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.     

Expression of the T-cell activation antigens CD27 and CD28 in normal and psoriatic skin

Activated T lymphocytes are thought to be involved in the pathogenesis of psoriasis. From studies with peripheral blood T lymphocytes it is known that T cells show a decrease in membrane expression of CD27 molecules during continuous antigenic stimulation. The T-cell activation molecule CD28 is thought to be involved in the transduction of an antigen-non-specific costimulatory signal. Therefore, in order to elucidate further the pathogenesis of psoriasis we studied the expression of CD27 and CD28, together with CD4, CD8 and CD45RA in this benign inflammatory dermatological disease. We used immunohistochemical techniques to determine absolute numbers of T lymphocytes and expression of these T-cell activation and T-subset-specific molecules in normal (n= 7), uninvolved perilesional (n= 7) and lesional psoriatic (n= 7) skin. We found that not only lesional but also clinically uninvolved perilesional skin showed an increased number of T cells. Further, immunohistochemical studies showed that CD27 is expressed by a minority of normal skin T cells, while in lesional psoriatic skin, expression was even lower, and almost absent in perilesional skin sections. In contrast to normal skin, both perilesional and lesional psoriatic skin contained no CD28 positive T cells. In lesional psoriatic skin, however, T cells showed predominantly the CD4 phenotype, while in perilesional skin CDS positive T cells were dominant. Two conclusions were reached: first, the absolute number of T cells, their CD27, CD28 and CD45RA expression, and the influx of CD8 positive T cells, indicate that perilesional psoriatic skin is different from normal and lesional psoriatic skin; and secondly, the data on CD27 and CD28 suggest that not only lesional but also perilesional psoriatic skin is subject to continuous antigenic stimulation, thus leading to decreased CD27 and CD28 expression on skin T cells.     

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.     

Lymphocyte trafficking in psoriasis: a new perspective emphasizing the dermal dendrocyte with active dermal recruitment mediated via endothelial cells followed by intra-epidermal T-cell activation

Prominent within the inflammatory infiltrate of psoriasis are HLA-DR positive T lymphocytes and factor XIIIa positive dermal dendrocytes. Many investigators studying psoriasis have assumed that the HLA-DR positive T cells are activated, and thereby capable of producing lymphokines such as gamma interferon. However, by immunohistochemical analysis, greater than 95% of the dermal T cells in psoriatic lesions are Ki-67 negative, which suggests that they are in a resting or non-cycling (Go) state. In contrast to the dermal T-cell population, the epidermal T-cell population contains a greater population of Ki-67 positive lymphocytes. The entry of the T cells into the epidermis is, therefore, apparently associated with an important activation event, which in all likelihood involves interaction with the keratinocyte. The presence of activated intraepidermal T cells has been substantiated by the ability to detect gamma interferon mRNA by polymerase chain reaction in epidermal sheets of psoriatic lesions. The pathophysiologic implication in psoriasis for these distinctions and compartmentalization involving dermal and epidermal T cells are placed into the context of a cascade of cellular trafficking events, which are further dissected into a specific network of molecular mediators of inflammation. This report suggests that more attention should be placed on the microenvironment of the skin, with specific emphasis on the mechanism by which T cells accumulate in the dermis and epidermis, and elucidation of the selective inductive and recruitment capabilities of endothelial cells, perivascular dermal dendrocytes, and keratinocytes.     

Skin-infiltrating lymphocytes in normal and disordered skin: activation signals and functional roles in psoriasis and mycosis fungoides-type cutaneous T cell lymphoma.

