus.

OBJECTIVE: To examine the expression of costimulatory molecules of the B7 and CD28 receptor families in active skin lesions of patients with systemic lupus erythematosus (SLE), subacute cutaneous lupus erythematosus (SCLE), and chronic discoid lupus erythematosus (CDLE). METHODS: The in situ expression of B7-1, B7-2, BB-1, and CD28 was studied by immunohistochemistry, and B7-1 and B7-2 RNA expression was examined by reverse transcription-polymerase chain reaction. RESULTS: Only in lesional skin from SLE, SCLE, and CDLE patients did dermal and epidermal antigen-presenting cells (APC) express B7-1 and B7-2, particularly when in apposition to CD28+ T cells. These B7-1+ and B7-2+ APC bound CTLA-4 fusion protein. In lesional (but not in nonlesional) skin, keratinocytes expressed BB-1. The majority of infiltrating T cells were CD28+. B7-1 and B7-2 RNA were expressed in lesional skin from SLE, SCLE, and CDLE patients; when dermis was separated from epidermis, only faint B7-1 and B7-2 RNA signals were detectable in the epidermis, indicating that dermal but not epidermal cells were the major source of B7-1 and B7-2 RNA. During treatment, both B7-1 and B7-2 protein and RNA expression were reduced. CONCLUSION: These in situ findings suggest that costimulation via the B7-CD28 pathway may be important for the generation and/or propagation of T cell activity in skin lesions of humans with lupus erythematosus. Thus, the manipulation of this pathway (e.g., by CTLA-4 fusion protein) could be an important target for the development of future therapies for LE.

Antigens, CD↗
PubMed1997

[Characterization of nonresponders in high dosage UVA1 therapy of acute exacerbated atopic dermatitis].

High-dose UVA1 therapy is an effective treatment of patients with acute atopic dermatitis. However, some patients do not respond well to this new therapy. We attempted to further characterize the non-responder population in a retrospective study. Two closely matched groups of responders (n = 20) and non-responders (n = 20) were compared. No significant differences were observed between both groups with respect to the following parameters: skin type, minimal erythema dose, single and cumulative doses of UVA1, and peripheral blood eosinophils. However, non-responders were characterized by a highly elevated atopic score, and by high levels of total IgE and of specific IgE. Furthermore, colonization of the skin with Staphylococcus aureus occurred at higher densities, and intestinal growth of Candida albicans was more frequently observed. These data indicate that high-dose UVA1 irradiation is not effective in all patients suffering from atopic dermatitis. We conclude that non-responders with complicating infections might benefit from the combination of high-dose UVA1 therapy and antibiotic or antimycotic treatment.

Adolescent↗
PubMed1997

Treatment of chronic palmoplantar eczema with local bath-PUVA therapy.

BACKGROUND: Systemic PUVA therapy may be useful in the treatment of chronic palmoplantar eczema. Topical PUVA-paint avoids some of the unwanted side effects of systemic psoralens and has been used successfully in the treatment of palmoplantar eczema and psoriasis. However, few data are available on the effectiveness of local bath-PUVA therapy in palmoplantar eczema. OBJECTIVE: Our purpose was to assess the effectiveness of local bath-PUVA therapy in 28 patients with chronic palmar or plantar eczema or both who were resistant to conventional topical treatment. METHODS: After fungal or bacterial infection had been excluded in all patients, hands or feet or both were soaked for 15 minutes in warm water containing 1 mg/L 8-methoxypsoralen. Immediately after, the skin was irradiated with increasing doses of UVA, starting with 0.5 J/cm2. PUVA-bath therapy was performed 4 times a week up to a total of 25 treatments. No additional therapy was allowed except emollients. RESULTS: Excellent or good effects were achieved in 93% of the patients with dyshidrotic and in 86% of the patients with hyperkeratotic eczema. In the patients with dyshidrotic eczema, the cumulative doses and the highest single doses of UVA were lower than those in the patients with hyperkeratotic eczema (21.4 vs 27.9 J/cm2 and 2.4 vs 3.0 J/cm2 of UVA), but this was not statistically significant. No phototoxic reactions were observed. CONCLUSION: Local bath-PUVA therapy is of value in the management of chronic palmoplantar eczema resistant to standard modes of topical treatment. Compared with topical PUVA-paint, local bath-PUVA therapy has several advantages, particularly the absence of phototoxic reactions, severe hyperpigmentation, and protracted photosensitivity.

Adolescent↗
PubMed1997

High CD44 surface expression on primary tumours of malignant melanoma correlates with increased metastatic risk and reduced survival.

