Increases in levels of antibody to hepatitis B surface antigen in an immunized population

OBJECTIVE AND IMPORTANCE: Mycosis fungoides is a rare T-cell lymphoma of the skin that can, in one-half to three-quarters of patients suffering from this disease, involve the viscera in late stages of the disease. Although autopsy series performed more than 2 decades ago showed that the incidence of metastatic mycosis fungoides to the central nervous system is approximately one of seven, a total of only several dozen cases have been reported to date. As compared to meningeal involvement, intraparenchymal metastases are even rarer. We describe a biopsy-proven case of intraparenchymal central nervous system mycosis fungoides in a patient with nonprogressive skin involvement and no detectable visceral involvement, and we present a review of the relevant literature. CLINICAL PRESENTATION: A 68-year-old man, 3 years after the diagnosis of his skin disease, developed fatigue, confusion, and frontal lobe signs without the presence of cerebriform cells in the peripheral blood or any other clinical evidence of visceral involvement. Magnetic resonance imaging revealed a diffuse area of increased T2-weighted signal involving the white matter of both cerebral hemispheres as well as a focal area of T2 abnormality along the body of the corpus callosum. The radiological differential diagnosis was either leukodystrophy caused by chemotherapy, progressive multifocal leukoencephalopathy, or glioma with associated white matter changes. INTERVENTION: A stereotactic serial brain biopsy revealed diffuse perivascular infiltrates of atypical lymphocytes, as well as several large cells with cerebriform nuclei consistent with mycosis fungoides. The cells were immunoreactive for LCA, MT1, UCHL1, and CD3. CONCLUSION: We stress the importance of including mycosis fungoides as part of the differential diagnosis for a brain lesion in patients with cutaneous T-cell lymphoma, because treatments do exist, and we conclude that a serial stereotactic biopsy may be necessary to provide a definitive diagnosis.     

The expression of CD26 and CD40 ligand is mutually exclusive in human T-cell non-Hodgkin's lymphomas/leukemias

CD26 and CD40 ligand (CD40L) are surface molecules on human activated T lymphocytes that play a critical role in the regulation of lymphopoiesis. Both molecules are expressed on a restricted fraction of human T-cell non-Hodgkin's lymphomas (NHL)/leukemias; however, little is known about their functional and/or clinical significance in these disorders. In this study, the pattern of expression of CD40L was compared with that of the CD26 molecule. A series of 67 human T-cell NHL/leukemias and a panel of leukemia/lymphoma T-cell lines were evaluated by immunohistochemistry, flow cytometry, and RNA studies. The overall frequency of CD26+ and CD40L+ samples was rather similar (25/67 [37%] v 18/67 [27%]). However, the majority of CD26-expressing cases clustered in the lymphoblastic lymphomas (LBL)/T-acute lymphoblastic leukemias (ALL; 12/23) and CD30+ anaplastic large-cell (ALC) lymphomas (5/8), whereas CD40L+ lymphomas included a large fraction of mycosis fungoides (11/21 [52%]). CD26 and CD40L coexpression was found only in 2 myocosis fungoides cases and 1 small lymphocytic lymphoma. Thus, the expression of the two antigens was mutually exclusive in almost all T-cell lymphomas/leukemias. Accordingly, lymphoma cell lines expressed either one of the molecules or the relative amounts of CD26 and CD40L were inversely proportional. In contrast, reactive T lymphocytes from patients with non-neoplastic T-cell expansions and in vitro activated CD3+ or CD4+ normal T cells were found to coexpress CD40L and CD26. Results of a multivariate analysis showed that the expression of CD26 in T-cell LBL/ALL patients was associated to a worse outcome in terms of survival, as compared with patients with CD26- tumors (P < or = .0001). Based on our results, it can be concluded that, (1) as opposed to activated or reactive normal T cells, the expression of CD26 and of CD40L is mutually exclusive in human T-cell lymphomas/leukemias; (2) expression of CD26 is restricted to aggressive pathologic entities, such as T-cell LBL/ALL and T-cell CD30+ ALC lymphomas, whereas CD40L is expressed on slow progressing diseases such as mycosis fungoides; and (3) within the T-cell LBL/ALL group of tumors, CD26 may identify a subset of poor prognosis patients.     

