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Biomedical subjects

A M Mommaas

Publications and source records attributed to A M Mommaas.

53 records · Page 3Linked to original sources
PubMed1993

Ultrastructural studies bearing on the mechanism of UVB-impaired induction of contact hypersensitivity to DNCB in man.

In both murine and human experimental systems, acute, low dose exposure of skin to ultraviolet B light (UVB) impairs the induction of allergic contact dermatitis (ACD) by haptens such as dinitrochlorobenzene (DNCB) in a significant proportion of individuals. By light microscopy, epidermal Langerhans cells (LC) have been reported to be depleted by UVB exposure as well as by epicutaneous hapten application, implying that LC may be the locus of action of the effects of both UVB and DNCB. However, light microscopy can not readily distinguish cell density changes secondary to LC necrosis from changes resulting from down-modulation of expression of LC surface molecules. Using a highly sensitive immunogold electron microscopic approach, we have evaluated the differential effects of UVB and/or DNCB on human epidermal LC. The results reveal that DNCB alone caused significant up-regulation of cell surface HLA class II expression on a very small number of LC, the major fraction of LC expressing normal levels of HLA class II. Furthermore, DNCB alone caused a modest reduction in the density of LC at the treated sites without evidence of cell necrosis. Treatment with UVB alone or UVB exposure followed by DNCB resulted in a reduction in the density of LC, with widespread evidence of LC necrosis. However, the few remaining intact LC were all intensely HLA class II-positive after UVB exposure followed by DNCB, whereas treatment with UVB alone did not result in changes in LC HLA class II expression. The findings that after DNCB painting only a small proportion of the LC were strongly HLA class II-positive, but after UVB exposure followed by DNCB all intact LC displayed significant up-regulation of cell surface HLA class II expression, imply that UVB exposure inhibits the migration of epidermal LC. This is consistent with the view that DNCB fails to induce ACD when hapten is painted on UVB-exposed skin because insufficient LC are available to initiate T cell activation in the draining lymph node.

Cell Count↗
PubMed1993

Minimising the risks of PUVA treatment.

Psoralen photochemotherapy (PUVA) is a combination of orally administered psoralen and long wave ultraviolet-A radiation (UVA), and is one of the most effective forms of therapy for psoriasis. The unwanted effects of PUVA therapy can be divided into short and long term adverse effects. The short term adverse effects include erythema, pruritus, nausea and headache. While short term adverse effects are limited and reversible after discontinuation of treatment, potential long term adverse effects such as chronic actinic skin damage, dyskeratotic and precancerous skin conditions, nonmelanoma skin cancer, immunological alterations and cataract formation are of greater concern. Long term risks associated with PUVA therapy can be minimised by several measures. Careful patient selection is mandatory; for example, patients with chronic actinic damage and a history of skin cancer may bear a higher risk for the development of new cancers, and previous arsenic intake and ionising radiation also increase the risk of nonmelanoma skin cancers. Certain drug combinations make it possible to lower the UVA dose, which is important because of the dose-dependent increase in the incidence of squamous cell carcinomas in patients treated with PUVA. It has been demonstrated that 200 treatments or a total UVA dose of 1200 J/cm2 seems to be the threshold for development of nonmelanoma skin cancer. Shielding male genitalia during PUVA treatment is essential because of the increased risk of genital squamous cell carcinomas. Yearly dermatological examination to detect skin cancer at an early stage is highly advisable. Sunscreen use, protective clothing and avoidance of sun exposure reduce the uncontrolled dose of solar UV radiation. Other psoralens with a less carcinogenic potential can be used. UVA-opaque sunglasses during the entire period of increased photosensitivity after psoralen ingestion help avoid cataract formation. Assignment to PUVA ought to be based on the risk-benefit ratio for the individual patient and should be limited to those who can be monitored and controlled by informed, competent and conscientious physicians.

Humans↗
PubMed1993

PUVA keratosis. A clinical and histopathologic entity associated with an increased risk of nonmelanoma skin cancer.