T lymphocytes recruited into the skin can experience several different outcomes. On the one hand, they may be recruited by adhesion molecules and chemoattractants to enter the perivascular space, but never undergo activation. Other T cells undergo activation and further differentiation under the influence of the cutaneous milieu. These activated lymphocytes then coordinate specific and non-specific immune responses characteristic of inflamed tissue. We have explored two models for studying the activation and function of skin infiltrating T lymphocytes (SIL's). In the first model, we have identified a family of Langerhans cell-related professional dendritic antigen presenting cells that exist in the epidermis and dermis of normal skin, atopic skin, and mycosis fungoides skin. These have APC abilities to activate freshly recruited resting blood T cells that are distinct from another family of macrophage-related cells abnormally present in sunburned or psoriatic skin. In the second model, we examined the function of cells that have already been recruited into the skin of patients with psoriasis and mycosis fungoides. Lesional psoriasis and mycosis fungoides T cells exhibited a variety of T cell receptor gene rearrangements, conclusively demonstrating that heterogeneous populations of T lymphocytes exist in inflamed human skin. From psoriasis, clones were identified that were particularly effective at inducing normal keratinocytes to assume "psoriatic" phenotypic features and functions. Thus, lesional psoriatic SIL's could induce HLA-DR, ICAM, and CDw60 on normal keratinocytes. In addition, psoriatic SIL's induced increased keratinocyte proliferation and cytokine profile changes characteristic of psoriatic epidermis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mechanisms of cyclosporine A inhibition of antigen-presenting activity in uninvolved and lesional psoriatic epidermis

To elucidate how cyclosporine A affects antigen-presenting cell subsets and their function in human skin, we studied patients with psoriasis undergoing a therapeutic trial of cyclosporine A. Immunologic parameters abnormal in psoriatic epidermis were evaluated before and early in the course of therapy. We quantitated function and numbers of skin biopsy-derived epidermal cells with potential antigen-presenting cell (APC) activity. The antigen-presenting capacity of epidermal cells from normal-appearing skin to activate allogeneic T cells was profoundly inhibited (81% decrease) 7 d after the onset of therapy (p less than 0.05). Thus, cyclosporine A therapy inhibited T-cell activation mediated by Langerhans cells in uninvolved skin. By contrast, in lesional skin epidermal allo-antigen presenting activity was only partially inhibited at this early time point (55 +/- 7% decrease) (p less than 0.01, n = 8). The percentage decrease in allo-antigen-presenting cell activity correlated with reduced clinical activity of the lesions, r = 0.84. In three patients also examined at 14 d, we found an additional 42 +/- 5% decrease between day 7 and 14. Decreased allo-antigen-presenting activity in lesional skin was not associated with a decrease in the number of CD1+ Langerhans cells or epidermal cell release of detectable amounts of cyclosporine A or other soluble factors that abrogate T-cell alloreactivity. The time course and degree of inhibition of antigen-presenting capacity within involved psoriatic skin correlated best with a significant (p less than 0.01) reduction in non-Langerhans cell DR+ leukocytes (from 3.0 +/- 1.2% to 1.0 +/- 0.6% at day 7) (r = 0.71). Cyclosporine A therapy was associated with a rapid and complete loss of HLe1-DR+ keratinocytes (94% decrease at 7 d) in lesional skin despite the skin still being quite involved with psoriasis at this point and antigen-presenting cell activity being only 60% reduced. In conclusion, cyclosporine A interferes with T-cell activation by human epidermis through at least two mechanisms: 1) in uninvolved skin, rapid inhibition of Langerhans cell-mediated activation of T cells, and 2) in lesional skin, delayed inhibition of antigen-presenting activity which appears to correlate with the time course and level of reductions in non-Langerhans cell DR+ leukocytes. The antigen-presenting activity of the latter cells appears to be cyclosporine A resistant. In psoriatic lesions, early and complete loss of DR expression on lesional keratinocytes during cyclosporine A therapy is likely due to decreased lesional T-cell lymphokine production critical for keratinocyte DR expression.(ABSTRACT TRUNCATED AT 400 WORDS)     

Early migration of cutaneous lymphocyte-associated antigen (CLA) positive T cells into evolving psoriatic plaques

