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Biomedical subjects

O Baadsgaard

Publications and source records attributed to O Baadsgaard.

At least 55 records · Page 3Linked to original sources
PubMed1992

UV exposure reduces immunization rates and promotes tolerance to epicutaneous antigens in humans: relationship to dose, CD1a-DR+ epidermal macrophage induction, and Langerhans cell depletion.

Increasing UVB radiation at the earth's surface might have adverse effects on in vivo immunologic responses in humans. We prospectively randomized subjects to test whether epicutaneous immunization is altered by prior administration of biologically equalized doses of UV radiation. Multiple doses of antigens on upper inner arm skin (UV protected) were used to elicit contact sensitivity responses, which were quantitated by measuring increases in skin thickness. If a dose of UVB sufficient to induce redness (erythemagenic) was administered to the immunization site prior to sensitization with dinitrochlorobenzene (DNCB), we noted a marked reduction in the degree of sensitization (P less than 0.0006) that was highly dose responsive (r = 0.98). Even suberythemagenic UV (less than a visible sunburn) resulted in a decreased frequency of strongly positive responses (32%) as compared to controls (73%) (P = 0.019). The rate of immunologic tolerance to DNCB (active suppression of a subsequent repeat immunization) in the groups that were initially sensitized on skin receiving erythemagenic doses of UV was 31% (P = 0.0003). In addition, a localized moderate sunburn appeared to modulate immunization with diphenylcyclopropenone through a distant, unirradiated site (41% weak responses) as compared to the control group (9%) (P = 0.05). Monitoring antigen presenting cell content in the epidermis revealed that erythemagenic regimens induced CD1a-DR+ macrophages and depleted Langerhans cells. In conclusion, relevant and even subclinical levels of UV exposure have significant down modulatory effects on the ability of humans to generate a T-cell-mediated response to antigens introduced through irradiated skin.

Antigens, CD↗
PubMed1992

Psoriatic skin reveals the in vivo presence of an epidermal IL-1 inhibitor.

Production of inhibitor(s) of IL-1 activity can be induced in keratinocytes by exposure to UVB. We describe in this study the characterization of an endogenous constitutively expressed IL-1 inhibitor which is present in extracts of human psoriatic epidermal keratome biopsies. Size-fractionated extracts of normal human epidermis did not reveal IL-1 inhibitory factor(s) activity in normal epidermis. Psoriatic epidermal extracts, however, contained virtually no IL-1 bioactivity and inhibited the activity of recombinant human IL-1 beta. This IL-1 inhibitor has a molecular weight of approximately 30 kDa and a pI of 5.3, as revealed by fast protein liquid chromatography size fractionation and chromatofocusing of psoriatic epidermal extracts. IL-1 inhibitory activity was not blocked by neutralizing anti-TGF beta monoclonal antibody. It did not have any inhibitory effect upon normal cellular proliferation but could block the IL-1 induction of IL-2 production by LBRM.33 cells as late as 4 h after exposure of LBRM.33 cells to IL-1. Thus, in vivo human psoriatic epidermis expresses an IL-1 inhibitor that specifically inhibits IL-1 activity but which appears distinct from previously described UV-induced epidermal IL-1 inhibitory activity or TGF beta.

Biopsy↗
PubMed1992

T-cell activation is potentiated by cytokines released by lesional psoriatic, but not normal, epidermis.

BACKGROUND AND DESIGN: T-cell activation appears to be critical for the maintenance of psoriatic lesions. In this study, we determined whether cytokines released by epidermal cells from psoriatic lesions are providing signals that result in propagation of intralesional T-cell activation. Supernatants were obtained from epidermal cell cultures derived from skin biopsy specimens of psoriatic patients and normal subjects. These supernatants were added to purified normal CD4+ T cells activated via T-cell receptor (immobilized anti-CD3 and fibronectin) or via other activating pathways (anti-CDw60 or UM4D4). RESULTS: Psoriatic supernatants (n = 9), but not normal supernatants (n = 7, P < .0006), potentiated T-cell stimulation with anti-CD3 and fibronectin to 172% +/- 41% over control stimulation levels. The degree of lesional psoriatic epidermal cell potentiation correlated with the clinical severity of the lesion (r = .82, P = .007). Psoriatic epidermal cytokine potentiation of T-cell activation was not limited to T-cell receptor mediated stimulation; potentiation of anti-CDw60-stimulated CD4+ T cells was also observed. Neutralizing antisera to interleukin 1 and interleukin 8, but not interleukin 6, were found to reduce only partly the observed potentiation of T-cell activation. To determine whether cyclosporine is down modulating T-cell-potentiating cytokine activity in psoriasis, we compared samples obtained during a double-blind clinical trial of intralesional cyclosporine. T-cell-potentiating activity from psoriatic lesional sites treated with cyclosporine was not significantly modulated relative to the activity derived from vehicle-treated or untreated sites. CONCLUSION: These data demonstrate that lesional psoriatic epidermal cells release a balance of cytokines that potentiate T-cell activation. Because normal epidermal cells do not potentiate T-cell activation in this system, these findings demonstrate a mechanism by which the epidermis may non-specifically potentiate and perpetuate T-cell activation in psoriatic lesions.

