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Biomedical subjects

C E Griffiths

Publications and source records attributed to C E Griffiths.

At least 181 records · Page 10Linked to original sources
PubMed1990

Sulfasalazine improves psoriasis. A double-blind analysis.

In an 8-week double-blind trial of sulfasalazine for the treatment of moderate-to-severe psoriasis, 23 and 27 patients received the active and placebo tablets, respectively. At the end of the double-blind phase, there were 17 assessable patients receiving sulfasalazine; 7 (41%) had marked improvement, 7 (41%) had moderate improvement, and 3 (18%) demonstrated minimal change. Only 1 patient receiving placebo demonstrated moderate improvement, whereas the rest had minimal improvement or worsening of psoriasis. When the randomization code was broken, patients receiving sulfasalazine were allowed to continue therapy for an additional 4 weeks in an open manner, while those using placebo left the study. Six of 23 patients discontinued sulfasalazine therapy during the double-blind phase because of side effects, 4 due to the development of a cutaneous eruption and 2 due to nausea. Fourteen of 17 patients, who were assessable at the end of the 8-week double-blind phase, completed the additional 4 weeks of sulfasalazine therapy. Of these 14 patients, marked improvement occurred in 8 (57%), moderate improvement in 2 (14%), and minimal improvement in 4 (29%), compared with pretherapy. The low incidence of severe side effects makes sulfasalazine a consideration for oral therapy in patients whose disease severity does not justify use of methotrexate, etretinate, or psoralen plus UV-A, but whose disease severity is too widespread for safe and practical use of topical corticosteroids.

Adult↗
PubMed1990

Intraepidermal but not dermal T lymphocytes are positive for a cell-cycle-associated antigen (Ki-67) in mycosis fungoides.

The Ki-67 antibody, which reacts with nuclei of actively proliferating cells, was used in an immunohistochemical study to determine if there was any difference between T cells located in the epidermis rather than the dermis, in mycosis fungoides. In 12 of 14 cases of patch/plaque stage mycosis fungoides, the epidermal T cells were Ki-67 positive, while the dermal T cells were Ki-67 negative in all cases. Both epidermal and dermal T cells belonged primarily to the memory-versus-naive subset. The intraepidermal Ki-67-positive T cells were slightly larger than the dermal Ki-67-negative cells and could be easily distinguished from occasional basal keratinocytes that were also Ki-67 positive. We conclude that dermal T cells, despite expressing HLA-DR and a memory phenotype, are essentially in a resting (Go or noncycling state) in mycosis fungoides. Furthermore, it appears that the movement of T cells into the epidermal compartment is associated with activation and entry into the cell cycle. Such intraepidermal activation may lead to lymphokine release, and play an important pathophysiologic role in mycosis fungoides.

Antigens, Differentiation↗
PubMed1990

Oral cyclosporine in the treatment of inflammatory and noninflammatory dermatoses. A clinical and immunopathologic analysis.

Cyclosporine is known to be effective in the treatment of psoriasis. In this study, we have used oral cyclosporine (6 mg/kg per day) given for 5 to 30 weeks to 24 patients for the treatment of 12 different dermatoses. Patients with the following diseases demonstrated a marked response or total clearing: 1 patient each with pyoderma gangrenosum, pityriasis lichenoides chronica, and psoriasis of the acrodermatitis continua of Hallopeau type. Moderate to marked response occurred in both patients with epidermolysis bullosa acquisita and the patient with hidradenitis suppurativa. Minimal to moderate responses were obtained in both patients with granuloma annulare, 1 of 2 with acrodermatitis continua of Hallopeau, both patients with Darier's disease, and 1 of 6 patients with vitiligo. Little or no response was noted in both patients with sarcoidosis, all 3 patients with pityriasis rubra pilaris, 5 of 6 patients with vitiligo, 1 patient with pemphigus foliaceous, and 1 with pemphigus vulgaris. Clinical side effects were mild and transient and included dysesthesia, fatigue, hypertrichosis, nausea, and flushing. The most frequent clinically significant abnormalities were hypertension and renal dysfunction, with all factors normalizing within 1 month of discontinuation of cyclosporine therapy.

