Brief report: successive occurrence of T-cell and B-cell lymphomas after renal transplantation in a patient with multiple cutaneous squamous-cell carcinomas.
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Adult↗
Biomedical subjects
J Thivolet
Publications and source records attributed to J Thivolet.
Topical retinoids for warts and keratoses in transplant recipients.
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Adolescent↗
Effect of cyclosporins A, G, and H on normal and ichthyotic keratinocyte growth in culture.
Cyclosporin A (CsA) was first used in organ transplantation and for the treatment of autoimmune disorders because of its strong immunosuppressant properties. Several laboratory studies have demonstrated that CsA exerts an inhibitory action on the growth of various cell types in culture, including human skin cells. Such an influence on epidermal keratinocytes, if not associated with the serious adverse effects of CsA medication, would be of interest for the treatment of hyperproliferative genodermatoses such as non-bullous congenital ichthyotic erythroderma (NBCIE). In our study, we used cyclosporin G (CsG) and H (CsH), analogues CsA, to examine the impact of these three cyclosporins on normal and ichthyotic keratinocyte growth in vitro. Epidermal cells were grown in a low-calcium, serum-free medium in the presence or absence of cyclosporins A, G or H (1-10 micrograms/ml). The effects of a 72-h exposure to the drugs were evaluated by cell counting, 3H-thymidine incorporation and cytofluorimetric analysis of the BrdU-labelled cell suspensions. Our findings indicate a dose-dependent keratinocyte growth inhibition by the three cyclosporins. The data obtained with the three quantitation methods were in agreement and the cyclosporin-mediated effects were observed in both normal and ichthyotic keratinocyte cultures. CsG and CsH proved less effective than CsA, which induced a highly significant reduction even at 1 microgram/ml. Our results suggest, however, that ichthyotic keratinocytes are more sensitive to CsG and H when compared with normal cells (50% inhibition of 3H-thymidine uptake at significantly lower doses). A possible therapeutic action of non-toxic doses of CsG and CsH on NBCIE and other hyperproliferative epidermal diseases needs to be confirmed clinically.
Cell Division↗
Detection of multiple types of human papillomavirus in a giant condyloma from a grafted patient. Analysis by immunohistochemistry, in situ hybridisation, Southern blot and polymerase chain reaction.
Immunosuppressed patients such as transplant recipients are known to develop multiple lesions suggestive of human papillomavirus (HPV) infection. A giant anal condyloma was obtained from a transplant patient; several fragments taken from different areas were examined for the presence of HPV DNA using in situ hybridisation, polymerase chain reaction (PCR) and Southern blot. Typical koilocytes were seen in routinely stained tissue sections, suggesting an HPV infection; furthermore, group specific HPV antigen was detected in one of four frozen fragments. Different results were obtained by in situ hybridisation according to the fragment tested. HPV types 6/11 were detected in each of the five fragments, frozen or fixed in Bouin's or formalin solutions. However, the number of HPV DNA positive cells and the intensity of the reaction greatly varied with the specimen. HPV 16 and 18 probes also reacted positively with the sample fixed in formalin; a stronger signal was observed with HPV 18 in one large focus than with HPV 16. HPV type 5 was detected in a few isolated cells of two frozen fragments. With the Southern blot technique, the profile of an HPV 6/11 was seen only in one of two frozen fragments; in this case, the bands were intense. A slight positive reaction was also obtained in one frozen fragment with HPV 16 probe. Four frozen fragments were analyzed with PCR: HPV 6/11 was detected in each fragment; HPV 18 was detected in the four samples but with different intensities; HPV types 5 and 16 did not show any positive signal. In conclusion, the lesion is an example of infection with several HPV types, demonstrated by three different techniques. This suggests the need for careful dermatological or colposcopic follow-up of transplant recipients, in order to prevent possible malignant transformation of anogenital lesions.
Adolescent↗
Anti-CD4 monoclonal antibody therapy in severe psoriasis.
