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Biomedical subjects

D A Norris

Publications and source records attributed to D A Norris.

At least 91 records · Page 5Linked to original sources
PubMed1987

Isotretinoin produces significant inhibition of monocyte and neutrophil chemotaxis in vivo in patients with cystic acne.

The effect of oral isotretinoin (13-cis-retinoic acid) on in vivo chemotactic responses was studied longitudinally in 7 patients with cystic acne. As measured in a microchamber chemotaxis assay, both monocyte and neutrophil chemotaxis were inhibited 98% (p less than 0.001) during isotretinoin treatment. In vivo chemotactic responses returned to normal within 2 months of cessation of treatment. Biopsies of skin chamber sites from patients on isotretinoin showed no significant dermal or epidermal leukocytic accumulation in response to autologous zymosan-activated serum, whereas chambers from controls showed extensive neutrophilic infiltrates even in the epidermis. In contrast, in vitro chemotactic responses of neutrophils and monocytes from patients on isotretinoin were not diminished. Sera and plasma from patients on isotretinoin contained no inhibitors of chemotaxis, and activated sera from these patients were excellent attractants for normal monocytes. We postulate that isotretinoin produces significant anti-inflammatory effects by inhibition of monocyte and neutrophil chemotaxis across intact biologic barriers in vivo.

Acne Vulgaris↗
PubMed1986

An animal model of antibody binding in cutaneous lupus.

To study antibody binding in cutaneous lupus, we used human skin grafted onto nude mice. By immunofluorescence examination, mice injected with anti-Ro (SS-A) sera from subacute cutaneous or neonatal lupus erythematosus patients showed evidence of human IgG deposited in the skin, while mice injected with anti-native DNA or normal sera did not. We present evidence that there is specific binding of anti-Ro (SS-A) antibodies to Ro (SS-A) antigen in the skin, and we propose that these antibodies may be directly involved in cutaneous disease.

Adult↗
PubMed1986

Study of HLA-DR synthesis in cultured human keratinocytes.

Within the normal human epidermis only Langerhans and indeterminate cells express HLA-DR. Human keratinocytes (HK), however, may also express HLA-DR in certain disease states characterized by mononuclear cell infiltrates. Previous studies have shown that HK synthesize HLA-DR in response to stimulation by interferon gamma (INF-gamma). The purposes of this study were to define conditions under which cultured HK might express HLA-DR and to compare the HLA-DR synthesis of HK with that of monocytes. HLA-DR expression by HK as determined by indirect immunofluorescence of HK cultures was absent under standard low calcium conditions and remained absent with the addition of calcium, serum, mitogens, and supernatants from Pam-212 cells containing epidermal thymocyte-activating factor. HLA-DR expression in HK was induced by cocultivation with concanavalin A-stimulated peripheral blood mononuclear cells (PBMC), but not unstimulated PBMC. This effect was time-dependent and directly related to the number of PBMC. HLA-DR expression was also induced in a time- and dose-dependent manner by addition of supernatant from stimulated PBMC (SS) or by addition of recombinant INF-gamma but not by addition of interleukin (IL)-1 or IL-2. Induction by either SS or INF-gamma was blocked by an antiserum to INF-gamma. As determined by a semiquantitative immunoprecipitation technique, HLA-DR synthesis by HK was directly related to INF-gamma concentration. The pattern of HLA-DR peptides produced by HK was similar to that of monocytes, but the relative quantity synthesized was far less than that of monocytes.

Cells, Cultured↗
PubMed1986

Childhood pemphigus foliaceus: case report and review of the literature.

Childhood pemphigus foliaceus typically causes erythema and scaling of the scalp. Sometimes, blisters and oozing are present, which often are misdiagnosed as either impetigo or seborrheic dermatitis. The eruption may progress to involve the trunk and limbs, the lesions often having an arcuate pattern. The diagnosis can be established by histologic and immunologic evaluation. In children, the disease seems to be less severe than pemphigus vulgaris, as is the case with adults, and we recommend a trial of topical steroids before embarking on systemic therapy.

Administration, Topical↗
PubMed1985

Antibody-dependent cellular cytotoxicity and skin disease.

