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Biomedical subjects

O Baadsgaard

Publications and source records attributed to O Baadsgaard.

At least 37 records · Page 2Linked to original sources
PubMed1997

Lesional alopecia areata T lymphocytes downregulate epithelial cell proliferation.

Alopecia areata is characterized by peribulbar infiltration by activated T cells. The function of these T cells in the pathogenesis is unknown. To elucidate the potential role of lesional T cells in the regulation of hair growth, T-cell clones from the margin of involved alopecia areata lesions from three patients were obtained by cloning, using the limiting dilution method. Of these T-cell clones, 31 were CD4+CD8-, 15 were CD8+CD4- and 2 were CD4-CD8-. The T-cell clones were activated and the supernatant harvested 24 h later and tested for its capacity to regulate proliferation of neonatal keratinocytes. The majority of the T-cell clone supernatants inhibited epithelial cell proliferation in a dose-dependent fashion. When the cytokine profiles of conditioned T-cell medium were compared with the growth-regulatory capacity, it was found that T-cell clones that released high amounts of interferon gamma and/or tumour necrosis factor alpha inhibited keratinocyte growth. In conclusion, T cells derived from the margin of active alopecia areata lesions are able to downregulate epithelial cell proliferation. This points to an important role of the immune system, especially the T cells, in this disease.

Alopecia Areata↗
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

Lesional psoriatic T cells contain the capacity to induce a T cell activation molecule CDw60 on normal keratinocytes.

In this report we demonstrate, that in psoriatic skin, basal and suprabasal keratinocytes express CDw60. The CDw60-specific monoclonal antibody, UM4D4, has recently been shown to recognize the 9-O-acetylated disialosyl group on ganglioside GD3. The CDw60 antigen on cultured keratinocytes also seems to be identical with the 9-O-acetylated disialosyl group, because the anti-UM4D4 binding was markedly reduced after neuraminidase treatment of keratinocytes. To examine whether factors from T cells in psoriatic lesions are responsible for the overexpression of CDw60 on keratinocytes, T cell lines obtained from lesional skin were initiated and cloned by limiting dilution. Factors released from 19 of 19 activated T cell clones up-regulated CDw60 expression on cultured normal keratinocytes. T-cell-secreted cytokines, including interleukin (IL)-2, IL-3, IL-4, IL-6, IL-13, transforming growth factor-beta, granulocyte/macrophage colony-stimulating factor, and interferon-gamma were tested for their capacity to modulate keratinocyte CDw60 expression. IL-4 and IL-13 strongly up-regulated the expression of CDw60; by contrast, interferon-gamma down-regulated keratinocyte CDw60 expression. Interestingly, IL-13 may in part be responsible for the T-cell-induced up-regulation of CDw60, because anti-IL-13 partly neutralized this effect of the T cell supernatant. In conclusion, CDw60 expression on psoriatic epidermal keratinocytes is likely induced by intralesionally activated T cells and may in part be due to IL-13. These findings would represent a novel mechanism by which T cells participate in the pathogenesis of psoriasis.

Antibodies↗
PubMed1996

Staphylococcal enterotoxin B applied on intact normal and intact atopic skin induces dermatitis.