CD4-Positive T-Lymphocytes↗
PubMed1991

Hyperstimulatory CD1a+CD1b+CD36+ Langerhans cells are responsible for increased autologous T lymphocyte reactivity to lesional epidermal cells of patients with atopic dermatitis.

We studied whether abnormalities in epidermal APC could be responsible for intracutaneous T cell activation in atopic dermatitis (AD). In the absence of added Ag, patients' peripheral blood T cells demonstrated significantly increased proliferation to their autologous lesional epidermal cells (mean +/- SEM = 19,726 +/- 9,754 cpm [3H]TdR uptake) relative to epidermal cells from uninvolved AD skin (2179 +/- 697 cpm) (n = 10) (p = 0.0001, log transformed data). AD T cell proliferative responses to autologous epidermal cells were dependent upon cells expressing HLA-DR, CD1a, and CD36, and not upon keratinocytes or their cytokines. Ultrastructurally, these cells ranged from typical Langerhans cells to indeterminate cells with irregular nuclear contours. Enriched populations of lesional AD Langerhans cells were highly stimulatory for autologous T cells, whereas equal numbers of Langerhans cells from non atopic epidermis were poor stimulators, even at high concentrations. The dermal perivascular dendritic cell markers CD36 and CD1b, not usually present on normal epidermal APC, were expressed by 40 and 60% of lesional AD CD1a+ epidermal Langerhans cells, respectively. Addition of anti-CD1b to cocultures of AD epidermal cells and autologous T lymphocytes augmented T cell activation, suggesting that the expression of CD1b by AD Langerhans cells may represent over expression of a molecule functionally linked to the enhanced T cell stimulatory capacity of these cells. Thus, stimulatory signals for T cells contained within AD epidermis are carried by cells in an abnormal differentiation state as indicated by expression of phenotypic characteristics of both epidermal and dermal antigen presenting cells (HLA-DR+, CD1a+, CD1b+, CD36+). We propose that activation of autologous T cells by an altered cutaneous APC population may represent a mechanism for the hyperactive and disordered cell-mediated immune response that characterizes the dermatitic lesions of AD.

Antigen-Presenting Cells↗
PubMed1991

Epidermal interleukin 1 alpha functional activity and interleukin 8 immunoreactivity are increased in patients with cutaneous T-cell lymphoma.

Previous studies have suggested that epidermal-derived interleukin-1 is involved in the pathogenesis of cutaneous T-cell lymphoma (CTCL); however, the findings are conflicting and studies that combine immunohistochemistry and functional activity have not been performed. We investigated the interleukin-1 level in epidermis of patients with cutaneous T-cell lymphoma using both immunohistochemistry, enzyme-linked immunosorbent assays, and the thymocyte co-stimulation assay. Using supernatants obtained from epidermal cell cultures, we found a significant but small increase of interleukin 1 alpha protein release from involved CTCL epidermis compared to normal epidermis from healthy individuals. Both keratinocytes and leukocytes could release interleukin-1 alpha, but the majority was derived from the keratinocytes. Interleukin-1 beta protein was not detectable. In the thymocyte assay, interleukin-1 alpha was found to be biologically active. When lymphokines derived from a T-cell clone obtained from involved CTCL skin were co-cultured with epidermal cells, an enhanced release of epidermal interleukin-1 alpha could be demonstrated. Because interleukin 1 alpha was increased, we investigated the presence of interleukin 1-inducible keratinocyte-derived interleukin 8 and found it increased in CTCL epidermis compared to normal epidermis from healthy individuals. This study demonstrated an elevated epidermal IL-1 alpha level and IL-8 immunoreactivity in CTCL epidermis, which suggests that this elevated level is induced by lymphokines released from activated T cells.