Antibody dependent cellular cytotoxicity (ADCC) is a recently described mechanism of immunologic lysis in which cellular targets sensitized by specific antibodies are efficiently and selectively lysed by Fc receptor (FcR) bearing nonspecific effectors. Immunoglobulins of various classes (IgG, IgM, IgA, IgE) and various cellular effectors (large granular lymphocytes, monocyte/macrophages, T lymphocytes, neutrophils, and eosinophils) can induce ADCC in vitro, and the importance of ADCC in vivo is being tested experimentally in resistance to viral, bacterial, and parasitic infection, in tumor surveillance, in allograft rejection, and in inflammatory diseases. There is much indirect evidence that ADCC may be the mechanism of damage of different cellular targets in skin diseases, but the best direct evidence concerns immunologic keratinocyte damage, especially in cutaneous lupus erythematosus (LE). We have shown that keratinocytes of several species are highly susceptible to lymphocyte and monocyte-mediated ADCC, but not to neutrophil or eosinophil ADCC in vitro using two different cytotoxicity assays. In contrast, complement was a relatively ineffective mediator of lysis of metabolically intact keratinocyte targets. Patients with certain cutaneous lupus syndromes have serum antibodies capable of inducing monocyte and lymphocyte ADCC of targets coated with extractable nuclear antigens. We have shown that these antigens apparently move to the cell membrane of keratinocytes in vitro following ultraviolet irradiation. In an animal model, we have shown that antibodies to SSA/Ro bind to human keratinocytes in vivo, especially after ultraviolet irradiation. This antigen/antibody system is highly associated with 3 different photosensitive LE syndromes. The experimental linkage of UV radiation to autoantibody binding to keratinocytes and the demonstration of mononuclear cell-mediated ADCC causing keratinocyte lysis support our hypothesis that the keratinocyte damage and mononuclear cell infiltrate seen histologically in cutaneous LE are part of an ADCC process.

Animals↗
PubMed1985

The demonstration of SS-A/Ro antigen in human fetal tissues and in neonatal and adult skin.

Anti-SS-A/Ro antibodies have been statistically associated with congenital heart block and cutaneous lupus in the neonatal lupus syndrome, and with photosensitive cutaneous lupus in subacute cutaneous lupus erythematosus, but it had not been demonstrated that SS-A/Ro antigen is present in fetal tissues or at any age in human skin. We examined normal fetal tissues, normal neonatal and adult skin, and keratinocytes from purified serum-free cultures by immunofluorescence (IF) and by immunodiffusion or counterimmunoelectrophoresis (CIE) to determine the presence of SS-A/Ro antigen. We found SS-A/Ro antigen to be present in fetal hearts and in other internal organs. SS-A/Ro antigen could be demonstrated in biopsies of neonatal and adult skin by IF and was confirmed to be in keratinocytes by CIE. SS-A/Ro antigen may be found on the surface of keratinocytes in culture and therefore may be present at a relevant site for antibody binding. We have shown that SS-A/Ro antigen is a normal component of tissues that may be affected in neonatal lupus (fetal myocardium, neonatal epidermis) and in subacute cutaneous lupus erythematosus (adult epidermis).

Antibodies, Antinuclear↗
PubMed1985

Subacute cutaneous lupus erythematosus associated with hydrochlorothiazide therapy.

Photosensitive eruptions with clinical and histologic features of subacute cutaneous lupus erythematosus and antibodies to SS-A(Ro) antigen occurred in five patients taking hydrochlorothiazide. After drug therapy was discontinued, the eruptions cleared. In one patient anti-SS-A antibodies disappeared after discontinuation of thiazide, and in another rechallenge with hydrochlorothiazide produced an acute dermatitis with a photodistribution. These eruptions may represent a new type of photosensitive drug reaction in which the photoactive drug may be synergistic with anti-SS-A antibody in producing cutaneous lesions of photosensitive subacute cutaneous lupus erythematosus.

Adult↗
PubMed1985

Systematic comparison of antibody-mediated mechanisms of keratinocyte lysis in vitro.

