Search PubMed⌕ Search

Biomedical subjects

B J Nickoloff

Publications and source records attributed to B J Nickoloff.

At least 19 recordsLinked to original sources
PubMed1992

Dermal dendrocytes and T-cells in canine mycosis fungoides. Support for an animal model of human cutaneous T-cell lymphoma.

BACKGROUND: An extensive upper dermal network of human Thy-1+/Factor XIIa+ dermal dendrocytes (DD) exists in human mycosis fungoides (MF). METHODS: Immunophenotyping and morphologic studies on serial frozen and paraffin sections from 15 cases of canine MF were performed to see if a similar network exists in this disease, as has been proposed as an animal model of human MF. Primary antibodies were anti-human Factor XIIIa, Factor XIIIs, anti-canine Thy-1, CD4, CD8, CD18, CD45RA, Class II, MAC387, KP-1, EBM-11, and several other pan-T, pan-B, and pan monocyte markers. RESULTS: Thy-1+/Factor XIIIa+DD were seen in all cases and confirmed on identical cells by double immunofluorescence. These were seen throughout the upper dermis, similar to DD in human MF. Canine DD expressed the macrophage marker 2A2+, and were Class II+, CD4+, CD8-, CD18+, EBM11-, Factor XIII-, MAC387-, and KP-1. Epidermal and dermal lymphocytes in canine MF were Thy-1-, CD4+, CD8-, CD18+, CD45RA-, EBM11-, MAC387-, Factor XIIIa-, Factor XIIIs- in some cases, whereas others had a predominance of CD8+ lymphocytes. CONCLUSIONS: Thus, canine MF is immunophenotypically similar to human MF. Additional support for this disease as a model of human MF is demonstrated by the rich network of Thy-1+/Factor XIIIa+ DD in the upper dermis of canine MF similar to human MF.

Animals↗
PubMed1992

Epidermal growth factor and transforming growth factor-alpha decrease gamma interferon receptors and induction of intercellular adhesion molecule (ICAM-1) on cultured keratinocytes.

The link between the epidermal keratinocytes of the skin and the activated T lymphocytes of the immune system is mediated by a variety of cytokines, including gamma interferon (IFN-gamma). We studied the influence of keratinocyte mitogens such as transforming growth factor-alpha (TGF-alpha), epidermal growth factor (EGF), and somatomedin-C (SM-C) on the ligand binding of 32P-labeled IFN-gamma to cultured keratinocytes derived from normal appearing adult human skin. Keratinocytes placed in a medium devoid of mitogens become growth arrested, and these quiescent cells expressed 2.4 times (28,900 versus 12,200 sites/cell) as many high affinity IFN-gamma receptors (Kd = 0.22 nM) compared to keratinocytes which were actively growing in medium containing TGF-alpha (25 ng/ml) or EGF (10 ng/ml). The reduction in IFN-gamma receptor sites by TGF-alpha/EGF was mitogen specific, as adding SM-C (500 ng/ml) did not have any effect on ligand binding, although it similarly stimulated keratinocyte growth. The reduction in IFN-gamma receptors was time dependent, occurring primarily after 24-48 hours of change in tissue culture conditions. The reduction in the number of high affinity IFN-gamma receptors by TGF-alpha/EGF had immunobiological consequences, because quiescent keratinocytes in basal medium had an increased expression of HLA-DR and intercellular adhesion molecule-1 (ICAM-1) induced by IFN-gamma, compared to actively growing TGF-alpha/EGF treated keratinocytes. These results suggest that rapidly proliferating keratinocytes exposed to TGF-alpha/EGF but not SM-C are capable of altering their response to IFN-gamma by decreasing their number of cell surface high affinity receptors for IFN-gamma.

Cell Adhesion Molecules↗
PubMed1992

Pathophysiology of cutaneous inflammation.