Cells, Cultured↗
PubMed1991

In vivo ultraviolet irradiation of human skin results in profound perturbation of the immune system. Relevance to ultraviolet-induced skin cancer.

Ultraviolet exposure of human skin deletes the function of antigen-presenting Langerhans cells normally resident within the epidermis. Langerhans cells are capable of activating T-lymphocytes by presenting antigens (such as nickel or tumor antigens) to T-lymphocytes. Such activated T-lymphocytes may be involved in the development of contact dermatitis and the immune surveillance of immunogenic skin cancers. Deletion of the function of Langerhans cells does not result in abrogated epidermal antigen presentation since ultraviolet irradiation simultaneously induces the appearance of another epidermal antigen-presenting cell population that is distinct from the Langerhans cell population and seems to induce suppression of the immune response. Suppression of the immune response following ultraviolet irradiation in murine models is critical for growth of immunogenic ultraviolet-induced skin neoplasm. Thus, ultraviolet irradiation of human skin may facilitate the growth of human neoplasms, and the spreading of skin-associated infections due to induction of suppressor T cells.

Animals↗
PubMed1990

In vivo ultraviolet-exposed human epidermal cells activate T suppressor cell pathways that involve CD4+CD45RA+ suppressor-inducer T cells.

In vivo UV exposure of human epidermis abrogates the function of CD1+DR+ Langerhans cells and induces the appearance of CD1-DR+ Ag-presenting macrophages. Epidermal cells from UV-exposed skin, in contrast to epidermal cells from normal skin, potently activate autologous CD4+ T cells, and, in particular, the CD45RA+ (2H4+) (suppressor-inducer) subset. We therefore determined whether UV-exposure in humans leads to a T cell response in which suppression dominates. Autologous blood T cells were incubated with epidermal cell suspensions from in vivo UV-irradiated skin. After activation, repurified T cells were transferred in graded numbers to autologous mononuclear cells (MNC) stimulated with PWM and the resultant IgG production analyzed by ELISA. Relative to T cells activated by unirradiated control epidermal cells, T cells activated by UV-exposed epidermal cells demonstrated enhanced capacity to suppress IgG production (n = 6; p less than or equal to 0.03). Within the T cell population, CD8+ cells stimulated by UV-exposed epidermal cells could be directly activated to suppress PWM-stimulated MNC Ig production if IL-2 was provided in the reaction mixture. The suppressive activity was also transferable with purified CD4+ T cells stimulated by UV-exposed epidermal cells (n = 10; p less than or equal to 0.01), and was radiosensitive. Suppression was decreased when PWM-stimulated MNC were depleted of CD8+ T cells before mixing with CD4+ T cells activated by UV-exposed epidermal cells, suggesting indirect induction of CD8+ Ts cells contained within the responding MNC populations. Indeed, physical depletion of CD45RA+ cells resulted in total abrogation of the suppressor function contained in the CD4+ T cells. Activation of suppressor function was critically dependent on DR+ APC contained in UV-exposed epidermis. The data suggest that UV-exposure modulates cutaneous APC activity in humans, as in mice, such that the dominant immune response is tilted toward suppression. These mechanisms in normal individuals may function to dampen responses to UV-induced endogenous Ag that are pathogenic in autoimmune disorders. However, these mechanisms might also facilitate the growth of UV-induced skin cancers.

Antibody Formation↗
PubMed1990

IL-1 activity is reduced in psoriatic skin. Decreased IL-1 alpha and increased nonfunctional IL-1 beta.