Predominance of epidermal CD8+ T lymphocytes in bullous cutaneous reactions caused by beta-lactam antibiotics

The phenotype and functional characteristics of skin-infiltrating lymphocytes in beta-lactam antibiotic-induced vesiculobullous exanthemas were studied in vivo and in vitro. Immunohistochemical analysis demonstrated that CD8+ T lymphocytes were the predominant epidermal T-cell subset in these reactions. Epidermal T lymphocytes were isolated and expanded for in vitro studies. Fluorescence-activated cell sorter analysis showed the majority of epidermal T cells to be CD3+, T-cell receptor alpha/beta+, CD4-, CD8+, and HLA-DR+, which correlated with the predominance of epidermal CD8+ T lymphocytes found in situ. Three CD8+ epidermal T-cell clones derived from cutaneous lesions proliferated in response to penicillin-pulsed autologous antigen-presenting cells but not allogeneic antigen-presenting cells, indicating that those clones were antigen and major histocompatibility complex specific. All T-cell clones produced significant amounts of interleukin-2, interferon-gamma, and granulocyte-macrophage colony-stimulating factor. Additionally, the T-cell clones displayed cytotoxicity against epidermal cells in lectin-mediated cytotoxicity and against B-cell lines in T-cell receptor-triggered cytotoxicity. These data demonstrate the presence of epidermal drug-specific CD8+ T cells in bullous drug reactions. Because these CD8+ T cells have a cytotoxic potential, they may contribute to the necrosis of keratinocytes associated with drug-induced blister formation.     

Oocyte donation: does a previous attempt affect a subsequent attempt?

Epidermal infiltration by neoplastic CD4+ T cells is a characteristic histologic feature of early stage mycosis fungoides, the most common type of cutaneous T cell lymphoma (CTCL). The mechanisms involved in epidermotropism are unknown. It has been suggested that the CXC chemokines IL-8 and interferon-gamma inducible protein 10 (IP-10) may play a role, but evidence that these chemokines are produced within the epidermis in epidermotropic CTCL is lacking. In this study skin biopsies from 17 CTCL patients, including 12 mycosis fungoides, four pleomorphic CTCL, and one CD8+ CTCL, were investigated for epidermal IL-8 and IP-10 mRNA expression by RNA in situ hybridization. In addition, the expression of monokine induced by gamma-interferon (Mig) mRNA, a CXC chemokine closely related to IP-10, was studied as well. The expression of IL-8 receptors A and B (CXCR1 and CXCR2, respectively) was investigated by immunohistochemistry. The results were correlated with the number and phenotype of epidermotropic T cells. Epidermal expression of IP-10 and Mig mRNA was detected in 10 of 11 and seven of 11 epidermotropic CTCL, respectively, but not in five nonepidermotropic CTCL biopsies or normal human skin. Epidermal IP-10 and Mig mRNA expression correlated with epidermal infiltration of CD4+ T cells, but not of CD8+ T cells. IL-8 mRNA was demonstrated in the epidermis of only two of 15 CTCL biopsies, and was associated, in both cases, with accumulation of neutrophils. Consistently, immunostaining of the (intraepidermal) T cells with antibodies against CXCR1 and CXCR2 was not observed. In conclusion, the results of this study indicate that IP-10, and to a lesser extent Mig, but not IL-8 is involved in the preferential infiltration of neoplastic CD4+ T cells in CTCL.     

Immunohistochemical analysis of mycosis fungoides on paraffin-embedded tissue sections