For the better part of the past century, dermatologists have regarded the skin primarily as a large protective coat. Epidermal keratinocytes were highlighted for their production of keratins and lipids, which contributed to the structural integrity and barrier formation of skin. This "saran-wrap" perspective of skin mentioned keratinocytes only in cutaneous inflammatory reactions as passive targets for damaging diffusion products of infiltrating leukocytes. However, sufficient compelling in vitro and in vivo evidence is rapidly accumulating to support the novel perspective that epidermal keratinocytes can initiate and actively participate in the perpetuation of numerous cutaneous inflammatory reactions that involve a highly diverse array of inciting agents. This presentation emphasizes the keratinocyte and highlights the dynamic immunomodulatory capacity of this overlooked epidermal cell.

Animals↗
PubMed1992

Keratinocyte activation following T-lymphocyte binding.

T lymphocytes infiltrate the epidermis and follicular epithelium adhering to keratinocytes within hours following induction of cutaneous inflammation. To determine if the physical binding interaction between a T cell and keratinocyte induces transmission of activation pathways, CD3+ T cells (HUT 78) were allowed to directly bind to non-cytokine-treated cultured keratinocytes. When these T cells bound to keratinocytes, the keratinocytes were activated as evidenced by detection of tumor necrosis factor-alpha, interleukin-6, and intercellular adhesion molecule-1 mRNA. This induction was relatively mRNA specific, as several other mRNA were not found to be altered. This activation process appeared to be one-sided, as no change in HUT cell mRNA levels was detectable. The keratinocyte activation process was confined to cultures that had direct physical binding by HUT cells, because co-culturing the HUT cells immediately above the keratinocyte monolayer (but not in direct contact), resulted in no such mRNA alterations. This direct adhesion-mediated activation of keratinocytes by T lymphocytes may be important in the genesis of cutaneous inflammation by amplifying the original stimulus, as well as contributing to the trafficking pattern of inflammatory cells as they leave the general circulation and enter the skin.

Cell Adhesion Molecules↗
PubMed1992

Oral submucosal dendrocytes: factor XIIIa+ and CD34+ dendritic cell populations in normal tissue and fibrovascular lesions.

Factor XIIIa+ and CD34+ dendritic cells, believed to be subsets of monocyte/macrophages, have been identified in dermis and in dermal tumors. The purpose of this study was to determine the presence and distribution of analogous cell types in oral submucosa and oral fibro-vascular lesions. Antibodies to XIIIa, CD34, S-100 protein, and macrophage antigen (MAC 387) were tested on formalin-fixed, paraffin-embedded tissue sections from normal mucosa, peripheral fibroma (PF), peripheral ossifying fibroma (POF), peripheral giant cell granuloma (PGCG), pyogenic granuloma (PG), lymphangioma (La), benign fibrous histiocytoma (BFH), idiopathic histiocytosis (IH), angiofibroma (Af) using an ABC immunoperoxidase technique. Numbers of positively stained cells were compared to unstained cells in the tumors. XIIIa positive submucosal dendrocytes (CD34-, S-100-, MAC 387-) were found in abundance in normal tissue in characteristic distributions: collagen-associated, vessel-associated, and lymphoid-associated. The percentage of XIIIa+ cells in the oral tumors was as follows: PF: 10-30%, POF: 5-10%, PGCG: 0-5%, PG: 5-20%, La: 0%, BFH: 5-25%, IH: 0%, and Af: 10-20%. CD34+ dendrocytes (XIIIa-, S-100-, MAC 387-) were few in number and were found in deeper submucosa, especially around skeletal muscle. Other than blood vascular endothelium, CD34+ cells were not generally seen in the oral tumors studied. It is concluded that two previously unrecognized dendrocyte populations reside in normal submucosa. XIIIa+ cells participate in the formation of some oral reactive and neoplastic lesions.

Antigens, CD↗
PubMed1992

Cutaneous expression of Thy-1 in mycosis fungoides.