BACKGROUND AND DESIGN: Colonization of inflammatory skin diseases with Staphylococcus aureus is a frequent phenomenon and may cause exacerbation of the skin disease. Staphylococcus aureus strains present on atopic dermatitis are capable of releasing staphylococcal enterotoxins, a group of superantigens that are very potent T-cell activators. To determine whether the superantigen staphylococcal enterotoxin B can induce inflammation when applied on the skin, staphylococcal enterotoxin B was applied with and without occlusion on the volar aspect of the skin on the forearm of 10 subjects without skin disease and six subjects with atopic dermatitis of minimal activity and no eczema on the volar aspect of the skin on their forearm. The main outcome measures were clinical rating; determination of the increase of the thickness of the skin-fold; and determination of skin blood flow. RESULTS: Clinically, staphylococcal enterotoxin B induced skin changes of erythema and induration in 10 of 10 healthy volunteer subjects and six of six subjects suffering from atopic dermatitis, while the vehicle induced clinically evident skin changes in only one of 10 healthy subjects and none of six subjects with atopic dermatitis. On day 3 after the application of an occluded patch containing 10 micrograms/cm2 of staphylococcal enterotoxin B in the healthy subjects, the thickness of the skinfold increased 0.47 +/- 0.49 mm (mean +/- SD) (n = 9; P < .02) relative to the increase in the thickness of the skinfold following application of the vehicle. The Doppler laser-measured skin blood flow index had increased from 1.0 +/- 0.4 to 5.3 +/- 3.7 (mean +/- SD) (n = 10; P < .002). On day 3 after the application of occluded patchs containing 10 micrograms/cm2 of staphylococcal enterotoxin B in the subjects suffering from atopic dermatitis, the increase in the thickness of the skinfold increased 0.20 +/- 0.24 mm (n = 6; P, not significant) relative to the increased thickness in the skinfold following application of the vehicle. The Doppler laser-measured skin blood flow index had increased from 1.1 +/- 0.4 to 3.7 +/- 2.2 (n = 6, P, not significant). Three of six subjects suffering from atopic dermatitis experienced a flare of their disease in the elbow flexure ipsilaterally to where the staphylococcal enterotoxin B patch was applied. CONCLUSIONS: The superantigen staphylococcal enterotoxin B applied on intact skin from both normal subjects and patients with atopic dermatitis induces an inflammatory reaction. This finding suggests that superantigens released from S aureus present on the skin in inflammatory skin diseases may exacerbate and sustain the inflammation.

Adult↗
PubMed1996

Ultraviolet B-exposed major histocompatibility complex class ii positive keratinocytes and antigen-presenting cells demonstrate a differential capacity to activate T cells in the presence of staphylococcal superantigens.

In this study we tested the capacity of ultraviolet B (UVB)-irradiated major histocompatibility complex (MHC) class II+ keratinocytes, monocytes and dendritic cells to activate T cells in the presence of Staphylococcus enterotoxin B. We demonstrated that UVB irradiation of MHC class II+ keratinocytes does not change their capacity to activate T cells in the presence of Staphylococcus enterotoxin B. In contrast, UVB irradiation of antigen-presenting cells decreases their capacity to activate T cells. This differential capacity to activate T cells after UVB irradiation was not due to factors released from UVB-irradiated cells. The interferon-gamma induced upregulation of HLA-DR and intercellular adhesion molecule-1 on keratinocytes does not seem to be the only explanation, since UVB irradiation decreased the accessory cell function of interferon-gamma pretreated monocytes. Differential requirements for and UVB regulation of costimulatory molecules may be involved, since blocking of the B7/CD28 pathway affects the capacity of dendritic cells but not keratinocytes to activate T cells in the presence of Staphylococcus enterotoxin B. Thus, MHC class II+ keratinocytes in the presence of superantigens released from staphylococci may activate T cells and maintain inflammation despite UVB treatment.

Adult↗
PubMed1995

Superantigens. Do they have a role in skin diseases?

Superantigens are a group of bacterial and viral proteins that are characterized by their capacity to stimulate a large number of T cells. They bind directly to the major histocompatibility complex class II molecule on the antigen-presenting cell and cross-link the antigen-presenting cell with T cells expressing certain T-cell receptors, leading to polyclonal T-cell activation. They have been shown to play a role in toxic shock syndrome and mucocutaneous lymph node syndrome and are postulated to play a role in other systemic diseases. Because inflammatory skin diseases such as atopic dermatitis and psoriasis are often known to be colonized with superantigen-releasing Staphylococcus aureus, the role of superantigens in skin diseases is of major importance. Recent studies have demonstrated that if a staphylococcal superantigen is applied on intact human skin, a clinical picture of dermatitis evolves. Furthermore, in the presence of superantigens, epidermal cells potently activate T cells. Thus, superantigens may play a role in the induction and exacerbation of inflammatory skin diseases.

Humans↗
PubMed1995

CDW60, which identifies the acetylated form of GD3 gangliosides, is strongly expressed in human basal cell carcinoma.