Mycosis fungoides (MF) is typically characterized by dermal and epidermal infiltration of T lymphocytes with a helper/inducer phenotype. Immunophenotypic analysis of such cases was traditionally performed by flow cytometry or immunohistochemistry on cryostat sections. With the advent of new monoclonal antibodies developed against T-cell antigens, including CD3, CD4, CD5, and CD8, it is now possible to immunophenotype T-cell subpopulations in paraffin-embedded tissues. To investigate the potential use of these antibodies for the evaluation of cutaneous lesions, 35 specimens (34 skin and 1 lymph node) from 29 patients with MF were retrospectively reviewed and immunophenotyped in paraffin sections with antibodies to CD3 (T-cell CD3), CD4 (NCL-CD4-1F6), CD5 (NCL-CD5-4C7), CD8 (CD8/144B), and CD20 (L26). Epidermal and dermal distribution of T and B cells were analyzed, and we assessed the ratios of CD4+ to CD8+ T cells. All of our 35 cases demonstrated a predominant CD3+ T-cell population. In 32 cases, the neoplastic cells expressed CD3, CD4, and CD5 consistent with a T-helper/inducer phenotype. In three cutaneous cases, the neoplastic CD4+ T cells showed minimal or absent expression of CD5, indicating an aberrant phenotype. In the majority of cases, minimal CD8+ T cells were present in the background, but in four cases, the CD4:CD8 ratios were 2:1 or less. Thirty-two cutaneous cases demonstrated epidermotropism exclusively by CD4+ T cells; one case showed both CD4+ and CD8+ T cells. In 17 cutaneous cases, scattered dermal CD20+ B cells were found individually or in small clusters within the background surrounding the neoplastic infiltrates. We concluded, therefore, that the immunophenotypic analysis of T-cell subpopulations using monoclonal antibodies of CD3, CD4, CD5, and CD8 was useful for histologic evaluation and confirmation of MF lesions in paraffin-embedded tissue. These antibodies might also provide an effective method of immunophenotyping other neoplastic and non-neoplastic T-cell populations in paraffin-embedded tissues.     

Demonstration of the Th1 to Th2 cytokine shift during the course of HIV-1 infection using cytoplasmic cytokine detection on single cell level by flow cytometry

OBJECTIVE: To characterize changes of Th1/Th2 cytokine production by peripheral blood mononuclear cells (PBMC) that occur during the course of HIV infection by cytoplasmic cytokine staining on single cell level. DESIGN AND METHODS: Mitogen-stimulated PBMC from 16 healthy donors, 18 HIV-1-infected individuals without AIDS and 14 patients with AIDS were stained intracellularly with fluorescein-labelled MAb against interleukin (IL)-2, IL-4, IL-10 and interferon (IFN)-gamma. Additionally, co-staining of CD4+ T-cell, CD8+ T-cell, natural killer (NK) cell, B-cell and monocytic markers was performed. Fluorescence staining was analysed by three-colour flow-cytometry. RESULTS: A reduced percentage of IL-2 and IFN-gamma (Th1 type)-producing cells among CD4+ T cells from HIV-1-infected individuals could be demonstrated. There was a continuous decrease of IFN-gamma-producing CD4+ T cells in the course of HIV infection and a dramatic reduction of IL-2-expressing cells among CD4+ T cells in patients with AIDS. In contrast to Th1 cytokines, the frequency of Th2 cytokine expressing cells among CD4+ T cells increased in HIV-infected individuals. The maximum frequency of IL-4-expressing cells among CD4+ T cells was seen in HIV-infected individuals without AIDS, whereas the rate of IL-10-producing cells was highest in patients with AIDS. In HIV-infected individuals no significant proportion of Th0 cells expressing both Th1 and Th2 cytokines was detectable. In CD8+ T cells the percentage of IL-2 was expressing cells decreased continuously accompanied by a strong increase of the frequency of IFN-gamma-producing cells. CONCLUSION: The decreased percentage of cells expressing IL-2 and IFN-gamma in conjunction with an increased proportion of IL-4- and IL-10-producing cells among the CD4+ T cells in HIV-1-infected individuals demonstrate a Th1 to Th2 cytokine shift in the course of HIV infection on a single cell level. There was no evidence of a Th1 to Th0 cytokine shift. In addition to the loss of CD4+ T cells in HIV infection, the qualitative changes of Th1/Th2 cytokine expression may serve as a marker for progressive failure of cell-mediated immunity.     