We report here the treatment of psoriasis, a chronic inflammatory skin disease characterized by uncontrolled keratinocyte proliferation, with BB14, a CD4 murine IgG1 antibody. Three patients with severe psoriasis were treated with anti-CD4 mAb infusions (0.2 mg/kg/day for the first patient, 0.4 mg/kg/day for 2 days and 0.8 mg/kg/day during the following days for the 2 others) for 7 or 8 days, without other therapy. Rapid clinical improvement, with major reduction of the Psoriasis Area Severity Index, was observed during 1 month after treatment. Moderate decreases in CD4+ blood cells occurred in the last two patients but not in the first one. Circulating T cells coated with anti-CD4 mAb were detectable during the first 48 h in the first patient and from day 1/2 to day 7/8 in the two others. The density of CD4 molecules on the surfaces of peripheral blood lymphocytes was decreased in all patients and remained low as long as anti-CD4 mAb was detectable in patient serum. The maximal 24 h residual mAb levels ranged from 0.3 microgram/ml in the first patient to 3.8 and 7.0 microgram/ml in the two others. The three patients produced IgM antibodies against the anti-CD4 mAb at day 7/8 or 15 and two patients had IgG antibodies at day 15. Lesional skin samples demonstrated (1) gradual improvement in parakeratosis, papillomatosis and acanthosis, (2) decreased expression of ICAM-1 and HLA-DR by keratinocytes, (3) an increase in CD1a+ Langerhans cell number, (4) partial decrease in epidermal T cell infiltrate and (5) no major change in the dermal infiltrate composed of CD3+, TcR alpha beta+, CD45Ro+, HLA-DR+ T cells. We conclude that anti-CD4 mAb administration can induce a rapid and major improvement in psoriatic lesions, with immunohistochemical changes different from those induced by cyclosporin A or 8-methoxypsoralen plus long wave UV light (PUVA) therapy. Our data provide strong evidence for a critical role of CD4+ lymphocytes in psoriasis.
Adult↗
Influence of fixation on human papillomavirus DNA detection in frozen and embedded paraffin lesions by in situ hybridization with biotinylated probes.
Series of frozen or paraffin-embedded tissues from various body sites, taken from non-immunosuppressed or immunosuppressed patients with persistent papilloma lesions were examined for the presence of group specific antigen from human papillomavirus (HPV) by indirect immunofluorescence or HPV DNA by in situ hybridization with biotinylated probes. We have shown that it is possible to detect HPV DNA after fixation of tissues in neutral formalin, Bouin's or Baker's solution. However, the sensitivity was reduced as compared to frozen tissues. The HPV DNA was detected in nuclei of heavily infected epithelial cells such as plantar or hand warts or in dispersed cells containing high copy numbers of HPV DNA from lesions such as squamous cell carcinomas or keratoacanthomas. In premalignant or malignant lesions of both immunosuppressed or non-immunosuppressed patients, HPV DNA was rarely detected after fixation. HPV types commonly described for skin and genital samples were identified in non-immunosuppressed patients, whereas in transplant recipients oncogenic HPV type 16 was identified in benign warts as well as in premalignant or malignant lesions. Positive reactions with several HPV types were more frequent in lesions from grafted patients than from the normal population. Virus antigen was detectable more frequently in frozen sections than in fixed tissues. Our findings indicate that in situ hybridization is an appropriate and rapid technique to study the presence of HPV infection. However, numerous controls are needed to avoid misinterpretations.
Antigens, Viral↗
CD4 antibody therapy and cyclosporin A differentially affect HLA-DR and ICAM-1 expression in psoriatic skin.
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Antibodies↗
In vitro HIV-1 entry and replication in Langerhans cells may clarify the HIV-1 genome detection by PCR in epidermis of seropositive patients.