Dermal dendritic cells from eleven cases of mycosis fungoides (MF) (six patch and five plaque stage), two cases of pre-MF, and five specimens of normal human skin, were characterized immunohistochemically using a panel of antibodies including anti-human Thy-1, intercellular adhesion molecule-1 (ICAM-1; CD54), endothelial leukocyte adhesion molecule-1 (ELAM-1), vascular cell adhesion molecule-1 (VCAM-1), CD1a, CD2, CD14, CD18, CD34, MAC387, KP-1, EBM-11, factor XIIIa, factor XIIIs, and S100. Thy-1 expression in normal skin was limited to the microvascular endothelium and perivascular dendritic cells. An extensive interstitial network of Thy-1+ dendritic cells was seen in the papillary dermis of all cases of MF, whereas no epidermal cells were Thy-1+. The mean +/- standard deviation of interstitial Thy-1+ cells per high power field in the dermis was: normal skin, 2.86 +/- 0.34; pre-MF, 15; patch stage MF, 13.4 +/- 7.08; plaque stage MF, 49.96 +/- 21.29. Thy-1+ dendritic cells morphologically resembled the factor XIIIa+ "dermal dendrocyte" (DD) and shared their VCAM-1+, ICAM-1+, CD1a, CD2-, CD14+, CD18+, EMB11+, factor XIIIa+, factor XI-IIs-, S100-, MAC387- and KP-1-immunophenotype in MF. Double labeling studies revealed up to 50% of Thy-1+DD were also factor XIIIa+ in MF. Immediately beneath these cells was a similar network of CD34+, Thy-1-, factor XIIIa- dendritic cells limited to the reticular dermis. Strong microvascular endothelial cell expression of Thy-1 and VCAM-1, and focal vascular ELAM-1 expression were also seen in MF. Distinct cellular compartmentalization (papillary dermis versus reticular dermis versus epidermis) of dendritic cells is demonstrated by the differential expression of Thy-1, factor XIIIa, and CD34 antigens. The extensive number and prominent dermal dendritic network in the papillary dermis juxtaposed between epidermal keratinocytes (KC) and dermal/epidermal T cells, suggests an important pathophysiologic role for this newly recognized and immunophenotypically distinctive cell population in MF.

Antigens, CD↗
PubMed1992

HUT 78 T cells bind to noncytokine-stimulated keratinocytes using a non-CD18-dependent adhesion pathway.

The initial in vitro observation that cultured keratinocytes, when treated with cytokines such as gamma interferon, increased the binding of T lymphocytes, opened up a whole new avenue of research to understand epidermal trafficking patterns in inflammatory skin diseases. A growing body of data strongly supports the in vivo role of lymphocyte-function-associated antigen-1 (CD18) expression by T cells in the binding to intercellular adhesion molecule-1 (CD54) expressing keratinocytes. To further explore the molecular basis for other possible adhesive interactions involving T cells and skin-derived cellular constituents, the authors used 2 cell lines (HUT 78 cells and Jurkat cells) and added them to multipassaged human keratinocytes, fibroblasts, and melanocytes. The skin-derived cells were treated with cytokines alone, or in combination, with a phorbol ester. HUT cells were capable of binding to keratinocytes in the absence of pretreatment with cytokines at 25 degrees C, which was not inhibited by anti-CD18 antibodies, or sensitive to reducing the temperature of the adhesion assay to 7 degrees C. Fibroblasts and melanocytes also constitutively bound HUT cells, but the binding to fibroblasts was highly temperature-sensitive. When keratinocytes were pretreated for 48 hours with gamma interferon plus phorbol ester, a "superadhesive" state was induced, resulting in a synergistically increased binding ability of both HUT cells and Jurkat cells. This effect was related to quantitative increases in keratinocyte intercellular adhesion molecule-1 expression. Several other clear-cut qualitative and quantitative differences were detectable in the ability of HUT cells and JS cells to bind to nontreated and cytokine/phorbol ester-treated keratinocytes, fibroblasts, and melanocytes. These results emphasize the complexity of molecular associations underlying T-cell trafficking patterns, potentially operative in the dermal and epidermal compartments of the skin.

Antigens, CD↗
PubMed1992

Lymphoepitheliomalike carcinoma of the skin. A case report with immunophenotypic analysis and in situ hybridization for Epstein-Barr viral genome.