Neutrophils, differentiated macrophages, and monocyte/macrophage antigen presenting cells infiltrate murine epidermis after UV injury

We asked whether, as in humans, a population of antigen-presenting macrophages infiltrates the epidermis of ultraviolet (UV)-exposed BALB/c mice. Using three-color flow cytometry on cell suspensions plus in situ immunofluorescence microscopy, the phenotype of normal Langerhans cells was class II major histocompatibility complex (MHC+), CD11b+, NLDC-145+, BM8+ CD45+ and homogeneous. By contrast, in epidermal cells harvested 3 d following UV (UV-EC), there were two subsets of class II MHC+ cells: 1) class II MHChi CD11b+, and 2) class II MHClo CD11b-. Neither expressed the Langerhans cell markers BM8 and NLDC-145. In addition, there were two major populations of class II MHC- CD11b+ cells; half of these expressed the GR-1 neutrophil marker. Langerhans and dendritic epidermal T cells were markedly reduced after UV injury. By electron microscopy, immunomagnetic bead-purified CD11b+ cells in UV-EC were comprised of neutrophils, differentiated macrophages, and mononuclear cells with prominent lysosomes, but no Birbeck granules; the class II MHC+ subset resembled a monocytic cell in between differentiated macrophages and indeterminate dendritic cells. Functionally, immediately following in vivo UV exposure, the allogeneic antigen-presenting cell capacity of UV-EC was reduced to 21 +/- 6% of control epidermal cells (C-EC); by 3 d, antigen-presenting cell activity of UV-EC had recovered to 59 +/- 11% of C-EC, although at this time NLDC-145+ Langerhans cells had reached their lowest number. The recovered antigen-presenting cell activity was critically dependent upon the class II MHChiCD11b+ cells. Sensitization of BALB/c mice through skin that contained these antigen-presenting cells (3 d after UV) resulted in tolerance to dinitrofluorobenzene. By contrast, sensitization through UV-exposed skin immediately after the exposure resulted in unresponsiveness without tolerance, demonstrating temporal association of tolerance with leukocytic infiltration. In summary, murine epidermis responds to an acute UV injury in vivo with an initial abrogation of antigen-presenting activity followed by epidermal infiltration with neutrophils, differentiated macrophages, and monocytic antigen-presenting cells that are distinct from Langerhans cells with regard to expression of Langerhans cell markers and ultrastructure.     

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.     

Characterization of T-cell subsets infiltrating post-burn hypertrophic scar tissues

In this study, skin-infiltrating cells were characterized in both the active and remission phases of post-burn hypertrophic scar biopsies. Immunohistochemistry examination of active phase samples showed an abundant presence of Langerhans cells, T cells, macrophages, a low presence of natural killer cells and the lack of B lymphocytes. In active hypertrophic scars T lymphocytes infiltrate deep into the superficial dermis and are also observed in the epidermis: CD3+ cells were present at about 222 +/- 107 per 0.25 mm2. In particular the analysis of lymphocyte subpopulations showed that CD4+ T cells predominate in the dermis as well as in the epidermis of active hypertrophic scars whereas CD8+ cells were less well represented (CD4/CD8 ratio is 2.06). This distribution was also shown in remission phase samples and in normotrophic scar specimens, although the lymphocyte number was significantly lower. Approximately 70 per cent of T lymphocytes present in the tissue involved in active phase hypertrophic scar samples were activated (positive with anti-HLA-DR and IL-2 receptor antibodies) which is significantly higher than remission phase hypertrophic and normotrophic scars, in which positivity was 40 and 38 per cent, respectively. Upon activation, the lesional lymphocytes release several cytokines, locally and transiently, that interact with specific receptors in response to different stimulation. Central to the immune hypothesis of hypertrophic scars is that some of the T-cell lymphokines act on keratinocytes, fibroblasts and other cell types to induce changes characteristic of these scars. The presence and close proximity of activated T lymphocytes and antigen-presenting cells of various phenotypes in both the epidermis and dermis of hypertrophic tissues provides strong circumstantial evidence of a local immune response. However, the manner in which T cells achieve and maintain their activated state in hypertrophic tissues is not yet known, and both antigen-dependent and independent mechanisms may contribute.     