The cell surface glycoprotein CD44 has been implicated in the progression and metastasis of certain human tumours including malignant melanoma (MM). In animal models, certain MM cell lines, expressing high levels of CD44, displayed an augmented capacity for haematogenous metastasis, compared to those with low CD44 levels. To determine whether, in vivo, the level of CD44 expressed by primary tumours of MM (PMM) is related to their metastatic potential, CD44 expression on PMM was studied in 92 patients, classified by their metastatic risk based on histological measurement of vertical tumour thickness (VT): in situ PMM, low-risk PMM (VT < or = 0.7 mm), intermediate risk PMM (VT = 0.71-1.4 mm) and high-risk PMM (VT > 1.4 mm). Paraffin-embedded sections were stained immunohistochemically with a panCD44 MAb. The level of CD44 expression on PMM was analysed semiquantitatively with epidermal CD44 staining set as an internal standard. High levels of CD44 were detected in 58.3% of high-risk PMM, 40.6% of intermediate-risk PMM, 36.7% of low-risk PMM and 16.7% of in situ PMM. Seventy-four per cent (17/23) of patients who developed and/or died of MM metastasis were CD44 high, and importantly, among these were 5 patients, whose metastatic risk had been estimated low, based on the measurement of VT. Finally, Kaplan-Meier analysis revealed patients whose PMM were CD44 high to have a significantly reduced 5-year survival rate compared to those that were CD44 low (P < 0.05). We conclude that in our patient population, a high level expression of CD44 on PMM is associated with increased metastatic risk and reduced survival.

Antigens, Neoplasm↗
PubMed1997

Contrasting effects of ultraviolet-A and ultraviolet-B exposure on induction of contact sensitivity in human skin.

Ultraviolet-B (UVB), in addition to direct effects on DNA, induces immunological changes in the skin that predispose to the development of skin cancer. Whether ultraviolet-A (UVA) induces similar changes is unknown. This effect can be investigated in humans in vivo using epicutaneous antigens as a model of tumour antigens. Volunteers (n = 46) were randomly assigned to received no sensitization, sensitization with the allergen diphenylcyclopropenone (DPCP) on non-UV-exposed normal skin, or sensitization with DPCP on skin exposed to three minimal erythema doses (MED) of either UVA or UVB radiation 3 days before sensitization. Three weeks after sensitization all volunteers were challenged with five different concentrations of DPCP. The challenge reactions were scored clinically and the increase in skin thickness was measured using a micrometer. Sensitization on UVB-exposed skin reduced the immunization rate compared with sensitization on non-irradiated skin (P < 0.03) as previously described. In contrast, sensitization on skin exposed to three MED UVA radiation did not result in a decreased immunization rate compared with non-irradiated skin. These results indicate that in humans erythemagenic doses of UVA radiation do not reduce the immunization rates to epicutaneous allergens. Thus UVB and UVA irradiation have contrasting effects on cell-mediated immunity in humans. These findings may at least in part explain the less carcinogenic effect of UVA irradiation.

Adolescent↗
PubMed1997

The combination of oral acitretin and bath PUVA for the treatment of severe psoriasis.

We report four patients with severe erythrodermic, pustular psoriasis, or plaque-type psoriasis, who were treated with a combination of acitretin and bath PUVA. After 4 weeks out-patient treatment, the psoriasis in all patients had improved by > or = 90%. No patient had relapsed when reviewed at 3 months. No significant side-effects were seen with the combined retinoid/bath PUVA treatment. Acitretin and bath PUVA may be safely combined for the treatment of severe psoriasis.

Acitretin↗
PubMed1997

Detection of CD44 splice variants in formalin-fixed, paraffin-embedded specimens of human skin cancer.

The standard form of CD44 (CD44s) and CD44 isoforms, containing sequences encoded by one or several of 10 different variant CD44 exons (v1-v10), are thought to play a crucial role in the growth and metastasis of certain human tumors. Recently, monoclonal antibodies (mAbs) directed against all CD44 isoforms (panCD44), or against epitopes encoded by specific variant exons (CD44v) have been developed, which unfortunately only stain cryopreserved tissues. We wished to develop a technique to unmask chemically CD44s and CD44v epitopes in paraffin-embedded specimens of human skin cancers, so that they would be accessible for these mAbs. To address this issue, CD44s and CD44v expression was compared in cryopreserved and in formalin-fixed, paraffin-embedded biopsies obtained from the same basal cell carcinomas (BCC), squamous cell carcinomas (SCC), primary malignant melanomas (PMM) and metastatic malignant melanomas (MMM). Formalin-fixed tumors were deparaffinized and treated briefly with an antigen retrieval fluid (TUFTM) at 95 degrees C or left untreated. In untreated paraffin-embedded tissues, no CD44s or CD44v staining was detected. In contrast, in antigen retrieval fluid-treated biopsies CD44s and CD44v expression was identical to that in cryopreserved specimens of the same tumor with the exception of mAbs detecting v7/8 and v10. We conclude that antigen retrieval unmasks certain epitopes in formalin-fixed, paraffin-embedded tissues, thus facilitating future research on the relevance of CD44s and CD44v expression for human skin carcinogenesis.