BACKGROUND: Various types of hyperkeratotic lesions can be observed in patients with psoriasis treated with PUVA. Clinically it can be difficult to classify them and to differentiate benign from malignant hyperkeratotic lesions. Recently, we introduced the term PUVA keratosis, which we regard as a distinct entity. OBJECTIVE: The purpose of the study was to describe in more detail the clinical and histopathologic features of PUVA keratoses and to investigate a possible relation with nonmelanoma skin cancer. METHODS: A group of 13 psoriasis patients with PUVA keratoses was studied and compared with 247 psoriasis patients without these keratoses, who had also received long-term therapy with PUVA. RESULTS: The presence of PUVA keratoses was associated with an increased risk of nonmelanoma skin cancer. The estimated relative risk for skin cancer in patients with PUVA keratoses, adjusted for age, sex, and UVA dose, as compared with psoriasis patients without these keratoses, who had also received long-term PUVA treatment, was 6.5 (95% confidence interval, 1.3 to 32.1). Squamous cell carcinomas contributed the most to this increased risk. CONCLUSION: PUVA keratoses are associated with an increased risk of nonmelanoma skin cancer. Therefore careful clinical follow-up of psoriasis patients with PUVA keratoses is necessary, and cessation of PUVA treatment should be considered.

Adult↗
PubMed1992

HLA class II expression on human epidermal Langerhans cells in situ: upregulation during the elicitation of allergic contact dermatitis.

An immunoelectron-microscopic technique was applied to investigate the localization of molecules that are involved in the elicitation of allergic contact dermatitis in human epidermal cells in situ. Langerhans cells in the epidermis of lesions showed a strongly increased cell surface expression of HLA class II molecules as compared with normal skin. In addition, a high number of intracellularly located HLA class II molecules were present in Langerhans cells of lesional epidermis, suggesting increased biosynthesis of these molecules during the elicitation process. In contrast, no differences in the expression of CD1a by Langerhans cells was observed between normal and lesional skin. Frequently, the Langerhans cells were found in close apposition to mononuclear cells, which also exhibited a strong cell surface HLA class II expression. The number of Birbeck granules that are characteristic intracellular Langerhans cells organelles was increased in lesional Langerhans cells as compared with normal-skin Langerhans cells, which may correlate with the activated state of lesional Langerhans cells. These Birbeck granules were always HLA class II or CD1a negative. The increased synthesis and expression of HLA class II molecules on the cell surface of Langerhans cells suggests a direct role for these HLA class II molecules in the elicitation process of allergic contact dermatitis.

Adult↗
PubMed1992

Presence and interpretation of vascular immune deposits in human skin: the value of direct immunofluorescence.

Direct immunofluorescence investigation of the skin is an easy and valuable technique to establish the diagnosis immune complex vasculitis. Vascular immune deposits can be found in 60-80% of all cases. Absence of vascular immune deposits, however, does not exclude vasculitis per se, since the dynamics of the vasculitic process limit their presence in time. Knowledge of these dynamics is indispensable for both the clinician and the interpreter. Several practical options are discussed that may increase sensitivity. The specificity of vascular immune deposits has become a complex matter. Different immunoglobulin classes have different specificity, indicating that specificity also depends on the relative incidence of individual immunoglobulin classes. Some of these relative incidences seem to have changed over the years. Furthermore, several non-vasculitic diseases and conditions have now been described, that may show fluorescent pictures similar to vasculitis and thus decrease specificity.

Antigen-Antibody Complex↗
PubMed1992

LDL receptors in keratinocytes.

The presence of sufficient amounts of cholesterol in the epidermis is necessary for proper functioning of plasma membranes in the viable epidermal cell layers and also for the barrier quality of lipid intercellular bilayers of the stratum corneum. Cholesterol can be generated by local epidermal synthesis, or imported from the circulation as low-density lipoprotein (LDL), which is internalized by the cells by receptor-mediated endocytosis. Because of the complex structure of the skin, a model consisting of cultured human keratinocytes has been used to study in detail the regulation of epidermal sterologenesis in relation to keratinocyte differentiation. Experimental modulation of the differentiation of normal human keratinocytes has been achieved by varying extracellular calcium concentration or by comparison of a number of human squamous carcinoma cell lines and normal keratinocytes. These studies have clearly demonstrated a reciprocal correlation between the ability of cells to differentiate and LDL receptor activity. Regulation of LDL receptor expression has been found to occur at the DNA, mRNA, and protein levels, depending on the cell line studied. In normal but not malignant keratinocytes, the induction of keratinocyte differentiation was associated not only with a decrease of functional LDL receptors but also with changes in their cellular distribution. This conclusion is drawn from the observations that only in normal human keratinocytes, cultured at physiologic calcium concentrations, high levels of intracellular, cytoskeleton-associated receptors were found. Differentiation-related modulations of the LDL-receptor expression and of the cellular LDL-receptor distribution found in cultured keratinocytes were in agreement with observations made in the epidermis in situ.

Carcinoma, Squamous Cell↗
PubMed1992

Ontogenesis of the basement membrane zone after grafting cultured human epithelium: a morphologic and immunoelectron microscopic study.