The monoclonal antibody UM4D4, assigned to the CDw60 cluster of differentiation, identifies an epitope expressed on a subset of normal T cells, some malignant T cells, melanocytes, malignant melanoma cells and hyperproliferative psoriatic keratinocytes. CDw60 antibodies bind to the acetylated form of GD3 gangliosides. These gangliosides have been implicated in the control of cellular proliferation. Because the acetylated form of GD3 has been demonstrated in basal cell carcinomas, we determined whether the CDw60 epitope was expressed in basal cell carcinomas (n = 24) and squamous cell carcinomas (n = 2). Biopsies of these tumours were sectioned on a cryostat, and stained with anti-CDw60 using a sensitive indirect immunoperoxidase technique. A mean of 74 +/- 4% (mean +/- SEM) of the basal cell carcinoma cells expressed CDw60. In contrast, CDw60 expression in normal skin was confined to melanocytes and a few scattered keratinocytes at the basal cell layer. CDw60 expression in basal cell carcinomas was highly upregulated at the tumour front in most of the lesions, whereas the squamous cell carcinomas showed uniform CDw60 expression in all areas.

Aged↗
PubMed1994

Interferon gamma-treated keratinocytes activate T cells in the presence of superantigens: involvement of major histocompatibility complex class II molecules.

During inflammation in the skin keratinocytes can express major histocompatibility complex class II molecules but are unable to present nominal antigens to resting T cells. Certain bacteria including staphylococci produce a new class of antigens termed superantigens that are very potent T-cell activators. Using an in vitro model with cultured normal human keratinocytes and purified allogeneic T cells, we demonstrated that major histocompatibility complex class II+ keratinocytes can activate T cells in the presence of the superantigen staphylococcal enterotoxin B. Major histocompatibility complex class II+ keratinocytes activated T cells at concentrations of staphylococcal enterotoxin B as low as 100 pg/ml. The activation required contact between keratinocytes and T cells, was inhibited with a monoclonal antibody to human leukocyte antigen DR, -DQ, and was not affected by fixation of the keratinocytes. These data show that major histocompatibility complex class II+ keratinocytes activate T cells in the presence of the superantigen staphylococcal enterotoxin B.

Antibodies, Monoclonal↗
PubMed1994

In cutaneous T-cell lymphoma, class II MHC molecules on CD1+ antigen-presenting cells are upregulated in involved compared with uninvolved epidermis.

CD1+ antigen-presenting cells in involved epidermis of patients with cutaneous T-cell lymphoma exhibit and enhanced functional capacity to activate autologous CD4+ T cells compared with CD1+ antigen-presenting cells from uninvolved and normal epidermis. Class II major histocompatibility complex molecules are involved in antigen presentation, and their expression on CD1+ Langerhans cells is known to vary. The expression of all three class II (HLA-DR, -DQ, -DP) molecules was therefore determined on CD1+ epidermal cells from both involved and uninvolved epidermis, using flow cytometry. The involved CD1+ epidermal cells exhibited a 1.5-1.6-fold, statistically significant increase in fluorescence intensity after staining of the class II molecules (HLA-DR, -DQ, -DP) compared with CD1+ epidermal cells from uninvolved epidermis. The autologous CD4+ T cells, activation was almost completely blocked by anti-HLA-DR, and partly by anti-HLA-DQ and anti-HLA-DP. In contrast, an antibody against class I, and an irrelevant control antibody, had no blocking effect. In a pokeweed mitogen assay it was demonstrated that autologous CD4+ T cells, activated by involved epidermal cells, demonstrated suppressor activity rather than helper activity. The suppressor activity was dependent on the presence of HLA-DR-positive epidermal cells. Thus, in cutaneous T-cell lymphoma, class II molecules on the individual CD1+ antigen-presenting cell are upregulated in clinically involved compared with uninvolved epidermis, and these molecules are crucially involved in activation of CD4+ T cells.

Antigen-Presenting Cells↗
PubMed1994

Efficacy and safety of the 20-epi-vitamin D3 analogue KH 1060 in the topical therapy of psoriasis: results of a dose-ranging study.