IL-1 may influence or be influenced by a number of abnormalities present in psoriasis; including keratinocyte proliferation, eicosanoid production, fibroblast activation, endothelial cell adhesiveness, T cell infiltration and activation, cyclic nucleotide metabolism, and transmembrane signal transduction mechanisms. We assessed IL-1 regulation in normal, uninvolved, and involved skin of psoriatic patients using immunofluorescence microscopy, a sensitive ELISA method to quantitate immunoreactive IL-1 beta and IL-1 alpha protein levels, the thymocyte proliferation costimulation assay, costimulation of the LBRM.33 IL-1-sensitive cell line, and Northern blotting of cellular RNA to quantitate IL-1 alpha and beta mRNA. IL-1 beta was easily detectable by immunofluorescence microscopy and found to be localized predominantly in epidermal keratinocytes, whereas IL-1 alpha was not detectable with this method. Immunoreactive IL-1 beta was found to be elevated in cytosolic extracts derived from involved psoriatic keratomes relative to keratomes of normal skin. The elevated IL-1 beta protein was accompanied by elevated levels of IL-1 beta mRNA in psoriatic skin relative to normal skin. In contrast, immunoreactive IL-1 alpha levels were markedly reduced in lesional psoriatic skin. In functional assays using both the thymocyte proliferation assay and the LBRM.33 cell line, IL-1 activity from psoriatic involved skin keratomes was markedly reduced relative to that of uninvolved psoriatic keratomes and normal skin. All activity of both normal and psoriatic skin was attributable to IL-1 alpha. The elevated IL-1 beta immunoreactive protein present in psoriatic skin was found to be functionally inactive in these assays. The inactivity of the IL-1 beta was not due to an artifact of the cytosolic method of preparation because IL-1 beta released by psoriatic skin into the media was also nonfunctional. This was in keeping with the demonstration that the IL-1 beta was nonfunctional despite existing as a processed molecule. Taken together, these data demonstrate uncoordinated regulation of IL-1 alpha and Il-1 beta in psoriasis. The profound and complex changes in this system suggest IL-1 dysregulation may be integrally involved in the inflammatory, biochemical, and proliferative processes involved in the pathophysiology of psoriasis.

Biological Assay↗
PubMed1990

T cell receptor beta-chain gene rearrangement without gamma-chain gene rearrangement in cutaneous T cell lymphoma: an unusual finding.

T cells from the blood and skin of a patient with cutaneous T cell lymphoma demonstrated rearrangement of the T cell receptor beta-chain gene in the absence of rearrangement of the gamma-chain gene. To our knowledge, this has not been previously reported. This finding was unexpected in light of prevailing concepts of T cell ontogeny. Potential explanations for it are discussed.

Aged↗
PubMed1990

Interactions of epidermal cells and T cells in inflammatory skin diseases.

Multiple cell types and their factors and cytokines are involved in regulating the immune response in inflammatory skin diseases. Stimulatory and inhibitory factors interact to determine whether the immune response is regulated up or down. Normally, stimulatory signals are counteracted by inhibitory signals to prevent an immune reaction from being initiated. However, exogenous antigens and irritants or endogenous factors and altered immunogenic self-peptides can upset this balance. When that occurs, T cells are activated and an inflammatory skin reaction develops. Lymphokines released from such activated T cells can modify the phenotype and function of normal keratinocytes. They can induce the expression of adhesion molecules and receptors involved in antigen presentation. Furthermore, they can also stimulate keratinocyte proliferation. This may be important in development of the hyperplasia seen in inflammatory skin diseases, especially in psoriasis. Cytokines released from the activated keratinocytes can both stimulate and attract T cells to the epidermis and thereby continue the ongoing immune reaction.

Dermatitis↗
PubMed1990

Effects of cyclosporine on immunologic mechanisms in psoriasis.

A major impetus for further investigation of cellular immunologic mechanisms in psoriasis has been the discovery that cyclosporine, a potent immunosuppressive, is highly effective in the treatment of psoriasis. Cyclosporine has significant inhibitory effects on the ability of T cells to become activated. However, a direct activity of this drug on human keratinocyte signal transduction or growth has been difficult to demonstrate at relevant concentrations. Nevertheless, treatment of psoriasis or of 12-O-tetradecanoyl phorbol-13-acetate-treated murine skin with cyclosporine does reverse many epidermal abnormalities that are common to these two systems. This suggests that the compound exerts an indirect effect on epidermal keratinocytes in vivo, perhaps through immunocyte inhibition. During treatment of psoriasis patients, cyclosporine therapy resulted in selective changes in the numbers and functions of certain antigen-presenting cell subsets (which were distinct from Langerhans cells) and T-cell subsets. These changes were accompanied by indirect evidence of decreased T-cell lymphokine release. Lesional activity of cyclosporine-treated psoriasis patients was closely correlated with the degree of T-cell activation caused by antigen-presenting cells. Cyclosporine inhibition of lymphokine or cytokine release may result in decreased recruitment of non-Langerhans antigen-presenting cells into the epidermis and thus decreased immunoreactivity in the lesion.