Defective Th1 and Th2 cytokine synthesis in the T-T cell presentation model for lack of CD40/CD40 ligand interaction

In this study, T or NK cell clones used as antigen-presenting cells (T- or NK-APC) were shown to be significantly less efficient than professional APC in inducing Th1 and Th2 cytokines by antigen-specific T cell clones. This phenomenon was not related to a limited engagement of TCR by T-APC, since comparable thresholds of TCR down-regulation were shown when antigen was presented by either T-APC or professional APC. Rather, the stimulatory T-APC weakness was due to their inability, because they are CD40-, to provide the appropriate co-stimuli to responder T cells both indirectly via IL-12, and partially via direct CD40L triggering on T cells. Indeed, the simultaneous addition of IL-12 and reagents directly engaging CD40L on responder T cells restored T cell cytokine synthesis when antigen was presented by T-APC. In addition, either IL-12 production or blocking of T cell cytokine synthesis by anti-IL-12 p75 antibodies was evident only when professional APC were used in our antigen-specific system. The down-regulation of cytokine synthesis in the system of T-T cell presentation could represent a novel mechanism of immune regulation, which may intervene to switch off detrimental Th1- or Th2-mediated responses induced by antigen presentation among activated T cells infiltrating inflamed tissues.     

In vivo relevance of CD30 in atopic dermatitis

CD30 expression was evaluated by immunohistochemistry in lesional skin biopsies of eight patients with active atopic dermatitis (AD) and three patients with allergic contact (nickel-induced) dermatitis (ACD). CD30 expression was also assessed in a large panel of CD4+ and CD8+ T-cell clones generated from the skin biopsies of four patients with AD. Finally, the levels of soluble CD30 (sCD30) were measured in the serum of 41 patients with AD, 19 patients with ACD, and 60 healthy controls. In all specimens of lesional AD skin, where the great majority of infiltrating cells were CD4+ T cells, remarkable numbers of cells were CD30+, whereas virtually no CD30+ cells were found in the skin of patients with ACD. In CD4+ T-cell clones generated from the lesional AD skin, most of which produced both interleukin (IL)-4 and interferon-gamma (IFN-gamma) (Th0-like cells) or IL-4 and IL-5, but not IFN-gamma (Th2-like cells), CD30 expression directly correlated with the ability to produce IL-4 and IL-5, but was inversely related to IFN-gamma production. High levels of sCD30 (correlated with disease activity: r = 0.618) were detected in the serum of most AD patients, whereas there was no increase of sCD30 levels in the serum of patients with ACD. These data support the view that Th0/Th2-type responses predominate in the skin of patients with AD and suggest that the presence of CD30+ T cells in tissues and/or increased levels of sCD30 in biologic fluids are indicative of Th2-dominated responses.     

Calcipotriol inhibits the proliferation of hyperproliferative CD29 positive keratinocytes in psoriatic epidermis in the absence of an effect on the function and number of antigen-presenting cells

The aim of this study was to elucidate some of the possible mechanisms of action of the vitamin D analogue calcipotriol in vivo. Calcipotriol is finding increasing use in the treatment of psoriasis, but the primary target cell in vivo has not yet been identified. We treated psoriatic patients and healthy volunteers with calcipotriol and placebo ointment for 4 and 7 days, and obtained epidermal cell suspensions from treated areas. Epidermal cells were cocultured with autologous T cells, isolated from peripheral blood, in the absence or the presence of a classical antigen or a superantigen. In both psoriatic and normal skin, calcipotriol treatment did not alter the capacity of epidermal antigen-presenting cells to stimulate the proliferation of autologous T cells, either in the absence or in the presence of exogenous antigen. Epidermal cell suspensions were analysed further by staining for infiltrating leucocytes (CD45+) and Langerhans cells (CD1a+). Flow cytometric analysis showed that calcipotriol did not alter the number of CD45+ cells or Langerhans cells in psoriatic skin. These results indicate that calcipotriol does not alter either the number of the function of epidermal antigen-presenting cells in psoriatic epidermis. In contrast, we found that calcipotriol significantly inhibited the proliferation of epidermal cells isolated from psoriatic skin after in vivo treatment, as determined by propidium iodide staining and flow cytometry. More specifically, we stained for CD29+ keratinocytes and found an even more significant reduction in proliferative capacity. This cell type contains the population of hyperproliferative keratinocytes in psoriatic epidermis. In conclusion, calcipotriol seems to act via an inhibitory effect on hyperproliferative basal keratinocytes of psoriatic epidermis, rather than via an effect on infiltrating leucocytes, including antigen-presenting cells.     