Sheets of cultured epithelial cells have been successfully used as autografts for the permanent coverage of patients with full-thickness burns and as allografts to stimulate the healing of chronic skin ulcers. The basement membrane zone (BMZ), composed of lamina lucida, lamina densa, and anchoring fibrils, plays a pivotal role in the firm adherence of the epidermis to the dermis. The present study describes the ultrastructural development during various stages of wound healing after resurfacing different wound areas by cultured epithelial grafts. For this purpose, biopsies were obtained from five patients 5 d to 4.5 years after resurfacing full-thickness burns with cultured autografts, and from five patients at various stages after treatment of excised tattoos and chronic skin ulcers with cultured allografts. One biopsy was taken from a spontaneously healed burn wound 30 years post-injury. Ultrathin sections were prepared for transmission and immunoelectron microscopy, using monoclonal antibodies against type IV and VII collagen. Findings were compared to controls of age- and site-matched normal skin. Eleven days after grafting, the first BMZ features had regenerated, including lamina lucida, a discontinuous lamina densa, hemidesmosomes, and sparse anchoring fibrils. The process of de novo synthesis of BMZ components had begun, and within 4 to 5 weeks complete reformation of BMZ was observed, including normal distribution of anchoring fibrils. Immunolabeling of type VII collagen was first observed upon the lower part of lamina densa at day 11 and steadily increased, reaching normal values 5 weeks after grafting. In contrast, gold deposition of type IV collagen upon lamina densa was strongly increased at day 19 compared to normal. This high expression reduced a little at 5 weeks, but remained high up to 30 years after injury. Long-term burn scars exhibited pseudopodia-like extensions of all basal cells, abundant anchoring fibrils, and an increased amount of arching anchoring fibrils. These features might compensate for the lack of proper rete ridges.

Adolescent↗
PubMed1991

Decreased expression of decay-accelerating factor on endothelial cells of immune complex-mediated vasculitic skin lesions.

Endothelial cells may be damaged directly by the membrane attack complex of complement in immune complex vasculitis of the skin. However, for endothelial cell membrane injury to occur, normal regulatory mechanisms must fail. One of the main complement regulatory proteins of endothelial cells is decay-accelerating factor, a surface protein which interferes with either the classical or alternative pathway C3 and C5 convertases. We have investigated the expression of decay-accelerating factor in 4 patients with histologically proven cutaneous immune complex vasculitis, using an immuno-electronmicroscopic technique. We demonstrated that endothelial cells of upper dermal vessels in vasculitic lesions were almost completely devoid of decay-accelerating factor. By contrast, the expression of this protein on endothelial cells in uninvolved skin of the patients was the same as in skin of healthy volunteers. As yet, the mechanism responsible for depletion of decay-accelerating factor is not clear. Absence of decay-accelerating factor may follow enzymatic release from the phosphatidylinositol anchor, proteolytic stripping from the cell membrane or a down-regulation of decay-accelerating factor synthesis. Regardless of mechanism, endothelial cell injury or death could serve a phlogistic function to facilitate complement-mediated destruction of endothelial cells for removal and repair.

Adolescent↗
PubMed1991

Effect of topical sunscreens on the UV-radiation-induced suppression of the alloactivating capacity in human skin in vivo.

Exposure of mice or humans to solar or artificial ultraviolet radiation (UV) has been shown to induce a number of changes in the immune system that may influence their susceptibility to skin tumors. The protective effect of sunscreens on these changes is not clear. Thirty-two patients with a variety of dermatoses routinely undergoing treatment with standard UVB (n = 19) or PUVA (n = 13) therapy were studied. One of the two tested sunscreens or its vehicle was applied to the right flexor forearm immediately prior to each total-body UV exposure. Epidermal sheets were obtained by the suction-blister method from the left flexor forearm before treatment and from both flexor forearms after 4 weeks of photo- or photochemotherapy and used as stimulator epidermal cells (EC) in the mixed epidermal cell-lymphocyte reaction (MECLR). After 4 weeks of either UVB or PUVA therapy the MECLR responses on EC from both arms were markedly decreased. Neither the tested sunscreens nor their vehicles prevented the UV-induced suppression of the alloactivating capacity. The failure of sunscreens to protect against the UV-induced suppression of the alloactivating capacity could be explained in two ways. First, the energy not absorbed by the sunscreen could be sufficient to induce suppression of the alloactivating capacity. An alternative explanation could be systemic immune suppression by UV. In order to discriminate between these possibilities only the right forearms of 10 healthy volunteers, treated with a sunscreen or its vehicle, were irradiated with UVB during 4 weeks. In this manner systemic immune suppression by UVB could be excluded. This experiment resulted in a similar suppression of the MECLR responses, as induced by total body UVB irradiation, without any protection by the sunscreen. Apparently, the UV dose not absorbed by the sunscreen was capable to induce suppression of the alloactivating capacity. Our results indicate that people protected from sunburn by sunscreens may be exposed to UV for a long period of time, and thereby subject themselves to its immunosuppressive action.