KH 1060 is a 20-epi-vitamin D3 analogue, structurally related to 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). In vitro, KH 1060 is much more potent than 1,25(OH)2D3 in regulating cell growth and T lymphocyte mediated immune responses, despite a similar calcemic activity in vivo. Therefore, KH 1060 is of potential interest in the treatment of psoriasis and other diseases characterized by accelerated cell growth and T lymphocyte activation. In a multicenter, prospective, randomized, double-blind, vehicle-controlled right/left comparative study, patients with plaque-type psoriasis vulgaris were randomly assigned to one of the following treatment groups: (I) KH 1060 ointment 0.2 microgram/g versus placebo ointment, (II) KH 1060 ointment 0.2 microgram/g versus KH 1060 ointment 0.04 microgram/g, and (III) KH 1060 ointment 0.2 microgram/g versus KH 1060 ointment 1 microgram/g. All treatments were given twice daily for 6 weeks. Sixty-four of the 70 randomized patients completed the study. At the end of treatment, no difference was demonstrated between KH 1060 0.04 microgram/g and vehicle, whereas significantly increasing improvement was found for the doses KH 1060 0.2 microgram/g and KH 1060 1 microgram/g. According to the investigator's overall assessments at the end of treatment, KH 1060 1.0 microgram/g and KH 1060 0.2 microgram/g produced a marked or moderate improvement in most patients. Mild lesional irritation was observed after treatment with KH 1060 as well as with placebo. One patient was withdrawn because of an eczematous reaction, where KH 1060 1.0 microgram/g was applied.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

T-lymphocyte clones initiated from lesional psoriatic skin release growth factors that induce keratinocyte proliferation.

To investigate whether growth factors derived from T cells in psoriatic lesions are able to stimulate keratinocyte growth, T-cell lines were initiated from lesional psoriasis skin and cloned by limiting dilution. Eight clones with good proliferative capacity out of 40 clones from one patient were stimulated. After 24 h, the conditioned medium was harvested and the growth modulatory effect of the conditioned medium on keratinocytes was assessed. Seven of the eight T-cell clones stimulated keratinocyte growth to an extent ranging from 22% +/- 19 to 64% +/- 9 (mean +/- SD of three experiments) of maximal inducible keratinocyte growth, and one T-cell clone had no effect (-5% +/- 2) on keratinocyte growth. Keratinocyte growth was also induced by T-cell clones obtained from two other patients. Several cytokines were tested in this system to determine which T-cell growth factor may induce the keratinocyte growth. None of the cytokines interferon-g, transforming growth factor-beta, interleukin (IL)-2, IL-3, IL-4, IL-6, IL-8, or granulocyte-macrophage colony stimulating factor alone was found to possibly be responsible for the T-cell-induced keratinocyte growth. Thus the nature of the T-cell keratinocyte growth-promoting stimulus remains to be elucidated.

Cell Division↗
PubMed1993

Leukemic T cells from patients with cutaneous T-cell lymphoma demonstrate enhanced activation through CDw60, CD2, and CD28 relative to activation through the T-cell antigen receptor complex.

Antigen-dependent activation of T cells occurs through the T-cell antigen-receptor complex (TCR/CD3). Antigen-independent T-cell activation may occur through the surface molecules CDw60, CD2, and CD28. We wished to determine whether these antigen-independent T-cell-activation pathways could be involved in proliferation of leukemic T cells from patients with cutaneous T-cell lymphoma (CTCL). Whereas CDw60 was only expressed on 28% +/- 7% (mean +/- SEM) of blood T cells obtained from healthy control subjects (n = 4), CDw60 was expressed on 94% +/- 3% of blood T cells obtained from patients with CTCL (n = 4). Dual color immunofluorescence microscopy of the T-cell infiltrate in involved skin of these patients demonstrated that almost 100% of the T cells expressed CDw60. Not only did T cells in the patients with CTCL express CDw60, but triggering of the T cells with anti-CDw60 resulted in enhanced proliferation relative to anti-TCR/CD3 and mitogenic lectins. Other antigen-independent pathways also appeared highly active in the T cells from patients with CTCL because enhanced proliferation relative to anti-TCR/CD3 or mitogenic lectins was found when anti-CD2 or anti-CD28 plus phorbol ester was used as stimulant. Despite the brisk proliferation induced by anti-CDw60, anti-CD2, or anti-CD28, T cells from the patients did not produce detectable amounts of gamma-interferon. The inability to produce gamma-interferon correlates with our finding of absent (n = 3) or weak (n = 1) intercellular adhesion molecule-1 expression in the lesional keratinocytes in these patients. In conclusion, T cells of patients with CTCL demonstrate elevated expression of a T-cell-independent signaling molecule CDw60 and respond to antigen-independent activating signals.

Aged↗