Alternative Splicing↗
PubMed1997

Changes of cytokeratin expression in the epidermis with chronic venous insufficiency.

BACKGROUND: A specific, individual pattern of cytokeratins (Cks) is expressed by each epithelial cells as part of the cytoskeleton. Cks are established as markers of epidermal differentiation. Basal cells are characterized by CK5 and 14 expression, whereas CK 1, 10 and 11 are typical for the suprabasal compartment of normal epidermis. Here, we investigated changes of Pan-CK, CK 10, and CK 14 expression in the epidermis in various stages of chronic venous insufficiency (CVI). PATIENTS AND METHODS: In punch biopsies of 24 patients with chronic venous insufficiency and of 6 volunteers with normal skin Cks were detected by indirect immunofluorescence using monoclonal antibodies against CK 10, CK 14 and Pan-CK. RESULTS: CK 10 and Pan-CK staining intensity increased with the severity of CVI changes. Suprabasal cells showed an upregulation of CK 10 and Pan-CK expression first in venous eczema. CK 14 expression is under normal condition confined to the basal cell layer of the epidermis. However in venous eczema and lipodermatosclerosis, CK 14 is detected in the suprabasal epidermal compartment. CONCLUSIONS: It is therefore concluded that altered differentiation and stratification mechanisms occur in keratinocytes in the epidermis with CVI first detectable in the stage of venous eczema. These changes are accompanied by a characteristic CK expression pattern.

Adult↗
PubMed1996

Molecular characterization of cyclic and obligate parthenogens in the aphid Rhopalosiphum padi (L.).

Holocyclic clones of the aphid Rhopalosiphum padi (L.) reproduce by cyclic parthenogenesis, whereas anholocyclic individuals are obligate parthenogens. Mitochondrial DNA and (mtDNA) and random amplified polymorphic DNA markers in R. padi as well as plasmid DNA markers of its bacterial endosymbiont, Buchnera aphidicola, were examined to determine the extent of genetic divergence between clones with these differing breeding systems. These analyses revealed that cyclically parthenogenetic lineages possessed differing mtDNA and plasmid haplotypes than most obligately asexual clones. The extent of sequence divergence between the maternally inherited molecules suggest a relatively ancient origin of asexuality. Our work also identified a random amplified polymorphic DNA marker linked to the life-cycle variation in R. padi. This marker not only permits the rapid diagnosis of breeding system but sets the stage for studies to identify the gene(s) controlling this variation in mode of reproduction.

Animals↗
PubMed1996

CD40 is functionally expressed on human keratinocytes.

The CD40/gp39 pathway is known to be an important feature of B/T cell collaboration leading to T cell-dependent activation, proliferation or differentiation of B cells. Additionally, CD40 is involved in the regulation of B cell survival and apoptosis. Recently, CD40 has been shown to be expressed functionally on non-hematopoietic cells, i.e. endothelial cells. Here, we demonstrate that human keratinocytes (KC) cultured in vitro express CD40 constitutively. The surface expression of CD40 is markedly up-regulated following stimulation with interferon (IFN)-gamma, but not with tumor necrosis factor-alpha or interleukin (IL)-1 beta. This process is regulated at the CD40 mRNA level as demonstrated by Northern blot analysis. Furthermore, ligation of CD40 via soluble gp39, the CD40 ligand, enhances intercellular adhesion molecule (ICAM)-1 and Bcl-x up-regulation on IFN-gamma-stimulated KC, but not lymphocyte function-associated antigen (LFA)-3, B7-2, HLA-DR, or Fas expression. The release of IL-8 is also induced following CD40 ligation on KC. In psoriasis, a T cell-mediated inflammatory skin disease, KC have a markedly enhanced expression of CD40. This expression co-localizes with the expression of ICAM-1, Bcl-x, and an influx of CD3+ T cells. These findings suggest a functional role of CD40 on KC in inflammatory skin disorders such as psoriasis and could make a therapeutic intervention by disrupting the CD40/gp39 pathway an approach to consider in these inflammatory skin diseases.

Adult↗