We have conducted a systematic comparison of lysis of TNP-coated keratinocyte targets by TNP-specific antibody, by antibody plus complement, by antibody-dependent cellular cytotoxicity (ADCC), and by natural killing with the use of monocyte, lymphocyte, and neutrophil effectors. With chromium-release assays, human keratinocytes, HEp-2 cells (transformed human keratinocytes), PAM 212 cells (transformed mouse keratinocytes), and RSC (transformed rabbit keratinocytes) were all susceptible to monocyte- and lymphocyte-mediated ADCC (p less than 0.01 to p less than 0.02). All trypsinized keratinocyte targets were also susceptible to natural killing by monocyte or lymphocyte effectors (p = 0.05 to p less than 0.001). Antibody and antibody plus complement were poor mediators of keratinocyte lysis. If protein and complex lipid synthesis of keratinocytes were inhibited by 16-hr cycloheximide preincubation, then keratinocytes were susceptible to complement-mediated lysis, implying that the resistance of these cells to complement may be due to repair of transmembrane pores. Comparison of chromium-release assays with fluorescein diacetate dye uptake viability assays showed that human keratinocytes were still susceptible to monocyte and lymphocyte ADCC but not to antibody, antibody plus complement, or natural killing. The reproducible and uniform susceptibility of normal and transformed keratinocyte targets from three different species to monocyte and lymphocyte ADCC supports the hypothesis that this mechanism of cellular lysis may be important in antibody-associated diseases of epidermal cytotoxicity.

Animals↗
PubMed1984

The role of RNP, Sm, and SS-A/Ro-specific antisera from patients with lupus erythematosus in inducing antibody-dependent cellular cytotoxicity (ADCC) of targets coated with nonhistone nuclear antigens.

To better understand potential antibody-dependent mechanisms of tissue damage in lupus erythematosus (LE), an examination of whether antibodies to nonhistone nuclear antigens in LE patients' sera can induce ADCC of cellular targets coated with the corresponding antigens was undertaken. With high titer anti-RNP sera, significant ADCC was seen with monocyte (P less than 0.01), T-lymphocyte (P less than 0.001), and low-density lymphocyte (P less than 0.001) effectors. Using monocyte effectors, significant ADCC was seen with anti-RNP (P less than 0.01), anti-Sm (P less than 0.01), and anti-SSA/Ro (P less than 0.01), with the most profound lysis being with the anti-SSA/Ro sera. Neutrophils were ineffective in any nuclear antigen-antibody system tested. The effective mononuclear cell-mediated ADCC seen with anti-RNP, anti-Sm, and anti-SSA antisera may be related to the mononuclear cell-associated tissue change seen in cutaneous lupus lesions.

Antibodies↗
PubMed1984

Human keratinocytes synthesize, secrete, and deposit fibronectin in the pericellular matrix.

Fibronectin production by human keratinocytes cultured in serum-free, low-calcium medium without a fibroblast feeder layer was examined using several techniques. Immunohistochemical examination confirmed that the cultures were not contaminated with fibroblasts or Langerhans cells. By indirect immunofluorescence, fibronectin appeared as intracellular granules within all cells and as short radial fibrils between the cells and the substratum, and in the pericellular matrix. Conditioned media taken from 4-, 6-, 8-, 10-, and 12-day cultures contained fibronectin as measured by enzyme-linked immunosorbent assay in proportion to the cell number in cultures. Synthesis of fibronectin by 7-day keratinocyte cultures was determined by 18-h [35S]methionine metabolic labeling followed by sodium dodecyl sulfate polyacrylamide gel electrophoresis and autoradiography. Fibronectin accounted for 12% of the secreted protein under these culture conditions. Our results indicate that human keratinocytes under conditions that prevent terminal differentiation in vitro can synthesize, secrete, and deposit fibronectin in the extracellular matrix.

Enzyme-Linked Immunosorbent Assay↗
PubMed1984

Ultraviolet light induces binding of antibodies to selected nuclear antigens on cultured human keratinocytes.