Being dendritic antigen-presenting cells in skin and mucous membrane, Langerhans cells (LC) occur in areas at risk for inoculation by human immunodeficiency virus (HIV), and the question whether LC act as a target, reservoir, or vector for transmission of HIV has given rise to much controversy. To address this question, we first analyzed the epidermal compartment of skin from patients seropositive for HIV DNA. Second, we tested the susceptibility of each cell type normally found in this compartment to in vitro infection by HIV-1. A non-denatured DNA was obtained from epidermal sheets after a thermochemical treatment of biopsies (0.5 M ethylenediaminetetraacetic acid (EDTA), pH 7.5 at 60 degrees C for 90 seconds). Optimization of amplification of viral genome was performed with three primer pairs derived from gag, env, and pol sequences. Polymerase chain reaction (PCR) products were analyzed by Southern blot. Viral genome was found in five of 11 HIV-seropositive patients. To control the permissivity of epidermal cell population for HIV, cells isolated from the epidermal sheet of normal skin by trypsinization were co-cultured with HIV-1-carrying promonocytic cells (U937) and observed by electron microscopy. After 3-6 h of co-culture, numerous virions were either tightly bound or apparently engaged in the process of internalization through receptor-mediated endocytosis. At day 4 of co-culture, some infected LC appeared to release mature viral particles through bud formation. The in vitro HIV-1 entry and replication in LC may confirm the presence of the HIV-1 genome by PCR in epidermis of seropositive patients. The consequences of the permissivity of LC for HIV on the antigen-presenting function remain to be determined.
DNA, Viral↗
Langerhans cells, inflammation markers and human papillomavirus infections in benign and malignant epithelial tumors from transplant recipients.
Organ transplant recipients frequently develop warts which progress toward premalignant or malignant lesions after a rather long grafting period. The local immune responses of such lesions (warts, condyloma acuminata, actinic keratoses, Bowen, basal and squamous cell carcinomas) was studied in 32 frozen skin specimens taken from 15 male transplant recipients and compared to similar lesions from the normal population. We studied the expression of T cell subsets, Langerhans cell phenotype, HLA class 1 (beta 2-microglobulin), HLA class 2 (DR antigen), and intercellular adhesion molecule 1 (ICAM 1). The presence of HPV infection was also considered, using in situ hybridization with biotinylated probes in order to examine the correlation with immunological markers. In the dermis, the lesions from grafted patients showed a moderate to intense inflammatory reaction of HLA-DR-positive cells. Most of these cells were CD4+ and CD8+ without any predominance of a single T cell subset. In the epidermis, most lesions were characterized by a reduced number of CD1-positive cells; this was concomitant with a decrease or a loss of beta 2-microglobulin expression by epithelial cells. HLA-DR antigen was not expressed by keratinocytes or tumoral cells in any specimen; ICAM 1 antigen was observed in a few cases. The expression of these markers was similarly modified with or without the presence of HPV DNA. Conversely, most lesions from non-immunocompromised patients, except warts, showed intense inflammatory reactions, with a predominance of CD4-positive cells and large foci of ICAM 1-positive cells. Expression of activation markers by keratinocytes occurred mainly in condylomas and squamous cell carcinomas. In the normal population, HPV infection was only detected in papilloma lesions. These data indicate, in lesions from grafted patients, a lack of effective immune response with partial inhibition of activation markers expressed by keratinocytes. It is conceivable that immunosuppressive treatment with solar exposure may also be responsible for the local immune deficiency and thus for the conversion of benign warts toward malignant lesions in grafted patients.
Adult↗
Expression of neuron-specific enolase immunoreactivity by cutaneous and extracutaneous Langerhans-cell histiocytoses ("X").