Lymphoepithelioma is a malignant epithelial neoplasm of the nasopharynx. Similar malignancies--lymphoepitheliomalike carcinomas--of salivary glands, thymus, larynx, lung, stomach, and uterus have been described. We present here a case of lymphoepitheliomalike carcinoma of the skin in an 84-year-old woman. Histologically this neoplasm presented as a fairly discrete dermal aggregate of syncytial nests of epithelioid-appearing cells that displayed no squamous or glandular differentiation, surrounded by a dense lymphocytic infiltrate. Results of immunophenotypic studies showed expression of high molecular weight cytokeratins and increased density of dermal dendrocytes within and adjacent to the tumor. No Epstein-Barr viral genomic sequences were detected by in situ hybridization, which suggests that cutaneous neoplasms may have different etiologic agents compared with similar tumors, found to be associated with this DNA-containing virus, arising in extracutaneous sites. The combined light microscopic and immunohistochemical assessment of this rate cutaneous neoplasm permits distinction of lymphoepitheliomalike carcinoma from benign/malignant lymphoproliferative disorders or neuroendocrine carcinomas.

Aged↗
PubMed1991

Monocyte chemotaxis and activating factor production by keratinocytes in response to IFN-gamma.

Monocytes accumulate in the epidermis and along the dermo-epidermal junction in several different inflammatory skin diseases. To determine whether human epidermal keratinocytes elaborate a specific chemotaxin responsible for the accumulation of monocytes at these anatomic sites, monocyte chemotactic activity in conditioned 16-h cultured keratinocyte supernatants were assayed using human peripheral blood monocytes as the target cell. Dilutional analysis revealed directed monocyte migration in IFN-gamma-treated (100 U/ml) keratinocyte supernatants (80% maximal FMLP response) which was 10-fold more than IFN-gamma itself or untreated keratinocyte activity alone. Gel filtration chromatography revealed that this activity eluted just ahead of a 12.5-kDa molecular mass marker. Blocking studies demonstrated that a rabbit polyclonal antibody to monocyte chemotaxis and activating factor (MCAF) inhibited all monocyte chemotaxis by greater than 80%. Keratinocytes were metabolically labeled with 35S-cysteine/methionine, and after 16 h incubation the supernatants immunoprecipitated with the same anti-MCAF antibody. MCAF was detected as a protein doublet of 12 and 9 kDa only in IFN-gamma-treated (100 U/ml) keratinocyte supernatants. Incubation with IFN-gamma and TNF-alpha (250 U/ml) in combination resulted in increased production of MCAF protein. By Northern blot analysis, MCAF mRNA was constitutively expressed in keratinocytes and upregulated only in the presence of IFN-gamma. TNF-alpha, IL-1 beta, transforming growth factor-beta and phorbol esters had no positive or negative influence on MCAF mRNA. These studies demonstrate that biologically active MCAF is elaborated by human epidermal keratinocytes upon activation by IFN-gamma, a cytokine also required for the induction of adherence between monocytes and keratinocytes. Keratinocyte-derived MCAF is likely to be important in the regulation of cutaneous monocyte trafficking and may also be responsible for the recruitment of Langerhans cells and dermal dendrocytes, which share many phenotypic features with monocytes/macrophages, to their anatomic locations in skin.

Cells, Cultured↗
PubMed1991

Keratinocytes as initiators of inflammation.

Environmental stimuli responsible for inducing cutaneous inflammation include contact allergens and ultraviolet light. We postulate that these diverse stimuli trigger a cutaneous inflammatory response by directly inducing epidermal keratinocytes to elaborate specific pro-inflammatory cytokines and adhesion molecules. The consequences are activation of dermal microvascular endothelial cells and selective accumulation of specific mononuclear cells in the dermis and epidermis. Thus, keratinocytes may act as "signal transducers", capable of converting exogenous stimuli into the production of cytokines, adhesion molecules, and chemotactic factors (acting in an autocrine and paracrine fashion) responsible for initiation of "antigen-independent" cutaneous inflammation. The initiation phase may facilitate or promote an amplification phase with additional production of tumour-necrosis factor alpha and interferon gamma via an "antigen-dependent" pathway, and keratinocyte/T cell/antigen-presenting dendritic cellular associations. The direct activation of keratinocytes, with their ability to produce the complete repertoire of pro-inflammatory cytokines, can profoundly influence endogenous and recruited immunocompetent cells, thereby providing the critical trigger responsible for the swift and clinically dramatic alterations that occur following contact between the epidermis and a host of "noxious" agents.