Antibodies which bind to different nuclear antigens in tissue sections or in permeabilized cell cultures are useful markers of subsets of connective tissue disease, especially of lupus erythematosus (LE), but whether these antibodies are able to react with these intracellular sequestered antigens in vivo and cause immunologic tissue damage has been a matter of much debate. We report experiments which show that ultraviolet light-irradiated, cultured human keratinocytes bind IgG antibodies from the sera of LE patients with either monospecific anti-SSA/Ro, anti-RNP, or anti-Sm activity, which implies that these antigens have been made accessible on the cell surface by ultraviolet irradiation. Normal human sera or LE patient's sera with anti-double-stranded DNA, anti-single-stranded DNA, or antihistone activity do not bind to the surface of irradiated human keratinocytes. In control experiments, all antisera produced the expected patterns of nuclear and cytoplasmic staining of fixed permeabilized, unirradiated keratinocytes. Careful study of the viability and permeability of irradiated keratinocytes by several techniques showed that this apparent cell membrane expression of extractable nuclear antigens (SSA/Ro, RNP, and Sm) following irradiation was seen on injured keratinocytes whose cell membranes were intact, but not on dead cells. It is particularly significant that all six monospecific anti-SSA/Ro sera bound to irradiated keratinocytes, since this antibody antigen system is highly associated with photosensitive cutaneous LE.

Antibodies, Antinuclear↗
PubMed1983

Neonatal lupus syndrome in successive pregnancies.

Two female siblings, born 15 months apart, developed neonatal lupus syndrome. Both had cutaneous lupus erythematosus (LE) lesions resolving with telangiectasis. Their cutaneous lesions were temporally related to transplacental passage of anti-SS-A (Ro) autoantibodies from their asymptomatic mother. Infants with this transient collagen vascular syndrome may have LE skin lesions, congenital heart block, and liver or hematologic abnormalities, and are possibly at risk for developing systemic lupus erythematosus (SLE) later in life. It is important to recognize that this syndrome may occur in successive pregnancies.

Female↗
PubMed1983

Immunogenetics of the neonatal lupus syndrome.

Infants with neonatal lupus erythematosus have congenital heart block, transient cutaneous lesions, or both. Mothers of these infants have SSA/Ro autoantibodies that are passed across the placenta to the fetus and that have been temporarily associated with the syndrome. Six families with neonatal lupus were studied by HLA typing. All seven infants had transient cutaneous lesions, congenital heart block, or both. Five of six mothers were asymptomatic and one had Sjögren's syndrome. Six of seven infants and all six mothers had antibodies to SSA/Ro in their sera. The infants became seronegative by age 8 months. Five mothers were positive for HLA-DR3, five for HLA-MB2, six for HLA-MT2, and six for HLA-B8. No HLA associations were seen in infants. Gene products of the DR or similar regions may be associated with autoantibody production but not with other events in tissue injury.

Antibodies, Antinuclear↗
PubMed1982

The effect of epicutaneous glucocorticosteroids on human monocyte and neutrophil migration in vivo.

The effect of epicutaneous methyl prednisolone (MP) at 10-4, 10-5, and 10-6 molar concentration was studied in 54 normal, healthy volunteers using a new, in vivo microchemotaxis technique. Significant inhibition of monocyte chemotaxis occurred at all concentrations studied and persisted over a 24-hr period with 10-4 molar MP. Neutrophil chemotaxis was significantly inhibited only with 10-4 MP. The inhibitory effect of MP on neutrophil and monocyte chemotaxis occurred earlier and at lower concentrations if the skin sites were pretreated with steroid. Thus, when corticosteroids are applied on abraded skin in concentrations achievable in vivo, monocyte chemotaxis into tissue is inhibited for longer periods and at lower drug concentrations than is neutrophil chemotaxis. By avoiding the significant systemic effects of corticosteroids on circulating monocyte and neutrophil populations, these experiments establish that local inhibition of chemotaxis is an important anti-inflammatory effect of corticosteroids, with differential effect on monocytes and neutrophils.

Adrenal Cortex Hormones↗
PubMed1982

Humoral immunity in stage I mycosis fungoides: an increased incidence of lymphocytotoxic antibodies.

Thirteen patients with stage I mycosis fungoides (MF) were studied for the presence of circulating autoantibodies including cold-reactive lymphocytotoxic antibodies (LCA), antinuclear antibodies and rheumatoid factor antibodies to common food antigens, bovine gamma globulin and casein; and immune complexes as measured by cryoglobulins and I125 Clq binding. A significantly increased incidence (11/13) of LCA was found in the MF patients, and this may be related to the alterations in subpopulations of T cells seen in these patients. No significant increase in any other test was noted. there was no evidence of a diffuse hyperactivity of the humoral immune system as seen in systemic lupus erythematosus, which has a similar imbalance of T cell subpopulations.

Adult↗