The majority of T cells in lesional psoriatic skin express the skin homing receptor, cutaneous lymphocyte-associated antigen (CLA). We investigated whether this reflects the selective migration of CLA positive cells into evolving psoriatic plaques, consistent with an important role in disease onset, or whether this occurs in the context of an established cutaneous inflammatory response. We identified the advancing edge of plaques in 16 patients with chronic plaque psoriasis using scanning laser Doppler fluxmetry, and performed immunohistochemical analysis of i) lesional psoriatic skin, ii) clinically normal skin immediately in front of the advancing plaque edge, and iii) uninvolved skin distant from the plaque edge. The T-cell infiltrate was characterized using monoclonal antibodies to CD3, CLA and the integrin alphaEbeta7, which is associated with the retention of lymphocytes at mucosal sites. Epithelial proliferation was assessed using a monoclonal antibody to the nuclear proliferation marker Ki67. There was enrichment of CLA positive T cells in evolving psoriatic skin compared to distant, uninvolved skin (mean CLA positive 75.9% vs 47.8%; P<0.003). This accumulation of CLA positive cells occurred before epidermal hyperproliferation was evident, suggesting that this population of cells plays an important, early role in disease pathogenesis. Established lesional psoriatic skin contained a mixed infiltrate of CLA positive (mean 53.2%) and alphaEbeta7 positive (mean 18.2%) cells, suggesting less tissue-specific T-cell infiltration, although an additional, specific role for alphaEbeta7 in cutaneous inflammation cannot be excluded. Furthermore, this study has highlighted scanning laser Doppler fluxmetry as a useful investigative tool, permitting analysis of the earliest and therefore potentially most important changes in psoriatic plaque formation.     

Antigen-independent expansion of T cells from psoriatic skin lesions: phenotypic characterization and antigen reactivity

The pathogenesis of psoriasis appears to depend on T cells, which have been proposed to mediate the disease through an autoimmune process. To test this hypothesis we have propagated four T-cell lines from biopsies of psoriatic skin lesions by antigen-independent methods. Flow cytometric immunophenotyping showed the lines to be composed mainly of CD4-positive, αβ-cell receptor (TCR)-positive cells, which secreted a cytokine profile suggestive of predominant T-helper type 1 (Th1) status. Analysis of TCR variable region (Vβ) usage revealed two- to eight-fold increases in the expression of certain Vβ species in lesional lines as compared with autologous peripheral blood mononuclear cells (PBMC), with the increased Vβ species being expressed on more than 5% of cells in two of the lines. Lines were also used to test for responses to a range of epidermal antigen preparations in the presence of irradiated autologous PBMC as antigen-presenting cells. The lines failed to proliferate in response to psoriatic lesional stratum corneum extracts, dispase-separated normal human epidermal extracts, and an epidermal keratin preparation before and after trypsinization, in spite of good proliferative responses to anti-CD3 which indicated that the lines were not anergic. In addition, the lines and PBMC from normal volunteers and the patients with psoriasis gave little or no response to recombinant streptococcal M protein. Thus, in spite of accumulating evidence for selective expansion of certain Vβ-expressing T cells in psoriatic lesions, epidermal autoantigens have not been identified by using a bioassay which depended largely on the proliferation of lesional CD4-positive cells. The role of streptococcal M protein, which bears some homology with epidermal keratin is also open to question, at least in chronic plaque psoriasis. Further work is therefore required to obtain direct evidence that autoimmune processes are important in the pathogenesis of chronic plaque psoriasis.     

Psoriasis is characterized by accumulation of immunostimulatory and Th1/Th17 cell-polarizing myeloid dendritic cells