Catechols↗
PubMed1991

Detection of interferon-gamma mRNA in psoriatic epidermis by polymerase chain reaction.

Psoriatic skin lesions contain HLA-DR positive T lymphocytes, and other activation antigens, which suggest that the T cells may be producing lymphokines. Gamma interferon is produced by activated T cells, and its presence in psoriasis has been inferred by the lesional keratinocyte expression of 3 gamma interferon-inducible proteins i.e. HLA-DR, intercellular adhesion molecule-1, and gamma-IP-10. To determine whether gamma interferon is being produced directly in psoriatic lesions, punch biopsies of normal and diseased skin were separated into epidermal sheets and dermal fragments. Total cellular RNA was isolated from each epidermal and dermal compartment, and reverse transcribed followed by amplification of the resultant DNA by polymerase chain reaction. The amplification process involved the use of 5' and 3' primers for gamma interferon, and tumor necrosis factor-alpha, with beta-actin serving as a control. Gamma interferon mRNA, but not tumor necrosis factor alpha mRNA, was detectable in 4 of 5 psoriatic epidermal specimens. Neither mRNA was detectable in any normal skin dermal/epidermal specimens. Gamma interferon mRNA was also detectable in a single psoriatic dermal specimen. If reverse transcriptase was omitted, no polymerase chain reaction products were detected, indicating that the fragments detected were not derived from contaminating genomic DNA. These results indicate that gamma interferon mRNA can be extracted and successfully detected from human psoriatic lesional skin biopsies, using polymerase chain reaction technology. This molecular approach can easily be expanded to measure many other cytokines in both epidermal and dermal locations. The detection of gamma interferon in this clinical setting may be of particular pathophysiological significance because injection of gamma interferon has been reported to induce psoriatic lesions.

Actins↗
PubMed1991

Cellular, immunologic and biochemical characterization of topical retinoic acid-treated human skin.

Histologic and clinical improvement of sun-exposed skin following topical treatment with retinoic acid has been reported. Daily application of retinoic acid typically results within 2-5 d in an erythematous scaling reaction, which lessens with continued usage. The cellular, immunologic, and biochemical basis of this retinoid reaction and its role in the repair of photodamaged skin are not known. To investigate the retinoid reaction in man, we have treated non-sun-exposed skin with 0.1% retinoic acid cream (Retin-A, Ortho Pharmaceutical Corporation, Raritan, NJ) under occlusion for 4 d to induce erythema and then examined changes in 1) histology, 2) expression of cell-surface molecules, 3) the enzymes and second messengers of the phospholipase C/protein kinase C signal-transduction system, 4) levels of eicosanoids, and 5) levels of interleukin-1 protein and mRNA. These parameters were chosen for measurement both because they are indicators of epidermal function and previous studies suggest they may be responsive to retinoic acid treatment. Epidermal cell growth as judged by increased epidermal thickness and mitotic figures was significantly increased in retinoic acid-treated skin compared to vehicle-treated controls. Increased numbers of CD4+ T cells accompanied by prominence of dermal dendrocytes in the papillary dermis and focal keratinocyte expression of intercellular adhesion molecule-1 were observed in retinoic acid-treated biopsies. Phosphoinositide-specific phospholipase C activity and 1,2-diacylglycerol content were also elevated in retinoic acid-treated epidermis. Protein kinase C activity was reduced by one third in both the soluble and membrane fraction, suggesting down-regulation. Surprisingly, in view of the inflammatory nature of the retinoid reaction, no increases were observed in arachidonic acid, its metabolites, interleukin-1 alpha, or interleukin-1 beta. To examine the specificity of the retinoid reaction, subjects were treated with the irritant sodium lauryl sulfate, under conditions that resulted in a reaction clinically similar to that observed with retinoic acid. The histologic alterations induced by sodium lauryl sulfate were found to be indistinguishable from those induced by retinoic acid. These data indicate that, although a wide range of cellular and molecular alterations occur in retinoic acid-treated skin, these changes may not be necessarily specific or unique for retinoic acid.

Cell Adhesion Molecules↗