Administration, Topical↗
PubMed1991

Internalization of MHC class I molecules is a prerequisite for endocytosis of endorphin by lymphocytes.

The nature of the interaction between gamma-type endorphins and the HLA class I molecules was studied by immunoelectronmicroscopy. The HLA molecules were not involved in the actual binding of endorphin to the cell. In contrast, for the endocytosis of gamma-endorphin, co-internalization of the HLA class I molecules is essential. The internalization process starts with clustering of gamma-endorphin and HLA class I molecules in coated pits. Cells that do not carry HLA class I molecules (Daudi) or do not internalize HLA class I molecules (EBV-transformed B cells) bind but do not internalize gamma-endorphin. On the basis of these observations, we suggest that the MHC class I molecules may function as transport molecules. Whether it is a general phenomenon that non-immunological ligands use the HLA class I molecules to get into the cell and immunological ligands (viral proteins) to reach the cell surface, remains to be established.

Antibodies, Monoclonal↗
PubMed1990

Analysis of the protective effect of topical sunscreens on the UVB-radiation-induced suppression of the mixed-lymphocyte reaction.

The mixed-lymphocyte reaction (MLR) was used to test the protective capacity of several sunscreens against UVB-radiation-induced suppression of the immune response. The MLR was performed using stimulator cells that had been exposed to 120 mJ/cm2 of an UVB source, whereas in simultaneous experiments a sunscreen-covered piece of quartz glass was placed in between the light source and the culture dish. The MLR response after UVB radiation was significantly decreased in comparison with the MLR response of non-radiated cells. This UV effect was partly inhibited by the tested sunscreens, whereas their vehicles alone showed hardly any effect. The protective capacity of sunscreens with similar protection factors, which were determined using the minimal erythematous dose (MED), showed a significant variation. These results suggest that the MED is not an accurate method to determine protection against UV-induced immunologic damage.

Antibody Formation↗
PubMed1988

Lipid composition of cultured human keratinocytes in relation to their differentiation.

The present study was undertaken to explore the possibility of the use of cultured human keratinocytes for the study of changes in lipid composition in relation to epidermal differentiation. In a submerged culture system, in which the stratification is incomplete, no significant differences have been found between the lipid composition of cells grown either at low calcium concentration (0.06 mM) (at which the keratinocyte differentiation is markedly retarded) or at normal calcium concentration (1.6 mM) (at which some differentiation takes place). Under these conditions the amount of phospholipids and sterols was high and that of ceramides was low. Furthermore, the acylglucosylceramides (AGC) and acylceramides (AC), the latter one known to be involved in water barrier function, were found to be absent. Contrary to this, both AGC and AC were found to be present in significant amounts in an air-exposed model using de-epidermized dermis (DED) as a substrate (in which, as judged from morphologic criteria, the extent of keratinocyte stratification is similar to that seen under the in vivo conditions). Fatty acid analysis revealed significantly lower content of 18:2 and higher content of 16:1 and 18:1 acids with all culture conditions used, as compared to the parent epidermis. This is probably a result of fatty acid levels and composition in fetal calf serum (which was used in the present study) that differ markedly from the in vivo situation. The 20:4 content was similar to that in the epidermis only in cells cultured under the submerged conditions, during which they have been found (Isseroff et al. 1987. J. Lipid Res. 28: 1342-1349) to be able to convert 18:2 to 20:4. In DED cultures, however, the 20:4 content was markedly lower. Under all culture conditions used, the triglyceride content was higher as compared to the non-cultured epidermis. The high content of triglycerides and the fatty acid composition of the various lipid fractions showed a resemblance with what is found in the epidermis in essential fatty acid-deficient animals. This resemblance was confirmed by electron micrographs which revealed the presence of some partially or completely empty lamellar bodies. The results of the present study suggest that the air-exposed culture model, in which the keratinocytes show a high extent of stratification, could be of great value in the study of epidermal lipid metabolism. However, further alterations in culture conditions are necessary to more closely approximate the lipid composition of noncultured epidermis.