Myeloid dermal dendritic cells (DCs) accumulate in chronically inflamed tissues such as psoriasis. The importance of these cells for psoriasis pathogenesis is suggested by comparative T-cell and DC-cell counts, where DCs outnumber T cells. We have previously identified CD11c(+)-blood dendritic cell antigen (BDCA)-1(+) cells as the main resident dermal DC population found in normal skin. We now show that psoriatic lesional skin has two populations of dermal DCs: (1) CD11c(+)BDCA-1(+) cells, which are phenotypically similar to those contained in normal skin and (2) CD11c(+)BDCA-1(-) cells, which are phenotypically immature and produce inflammatory cytokines. Although BDCA-1(+) DCs are not increased in number in psoriatic lesional skin compared with normal skin, BDCA-1(-) DCs are increased 30-fold. For functional studies, we FACS-sorted psoriatic dermal single-cell suspensions to isolate these two cutaneous DC populations, and cultured them as stimulators in an allogeneic mixed leukocyte reaction. Both BDCA-1(+) and BDCA-1(-) myeloid dermal DC populations induced T-cell proliferation, and polarized T cells to become T helper 1 (Th1) and T helper 17 (Th17) cells. In addition, psoriatic dermal DCs induced a population of activated T cells that simultaneously produced IL-17 and IFN-gamma, which was not induced by normal skin dermal DCs. As psoriasis is believed to be a mixed Th17/Th1 disease, it is possible that induction of these IL-17(+)IFN-gamma(+) cells is pathogenic. These cytokines, the T cells that produce them, and the inducing inflammatory DCs may all be important new therapeutic targets in psoriasis.     

Psoriasis vulgaris – a sterile antibacterial skin reaction mediated by cross‐reactive T cells? An immunological view of the pathophysiology of psoriasis

The understanding of the pathogenesis of psoriasis vulgaris has advanced significantly since the therapeutic efficacy of immunosuppressive drugs has drawn attention to the role of immune mechanisms in psoriasis manifestation. Today, the results of many experimental studies provide evidence that psoriasis is largely a T-cell mediated disorder. It may result from antigen-specific activation of T cells in the skin of genetically predisposed individuals. These T cells apparently have a particular functional differentiation and promote the psoriatic skin changes by secreting a certain set of cytokines. Based on the fact that streptococcal throat infections are a trigger of guttate psoriasis, the putative psoriatic antigens are assumed to be in keratinocyte proteins that share structural homologies with streptococcal proteins and thus induce cross-reactive responses of antibacterial T cells against skin components. Together with the particular phenotype of psoriatic skin lesions these findings suggest that psoriasis represents a sterile antibacterial tissue reaction, which is mediated by streptococci-specific T cells that cross-react against epidermal autoantigens.     

Intraepidermal lymphocytes in psoriatic lesions are activated GMP-17(TIA-1)+CD8+CD3+ CTLs as determined by phenotypic analysis

The onset and persistence of psoriatic lesions are linked to the presence of an inflammatory infiltrate of CD3+ lymphocytes that includes CD4+ and CD8+ subsets. Since a primary susceptibility factor for psoriasis is the Class I HLA-Cw6 molecule, we set out to learn more about the features of the epidermal CD8+ lymphocytes. The markers tested were GMP-17, a cytotoxic granule protein found in activated cytotoxic lymphocytes (CTLs), and the alpha chain of the IL-2 receptor (CD25), a plasma membrane molecule found on activated T cells. Lymphocytes in lesional skin expressed the GMP-17 protein, whereas lymphocytes in non-lesional skin, resolving lesional skin and normal skin had little or no GMP-17. By flow cytometry analysis, lesional epidermal GMP-17+ cells were CD8+CD3+, with a subpopulation expressing the activation marker CD25+. Due to the abundance of activated GMP-17+CD8+CD3+ lymphocytes (the phenotype of activated cytotoxic cells) in psoriatic lesions compared to non-lesional and normal skin, we hypothesize that they are contributing directly to the psoriatic phenotype.     

Generation of terminal complement complexes in psoriatic lesional skin.