Mycosis fungoides presenting as keratosis lichenoides chronica

We report a patient with a 17-year history of reticulated keratotic papules on the trunk and limbs, and telangiectatic eruption on the face, in whom the diagnosis of keratosis lichenoides chronica was first established. However, the biopsies showed an epidermotropic infiltrate of small irregular CD4+ lymphocytes, and detection of a T-cell clone in the lesions by polymerase chain reaction confirmed the diagnosis of mycosis fungoides. Thus, keratosis lichenoides chronica can be an unusual and potentially misleading presentation of mycosis fungoides.     

Aggressive cutaneous T-cell lymphoma associated with the presence of Epstein-Barr virus. 2 cases

INTRODUCTION: The factors of prognosis of the cutaneous T-cell lymphomas are less well known as those of the B-cell lymphomas and the role of the Epstein-Barr virus (EBV) is not yet definitively evaluated. CASE REPORTS: Two male patients aged 62 and 82 years had a mycosis fungoides with a lethal outcome. The first patient had mutilating facial tumors; the RNA m of EBV and the genome of EBV were demonstrated in the diseased skin. The second patient had an erythrodermic course with enlarged peripheral lymph nodes and circulating Sézary's cells; the genome of EBV was demonstrated by PCR in the diseased skin. DISCUSSION: The role of the EBV has already been demonstrated in peripheral aggressive T-cell lymphomas. In the mycosis fungoides, the EBV is associated with the lesions in 0 to 32 p. cent according to the published series. EBV associated T-cell lymphomas have a poor survival rate and the EBV infection may be associated with the expression of the multidrug resistant gene-1 (MDR-1) and the risk of a terminal hemophagocytosis. In our both patients the presence of the EBV in the lymphocytes of the skin lesions is also an argument in favour of the pathogenic role of the virus.     

Selective expression of a novel surface molecule by human Th2 cells in vivo

The search for reliable marker molecules discriminating between human Th1 and Th2 cells identified a gene encoding a novel member of the G protein-coupled leukocyte chemoattractant receptor family, which is selectively expressed in Th2 but not Th1 lineage cells, thereby named CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells). Studies with anti-CRTH2 mAbs demonstrated that CRTH2 was expressed in a small population (0.4-6.5%) of CD4+ T cells in fresh PBMCs of healthy adults, but no remarkable expression was seen in B cells and NK cells. In some cases, CD8+ T cells ( approximately 3.5%) expressed CRTH2. Phenotypes of CD4+ T cells expressing CRTH2 were CD45RA-, CD45RO+, and CD25+, similar to those of Ag-activated effector/memory T cells. Freshly isolated CRTH2+ CD4+ T cells produced Th2- but little or no Th1-type cytokines upon stimulation with PMA and ionomycin. In addition, an allergen-induced proliferative response in fresh PBMCs was significantly and selectively reduced by subtracting CRTH2+ cells. Together, these results indicate that CRTH2 is selectively expressed in vivo in an activated state of Th2 cells including allergen-responsive Th2 cells, suggesting its pivotal roles in ongoing Th2-type immune reactions.     

Mycosis fungoides palmaris et plantaris

BACKGROUND: Mycosis fungoides primarily localized to the palms and soles is rare and has been previously reported as cutaneous lymphoma in four patients or as Woringer-Kolopp disease in eight patients. OBSERVATIONS: Four patients were initially diagnosed and treated unsuccessfully for various palmoplantar dermatitides until histopathologic findings revealed mycosis fungoides. Each case exhibited a clonal rearrangement of T-cell receptor gamma genes and immunohistochemical studies consonant with mycosis fungoides. All patients had limited skin involvement without evidence of extracutaneous involvement. CONCLUSIONS: Mycosis fungoides palmaris et plantaris is an uncommon expression of mycosis fungoides that manifests primarily on the palms and soles and clinically may mimic various inflammatory palmoplantar dermatoses. A biopsy is recommended in the evaluation of recalcitrant palmoplantar dermatoses.     