Cell Differentiation↗
PubMedDate not supplied

Production of inflammatory mediators and cytokine responsiveness of an SV40-transformed human proximal tubular epithelial cell line.

Proximal tubular epithelial cells (PTEC) play a central role in the physiology of the renal tubulointerstitium. To be able to study the relationship between tubular cells and inflammatory renal diseases the availability of cultured cells is of importance. This study describes an immortalized proximal tubular epithelial cell line which was generated using SV40 DNA. To determine whether the transformation altered the cell line, the transformed cell line was characterized phenotypically using different monoclonal antibodies directed against peptidases, which are characteristic of PTEC, such as adenosine deaminase binding protein (CD26), leucine amino peptidase and carboxy peptidase M by immunofluorescent staining and FACS analysis. All peptidases were clearly present on the parental cell line and the transformed cell line. However, the level of expression of the peptidases was lower on the transformed cell line as compared to the parental nontransfected cells. The morphology of the transformed cell line, determined using a transwell culture system and electron microscopy, showed a polarized morphology of the tubular cells, tight junctions and microvilli. The transformed cell line was compared with the parental proximal tubular epithelial cells in its ability to respond to inflammatory cytokines such as IL- 1alpha TNF-alpha, IFN-gamma. Stimulation with these cytokines resulted in enhanced production of complement components C2, C3, C4 and factor H, IL-6 and the chemokines IL-8 and MCP-1. The transformed cell line responded in a similar fashion as the parental cell line, although the amount of the different proteins produced was significantly higher in the transformed cell line. Overall, the transformed tubular cell line seems to be a suitable model to study different effects on tubular cells in relation to inflammatory kidney diseases.

Blotting, Southern↗
PubMedDate not supplied

Ultrastructural localization of HLA-DR and HLA-DQ molecules in Langerhans cells and B cells: an immunoelectronmicroscopic study.

Using the immunoelectronmicroscopic techniques of Lowicryl embedding and ultracryomicrotomy, the intracellular distribution of HLA class II molecules was investigated on a human B cell line and on human Langerhans cells. These techniques enabled us to localize the HLA class II molecules on fixed specimens in which mobilization or clustering induced by cross linkage with antibodies is ruled out. Compared with Lowicryl embedding, the ultracryomicrotomy clearly showed more labeling. Both in B cells and Langerhans cells, the HLA-DR molecules were predominantly found in intracellular vesicular structures and on the plasma membrane. The HLA-DQ molecules were less abundant than HLA-DR molecules in the B cells and Langerhans cells. In the B cells, HLA-DQ molecules were found on the plasma membrane and in the cytoplasm. In the Langerhans cells, some HLA-DQ molecules were also found in intracellular vesicular structures. These experiments show a different localization of HLA-DR and -DQ antigens both in Langerhans cells and B cells, suggesting a different function for these molecules. The localization of HLA-DR molecules may indicate that these molecules take part in the recycling process of the plasma membrane in B cells and Langerhans cells. The HLA-DQ molecules are not internalized or recycled by the B cells, and a limited internalization of these molecules takes place in Langerhans cells. Finally, no HLA class II or clathrin molecules were found on the Birbeck granules, suggesting that, when no cross-linking with antibodies takes place, Birbeck granules, suggesting that, when no cross-linking with antibodies takes place, Birbeck granules do not play a role in recycling of HLA class II molecules in Langerhans cells.

Antibodies, Monoclonal↗
PubMedDate not supplied

Short-term and long-term UVB-induced immunosuppression in human skin exhibit different ultrastructural features.

Short-term ultraviolet B light (UVB)-induced immune suppression was established by the ability of UVB to inhibit induction of allergic contact dermatitis (ACD) to dinitrochlorobenzene (DNCB). The long-term effect was assessed by a dramatic reduction of the mixed-epidermal cell lymphocyte reaction (MECLR) responses. Immuno electron microscopic (IEM) investigation of HLA class II localization on epidermal Langerhans cells (LC) (pivotal for the immune response of the skin) showed no difference in HLA class II expression after UVB-exposure compared to control skin, both after short-term and long-term UVB-exposure. Ultrastructural examination of the epidermis revealed a normal appearance of the epidermal cells after long-term UVB-exposure. However, after short-term UVB-exposure the epidermis exhibited many abnormalities, ranging from the stratum corneum to the basal membrane. So although both short- and long-term UVB exposures were able to cause immune suppression in the skin, those processes were not accompanied with identical morphological epidermal features.

Dermatitis, Allergic Contact↗