The complement system is thought to play an important role in the recruitment of neutrophils within the epidermis. In the present study we examined whether or not complement activation in psoriatic lesional skin results in the deposition of terminal complement complexes within the epidermis by measuring levels of SC5b-9 in the plasma and horny tissues of psoriatic patients. The levels of SC5b-9 in psoriatic plasma were significantly higher than those of controls or those of patients with atopic dermatitis. However, when the levels of SC5b-9 in the psoriatic plasma were compared before and after successful treatment of psoriasis, a significant reduction was observed after treatment. Studies of total protein extracts from lesional skin showed that, while no SC5b-9 was detected in the noninflammatory horny tissues, there were high levels of SC5b-9 in lesional horny tissues of psoriasis. By immunofluorescence using a monoclonal antibody to the C5b-9 neoantigen, deposition of C5b-9 was observed only in the stratum corneum of psoriatic skin. Thus the results of the present study suggests that in psoriatic lesional skin, the complement system is activated and that this complement activation proceeds all the way to the terminal step, generating membrane attack complex.     

Autocytotoxic T-cell clones in lichen planus

We examined the in vitro cytotoxic activity of cutaneous T-cell lines and clones from lichen planus (LP) patients against autologous epidermal keratinocytes. T cells were cultured from LP lesions and adjacent clinically normal skin and cloned by limiting dilution. Keratinocytes were cultured from LP lesions and adjacent clinically normal skin and immortalized by transfection with the E6 and E7 genes from human papillomavirus 16 (HPV16). The lesional T-cell line from one LP patient contained 27% gammadelta+ T cells and was significantly more cytotoxic against autologous lesional keratinocytes than the T-cell line from clinically normal skin. Clones isolated from the lesional T-cell line were significantly more cytotoxic against autologous lesional keratinocytes than clones isolated from the non-lesional T-cell line. Most cytotoxic clones from LP lesions were CD8+ and most non-cytotoxic clones from LP lesions were CD4+. One cytotoxic clone was CD4- and CD8- and expressed the gammadelta T-cell receptor. Two CD8+ LP lesional T-cell clones showed dose-dependent killing of HPV16 E6/E7-immortalized autologous lesional and normal keratinocytes, but no cytotoxic activity against Epstein-Barr virus-transformed autologous B-cell blasts. The cytotoxic activity of CD8+ lesional T-cell clones against autologous lesional keratinocytes was partially blocked with anti-major histocompatibility complex (MHC) class I monoclonal antibodies. These data support the hypothesis that CD8+ lesional T cells recognize an antigen associated with MHC class I on lesional keratinocytes and that CD8+ cytotoxic T cells lyse keratinocytes in LP lesions.     

Identification of Differentiation-Specific Antigens in Psoriatic Versus Normal Skin Using Monoclonal Antibodies

Human cell hybrids derived from fusions between carcinoma (HeLa) and normal epidermal keratinocytes can be used as immunogens to generate monoclonal antibodies against keratinocyte differentiation-specific antigens. We examined the immunofluorescent staining patterns of these monoclonals in normal human and psoriatic (lesional and uninvolved) skin tissue sections. The immunofluorescent staining patterns indicate that the monoclonal antibodies are recognizing a number of different keratinocyte antigens. Three monoclonals (HLK7, HLK3, and HLK20) displayed different immunofluorescent reactivity in these tissues. These new monoclonal antibodies will be useful tools to study the differentiation abnormalities in psoriasis and may serve as a marker of the psoriatic diathesis.     

Antitumour necrosis factor-alpha chimeric antibody (infliximab) inhibits activation of skin-homing CD4+ and CD8+ T lymphocytes and impairs dendritic cell function