Helicobacter pylori, achlorhydria and gastric atrophy: what kind of "ménage à trois"?

Cytokines play an important role in the mechanisms resulting in ultraviolet B-induced immunosuppression. They play a crucial role in the induction of local as well as systemic immunomodulatory events. Ultraviolet B irradiation directly induces the release of cytokines in the epidermis, resulting in complex and diverse interactions on epidermal cells, which results in migration out of the skin and infiltration into the skin of different cell types. Partly because of the interaction of locally produced cytokines with antigen-presenting cells, systemic effects, such as antigen-specific tolerance, can be observed. This review describes the different mechanisms whereby ultraviolet B exposure affects immune functions with special emphasis on the role of T-cell subsets and cytokines.     

Low expression of CD40 and B7 on macrophages infiltrating UV-exposed human skin; role in IL-2Ralpha-T cell activation

After UV exposure of skin, epidermal Langerhans cells (LC) are depleted, whereas CD11b+CD36 CD1a- monocytes/macrophages (UV-Mphi) infiltrate. Different immunological outcomes in vivo are mediated by LC (sensitization) and UV-Mphi (tolerance) which may be related to the distinct T cell activation states that these antigen-presenting cells (APC) induce. We previously demonstrated that CD4+ T lymphocytes activated by UV-Mphi are, in contrast to LC-activated T cells, IL-2Ralpha deficient, and we hypothesize that this differential T cell activation is related to differences in co-stimulatory molecules between UV-Mphi and LC. Using four-color flow cytometry, we found a reduced capacity to up-regulate expression of the important co-stimulatory molecules CD40, B7-1 and B7-2 by UV-Mphi relative to LC. This alteration in co-stimulatory molecule expression was selective, because UV-Mphi express equal levels of ICAM-1 and ICAM-3, and increased levels of LFA-1, relative to LC. After bidirectional signaling with T cells during alloantigen presentation, UV-Mphi still exhibited less CD40 and B7-1 than LC. Addition of IFN-gamma induced CD40 and B7-1 expression on UV-Mphi and restored IL-2Ralpha expression on UV-Mphi-activated T cells but had no effect on IL-2Ralpha on resting or LC-activated T cells. The restoration of IL-2Ralpha expression on UV-Mphi-activated T cells by IFN-gamma was inhibited (67 %, p = 0.005) by addition of neutralizing anti-CD40. Therefore, differences in co-stimulatory molecule expression, in particular CD40, on UV-Mphi and LC are critical in determining the distinct T cell activation induced by these APC.     

Analysis of tumor-infiltrating lymphocytes in cutaneous squamous cell carcinoma

OBJECTIVE: To characterize tumor-infiltrating lymphocytes (TILs) within lesions of cutaneous squamous cell carcinoma (SCC) and related disorders. DESIGN: Case series with 1- and 2-color immunohistologic, molecular biological analysis of T-cell clonality and in vitro cytotoxicity assays. SETTING: Academic medical center. PATIENTS: Twenty-one patients, including 6 with actinic keratoses, 4 with SCC in situ, and 11 with invasive SCC. RESULTS: CD8+ TILs were present within lesions of cutaneous SCC and AK. These cells constituted a variable minority of the total T-cell infiltrate, and many expressed a phenotype consistent with major histocompatibility complex-restricted cytotoxic T lymphocytes: CD3+, TIA1+, CD16-, CD56-, CD57-. They also expressed HLA-DR, suggesting their activation in vivo. Virtually all T cells were T-cell receptor (TCR)-beta + delta, indicating that they expressed the TCR-alpha beta protein heterodimer. Molecular biological analysis of TCR-gamma gene rearrangements by the polymerase chain reaction and denaturing gradient gel electrophoresis technique indicated that the TILs were polyclonal. Functional studies suggested that TILs derived from SCC lesions were cytotoxic for autologous tumor cell targets. CONCLUSION: Tumor-infiltrating lymphocytes within cutaneous SCC lesions contain a subpopulation of polyclonal, major histocompatibility complex-restricted cytotoxic T lymphocytes expressing the TCR-alpha beta heterodimer.