The immunohistochemical expression of Neuron-Specific Enolase (NSE) and of S100 protein was studied in 10 cases of cutaneous and 19 cases of extracutaneous Langerhans cell histiocytoses (LCH), including acute/proliferative forms (cutaneous Letterer-Siwe disease) and chronic/granulomatous forms (eosinophilic granuloma, Hand-Schüller-Christian disease). Of the LCH cases, 18 (62%) exhibited detectable NSE-immunoreactivity as compared to 82.8% for S100. NSE expression was found more frequently and intensely within acute (as compared to chronic) forms of LCH. This result lends further support to the cellular unicity of LCH, but also suggests some degree of heterogeneity among LCH cells. It can be speculated that NSE-expression is correlated with the proliferation/activation state of (abnormal) Langerhans cells.
Bone Diseases↗
Serological diagnosis of bullous pemphigoid (BP): comparison of the sensitivity of indirect immunofluorescence on salt-split skin to immunoblotting.
Specialized immunological assays are required for the accurate diagnosis of bullous dermatoses such as bullous pemphigoid (BP), epidermolysis bullosa acquisita and bullous lupus erythematosus. The aim of this study was to analyse and compare the sensitivity of indirect immunofluorescence (IF) on salt-split skin and immunoblotting for the detection of circulating autoantibodies in BP. Of the BP patients selected for the study, 74/79 (94%) had circulating autoantibodies detected by at least one of the two methods. Both methods had comparable sensitivity and detected BP-specific autoantibodies in 82-85% of the patients. Because 20% of the patients were found to be positive by only one of the methods, both methods should be used in the diagnosis of BP. Indirect IF on salt-split skin is easier to perform and is preferable in routine analysis, but Western blotting may be used as a complementary assay with sera showing no reactivity on salt-split skin.
Autoantibodies↗
Alpha-6 (CD 49f) integrin expression in genetic and acquired bullous skin diseases. A comparison of its distribution with bullous pemphigoid antigen.
Bullous pemphigoid (BP) antigen and alpha 6 integrin are hemidesmosome-associated glycoproteins of basal keratinocytes. In this work, the immunoreactivity of antibodies to BP and to alpha 6 in salt- or dispase-split human skin, and in 46 biopsy specimens of various genetic and autoimmune bullous dermatoses taken from various body sites, was studied by double-labeling immunofluorescence. In all specimens, both antigens localized at the same side of the blisters observed, i.e. the roof of the bulla in cases with a junctional or dermolytic cleavage, or the floor of the blister in those with intraepidermal cleavage. Immunostaining for alpha 6 was strong and present in all specimens studied, whereas the one obtained with the BP serum was absent from some specimens. These results show that the BP antigen and the alpha 6 integrin colocalize at the level of cleavage in bullous diseases; however, the more consistent and reproducible reactivity obtained with the anti-alpha 6 antibody suggests that this should be preferentially used in the immunohistochemical investigation of bullous dermatoses.
Antigens, Surface↗
CD1-reactive leukemic cells in bone marrow: presence of Langerhans cell marker on leukemic monocytic cells.
Langerhans cells originate in bone marrow and probably belong to the monocyte-macrophage lineage. CD1 is a specific marker of Langerhans cells. By immunofluorescence and immunoelectron microscopy, CD1a antigen and myeloid markers (CD11, CD13, CD14, CD15, CD33, HLA-DR) were studied in 53 cases of acute myeloid leukemias (AML) and 3 acute lymphoblastic leukemias (ALL). The 11 ANLL without monocytic component were CD1a negative. 2/5 of acute myelomonocytic leukemias (AML4) and 9/37 of acute monocytic leukemias (AML5) were positive. All 3 ALL were negative. No correlation was found between CD1a and myeloid markers. CD1a+ AML did not differ from CD1a- AML with regard to cytogenetics or response to therapy. The CD1a positive cells may originate from an abnormal proliferation of CD1a positive cells which are present in bone marrow and which may differentiate into Langerhans cell precursors.
Antigens, CD↗
Evaluation of human papillomavirus type 5 on frozen sections of multiple lesions from transplant recipients with in situ hybridization and non-isotopic probes.