BACKGROUND: Psoriasis is a chronic inflammatory skin disease characterized by hyperproliferation and altered differentiation of keratinocytes in reply to cytokines such as interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha, provided by infiltrating CD4+ and CD8+ T cells and natural killer cells. Infliximab is a chimeric monoclonal antibody that neutralizes both soluble and membrane-bound TNF-alpha, and that may give a long-term disease remission. OBJECTIVES: To determine the in vitro effects of infliximab on CD4+ and CD8+ T cells derived from lesional skin, and on dendritic cells (DCs). METHODS: Psoriatic T-cell lines were isolated from lesional skin of four patients with psoriasis and assayed for their proliferation, cytokine release and susceptibility to apoptotic stimuli in the presence of graded (1-100 microg mL(-1)) concentrations of infliximab. DCs were differentiated in the presence of infliximab from peripheral blood monocytes. Phenotype was assessed by fluorescence-activated cell sorting and antigen-presenting capacity in functional assays. RESULTS: In vitro activation of psoriatic as well as antigen (nickel)-specific skin-homing T cells was strongly and dose-dependently impaired by infliximab, in terms both of proliferation and of IFN-gamma release. Despite the significant reduction of IFN-gamma secretion, infliximab only marginally affected the release of interleukin (IL)-10 by skin T cells, thus determining a reduction of the IFN-gamma/IL-10 ratio at the site of inflammation. The effects were maximal when T-cell activation occurred in the absence of costimulation, or when T cells were activated by immature compared with mature DCs. In addition, skin-homing CD8+ T cells were more prominently affected by infliximab compared with CD4+ T lymphocytes, both in terms of inhibition of activation and in their susceptibility to apoptosis. Finally, infliximab directly affected the differentiation of monocyte-derived DCs, by inhibiting the expression of CD1a and CD86, and strongly impaired the antigen-presenting capacity of immature and, to a lesser extent, mature DCs. CONCLUSIONS: Infliximab directly affects psoriatic T cells and impairs the antigen-presenting capacity of DCs. These effects may help to explain the long-term disease remission obtained with the drug.     

Effects of administration of a single dose of a humanized monoclonal antibody to CD11a on the immunobiology and clinical activity of psoriasis

BACKGROUND: CD11a/CD18 comprise subunits of leukocyte function associated antigen (LFA-1), a T-cell surface molecule important in T-cell activation, T-cell emigration into skin, and cytotoxic T-cell function. OBJECTIVE: We explored the immunobiologic and clinical effects of treating moderate to severe psoriasis vulgaris with a single dose of humanized monoclonal antibody against CD11a (hu1124). METHODS: This was an open label study with a single dose of hu1124 at doses of 0.03 to 10 mg/kg. Clinical (Psoriasis Area and Severity Index [PASI]) and immunohistologic parameters (epidermal thickness, epidermal and dermal T-cell numbers, and keratinocyte intercellular adhesion molecule 1 [ICAM-1] expression) were followed. RESULTS: Treatment with hu1124, at doses higher than 1.0 mg/kg (group III), completely blocks CD11a staining for at least 14 days in both blood and psoriatic plaques. At 0.3 to 1.0 mg/kg, T-cell CD11a staining was completely blocked; however, blockade lasted less than 2 weeks (group II). Only partial saturation of either blood or plaque cellular CD11a was observed at doses of hu1124 between 0.01 and 0.1 mg/kg (group I). This pharmacodynamic response was accompanied by decreased numbers of epidermal and dermal CD3(+) T cells, decreased keratinocyte and blood vessel expression of ICAM-1, and epidermal thinning. Statistically significant drops in PASI compared with baseline were observed in group II patients at weeks 3 and 4 and in group III patients at weeks 2 through 10. No significant drop in PASI score was observed in group 1. Adverse events were mild at doses of 0.3 mg/kg or less and included mild chills, abdominal discomfort, headache, and fever. At a single dose of 0.6 mg/kg or higher, headache was the most common dose-limiting toxicity observed. CONCLUSION: Targeting CD11a may improve psoriasis by inhibiting T-cell activation, T-cell emigration into the skin, and cytotoxic T-cell function.     