Cyclosporins↗
PubMed1990

UM4D4+ (CDw60) T cells are compartmentalized into psoriatic skin and release lymphokines that induce a keratinocyte phenotype expressed in psoriatic lesions.

UM4D4 (CDw60), the surface molecule of a novel antigen-independent T-cell activation pathway, was found to be highly expressed on lesional psoriatic T cells. To examine whether UM4D4 represents a T-cell activation pathway for psoriatic T cells, a T-cell line was initiated from an acute skin lesion and cloned by limiting dilution. Clonality was verified by analysis of T-cell receptor gene rearrangement. All T-cell clones tested, whether CD4+2H4+CD8-, CD4+2H4-CD8-, or CD4-CD8+CD11b-, expressed UM4D4 and were activated by the monoclonal antibody anti-UM4D4. Lesional psoriatic T-cell clones were heterogeneous in the degree of anti-UM4D4-induced proliferation and in their production of IL-2 and gamma-interferon. Lymphokines released by anti-UM4D4 activation were capable of inducing ICAM-1 and HLA-DR expression on cultured normal keratinocytes. Thus, the high expression of UM4D4 on T-cells in psoriatic skin provides an alternative mechanism for T-cell activation that may be operative in the psoriatic lesional milieu. Indeed, activation of lesional T-cells through the UM4D4 molecule resulted in release of lymphokines that directly induced keratinocytes to express a phenotype displayed in psoriatic skin lesions.

Antigens, CD↗
PubMed1990

Interleukin-1 in human skin: dysregulation in psoriasis.

Cytokine dysregulation is an attractive concept to explain many of the observed abnormalities in psoriasis. IL-1, in particular, can potentiate immune cellular activation, activate fibroblasts, and increase endothelial cell adhesiveness to leukocytes. Here, we review IL-1 regulation in normal and psoriatic skin in vivo in relation to normal skin and cultured keratinocytes. Contrary to expectations, IL-1 functional activity in psoriatic lesions is reduced, not increased, relative to normal skin. The reduction is attributable to the presence of IL-1 inhibitors, reduced IL-1alpha levels, and an IL-1beta that lacked function in T-cell assays. IL-1beta protein is actually significantly increased in psoriatic lesions, but the mechanism of its non-functionality remains unclear. Unlike cultured keratinocytes, which accumulate large, inactive IL-1beta precursors, both normal and psoriatic skin process IL-1beta to a mature form. Novel mechanisms of post-translational processing by epidermis in vivo may generate a novel form of IL-1beta with unknown functions. The marked abnormalities of IL-1 regulation in psoriatic skin suggest that this molecule may be important in normal skin homeostasis.

Humans↗
PubMed1990

The role of immune system in the pathogenesis of psoriasis.

Psoriatic involved skin contains an increased number of activated T cells. The mechanism through which these T cells achieve and maintain their activated state is unknown, and both antigen-dependent and -independent mechanisms may contribute. Recently a novel pathway of antigen-independent T-cell activation has been described. This pathway is identified by a monoclonal antibody that binds to a T-cell membrane surface molecule termed "UM4D4." This molecule is expressed on a minority (20%) of psoriatic peripheral blood T cells but on a majority (75%) of the T cells in lesional skin. Thus, UM4D4 could play a role in antigen-independent T-cell activation in psoriasis. Indeed the monoclonal antibody anti-UM4D4 consistently induces proliferation of psoriatic UM4D4+ T-cell clones. The activity of antigen-dependent pathways are also enhanced in psoriatic epidermis in as much as involved skin relative to uninvolved skin contains an increased number and function of antigen-presenting cells. Upon activation, the lesional T cells release lymphokines. Central to the immune hypothesis of psoriasis is that some of these T-cell lymphokines act on keratinocytes to induce changes characteristic of psoriasis. Indeed lymphokines from lesional psoriatic T-cell clones directly alter in vitro keratinocyte phenotype through induction of intercellular adhesion molecule-I (ICAM-1) and HLA-DR cell-surface expression. Furthermore, the lymphokines also enhance keratinocyte growth. These data suggest a critical role for the immune system in the pathogenesis of psoriasis.

Antigens, CD↗