Transplant recipients are at high risk to develop multiple cutaneous lesions after grafting. The frequency of the potentially oncogenic human papillomavirus (HPV) type 5 DNA was evaluated in cutaneous lesions taken from sun-exposed areas in transplant recipients (92 lesions and 5 samples from normal skin) and compared with a nontransplanted population (22 lesions and 7 samples from normal skin) using in situ hybridization and biotinylated probes to HPV types 1, 2, 5, 16 and 18. HPV type 5 DNA was identified in 8/92 cutaneous lesions of transplanted recipients: 3 warts, 1 case of seborrheic keratosis, 2 actinic keratoses and 2 keratoacanthomas. HPV type 5 DNA was not detected in 27 malignant tumors (8 basal cell carcinomas and 19 squamous cell carcinomas) from transplant recipients. HPV DNA type 5 was detected in only 1 case of squamous cell carcinoma from the general population. The presence of HPV DNA 5 was confirmed with Southern blotting in 2 out of 6 cases from transplant recipients. The reaction was negative with the squamous cell carcinoma from nontransplant recipients. These data indicate that the presence of HPV DNA type 5 is not very frequent; it can be detected with in situ hybridization and nonisotopic probe, which is easier to handle than Southern blot.
Biopsy↗
Interleukin-6 in normal skin and psoriasis.
Interleukin-6 (IL-6 or BSF-2/IFN beta 2) is a component of normal human skin. IL-6 was immunologically detected in basal keratinocytes, endothelial cells and in a number of mononucleated cells and fibroblasts in normal skin and sudoriparous ducts. In psoriasis, intense labelling of the cytoplasm in the vicinity of keratinocyte membranes was detected in all epidermal layers and other skin appendages. The fact that this interleukin acts synergistically with respect to IL-1 and Tumour Necrosis Factor (TNF) strengthens the hypothesis whereby IL-6 may contribute via its receptor action to EGF function in modulating cell hyper-proliferation in psoriasis.
Adolescent↗
[Fibronectins].
Fibronectins are complex glycoprotein macromolecules whose molecular weight is 440 kilodaltons. These proteins, found throughout the body, are soluble in biological fluids and insoluble in connective tissue. They contribute to tissue morphogenesis through multiple interactions with cells and extracellular matrix components. Fibronectins play a key role in cell attachment and remodeling during embryonic development, in cell migration and anchorage during wound healing, and in immune responses. This review discusses the structure of fibronectins, their integrin cell receptors, their biologic properties and their implications for diseases.
Cell Adhesion↗
[Apropos of the nosology of autoimmune bullous skin diseases].
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Autoantibodies↗
Evaluation of mitochondrial content and activity with nonyl-acridine orange and rhodamine 123: flow cytometric analysis and comparison with quantitative morphometry. Comparative analysis by flow cytometry and quantitative morphometry of mitochondrial content and activity.
Mouse fibroblasts 3T3.4E and two cells lines obtained by fusion (3T3.4E cells x normal human keratinocytes), (3T3 x NHK), and (3T3.4E cells x hand wart keratinocytes), (3T3 x HWK), were compared for mitochondrial activity and content between 5 and 20 days of culture, from the 16th to 20th passage, by using Rh 123 and NAO respectively. In 3T3.4E cells both Rh 123 and NAO fluorescence were similar after 5 and 7 days of culture, indicating no modification of mitochondrial activity and content at that time. However, in cells derived from fusion of 3T3 x NHK or 3T3 x HWK, Rh 123 increased from 5 to 20 days whereas NAO fluorescence was maximal at 7 days of culture and then decreased, indicating that their mitochondrial activity differed from that of 3T3.4E cells. No difference was observed between the 16th and 20th passage. Quantitative morphometry and flow cytometry gave good correlations at 7 days of culture for the cell size, estimated either by the cell area or the cell diameter, and for mitochondria content, evaluated either by the number of mitochondria per cell or NAO fluorescence intensity.
Acridine Orange↗