The expression of syndecan-1 in psoriatic epidermis

Psoriasis is a chronic inflammatory skin disease characterized by exaggerated keratinocyte proliferation. Current opinion indicates that psoriasis is driven by T cell-mediated immune responses targeting keratinocytes. However, psoriasis cannot be explained solely on the basis of T-cell activation, and it is likely that an intrinsic alteration in epidermal keratinocytes plays a very important role in disease expression. Syndecans comprise a major family of cell surface heparan sulfate proteoglycans. Several studies indicate their role in adhesion, cell-extracellular matrix interactions, migration, keratinocyte proliferation and differentiation, inflammation, and wound healing. To determine the expression of syndecan-1 in psoriasis, skin samples from 29 patients with fully developed psoriasis and skin samples from 14 healthy volunteer persons with no personal or family history of psoriasis were immunohistochemically examined using monoclonal antibody against syndecan-1. The expression of syndecan-1 was analyzed in whole mount section of psoriatic and non-psoriatic skin biopsies under high magnification (400x). In addition, the intensity and topography of reaction in the cell, as well as localization of positive cells in the epidermis were evaluated. Strong syndecan-1 reactivity in epidermal cells in all non-psoriatic and psoriatic samples was observed. Statistical analysis showed no significant differences between two analyzed groups (P > 0.05). In normal skin syndecan-1 was expressed in full thickness of the epidermis. The strongest reaction was observed in membranes and intercellular junctions of spinous and granular layer while basal cells showed weaker expression that was confined to cytoplasm. In psoriatic skin syndecan-1 was expressed in the membrane and intercellular junction of cells located in thickened and elongated rete ridges of the epidermis. The strongest reaction was in basal and suprabasal layers and expression diminished through spinous layer. Cells in spinous layer lose syndecan-1 expression, which is opposite pattern to normal skin. Our results suggest that aberrant skin expression of syndecan-1 may be involved in the development of psoriasis.     

Plaque psoriasis vs. atopic dermatitis and lichen planus: a comparison for lesional T-cell subsets, epidermal proliferation and differentiation

BACKGROUND: T-cell infiltration in plaque psoriasis has recently been an important subject of investigation. Interestingly, comparative analyses of the disease-specific composition of the lesional T-cell infiltrate in plaque psoriasis and other inflammatory dermatoses have only sparsely been performed. OBJECTIVES: To compare plaque psoriasis vs. atopic dermatitis and lichen ruber planus with respect to T-cell subsets, epidermal proliferation and keratinization. PATIENTS AND METHODS: Biopsies were taken from untreated lesional skin of patients, six with psoriasis, six with atopic dermatitis and six with lichen planus. T-cell subsets (CD4+, CD8+, CD45RO+, CD45RA+, CD2+, CD25+), an epidermal proliferation (Ki-67) and a keratinization marker (K10) were stained immunohistochemically and quantified using image analysis. RESULTS: The high number of CD8+ T cells (52 +/- 13 cells mm(-1)) found in the psoriatic epidermis was not found in the epidermis of atopic dermatitis (9 +/- 4), nor in the epidermis of lichen planus (34 +/- 10). The other T-cell subsets in the epidermis and dermis showed no statistically significant differences between psoriasis and atopic dermatitis. In contrast to the limited presence of CD4+, CD8+ and CD2+ in the psoriatic dermis (110 +/- 19, 27 +/- 9, 127 +/- 41, cells mm(-1), respectively), more impressive numbers of these cells were observed in the dermis of lichen planus (300 +/- 53, 144 +/- 38, 272 +/- 48, respectively). CD45RO+ memory effector T-cell counts were significantly higher in the epidermis of lichen planus (39 +/- 10) than in psoriasis (19 +/- 5). Psoriatic epidermis proved to have major keratinocyte hyperproliferation (247 +/- 26 cells mm(-1) lamina basalis), as compared with atopic dermatitis (134 +/- 15) and lichen planus (128 +/- 20). Furthermore, a marked decreased expression of keratin 10 was observed in psoriasis (41% of epidermal area) contrary to atopic dermatitis (70%). CONCLUSIONS: Psoriatic epidermis exhibits a pronounced CD8+ epidermotropism with accompanying epidermal hyperproliferation and abnormal keratinization, which changes are only minimally expressed in atopic dermatitis and lichen planus. In plaque psoriasis, substantially fewer activated CD4+ and CD8+ T cells in the dermis and less CD45RO+ T cells in the epidermis are present in comparison with lichen ruber planus.