Administration, Oral↗
PubMed1990

Disseminated dermal dendrocytomas. A new cutaneous fibrohistiocytic proliferative disorder?

A 77-year-old white woman presented with 1 1/2-year history of progressively enlarging cutaneous papules, nodules, and plaques, some of which had spontaneously regressed. Her past medical history included untreated chronic lymphocytic leukemia for 10 years' duration. Multiple skin biopsy specimens revealed a diffuse superficial and deep dermal spindle-cell infiltrate accompanied by occasional foamy round cells and multinucleated giant cells. The spindle-shaped cells were focally arranged in a storiform pattern with prominent fibrous stroma. The spindle-shaped cells stained positively for numerous macrophage markers including CD45, factor XIIIa, Leu M5, HLA-DR, CD4, and Leu M3, consistent with dermal dendrocytes. They were also positive for nonspecific esterase and acid phosphatase, which is typical of tissue macrophages. The spindle-shaped cells were negative for CD-1, S-100, and ATPase activity, thus excluding a Langerhans cell immunophenotype. Combining the clinical features, light microscopy, immunohistochemistry, and enzymatic analysis, this patient appears to represent a novel cutaneous fibrohistiocytic proliferative disorder that features large numbers of dermal dendrocytes.

Aged↗
PubMed1989

Markedly diminished epidermal keratinocyte expression of intercellular adhesion molecule-1 (ICAM-1) in Sézary syndrome.

In mycosis fungoides the malignant T cells express lymphocyte function-associated antigen-1, which allows them to bind to epidermal keratinocytes expressing the gamma interferon-inducible intercellular adhesion molecule-1. In this report, a patient with leukemic-stage mycosis fungoides (Sézary syndrome) had widespread erythematous dermal infiltrates containing malignant T cells, but without any epidermotropism. We discovered that the T cells expressed normal amounts of functional lymphocyte function-associated antigen-1, but the keratinocytes did not express significant levels of intercellular adhesion molecule-1, which was probably due to the inability of the malignant T cells to produce gamma interferon. These results support the concept that the inability of malignant T cells to enter the epidermis may contribute to emergence of more clinically aggressive T-cell clones that are no longer confined to the skin, but infiltrate the blood, lymph nodes, and viscera, as is seen in Sézary syndrome.

Aged↗
PubMed1989

Characterization of intercellular adhesion molecule-1 and HLA-DR expression in normal and inflamed skin: modulation by recombinant gamma interferon and tumor necrosis factor.

Lymphocytes bind to cultured keratinocytes that are treated with interferon gamma (IFN-gamma) and tumor necrosis factor (TNF). When the lymphocytes are preincubated with antibody to lymphocyte function associated antigen-1 (LFA-1), this adherence is inhibited. Because intercellular adhesion molecule-1 (ICAM-1) is a ligand for LFA-1, we studied the cellular expression of ICAM-1, as well as two other IFN-gamma-inducible antigens, (HLA) human lymphocyte antigens DR and DQ, in both normal and diseased skin. The modulation of these cell surface antigens by IFN-gamma and TNF with the use of short-term organ cultures of skin was compared with isolated keratinocytes grown in a conventional tissue culture system. While in normal skin, keratinocytes did not express HLA-DR, DQ, or ICAM-1, when organ cultures were supplemented with IFN-gamma, rapid induction of keratinocyte ICAM-1 expression occurred after 24 hours; HLA-DR but not DQ expression occurred after 48 hours. TNF also induced keratinocyte ICAM-1 expression (although to a lesser degree than IFN-gamma) but did not induce either keratinocyte HLA-DR or DQ expression. There was good correlation of keratinocyte expression of ICAM-1 and HLA-DR by IFN-gamma and TNF when the epidermis of the organ culture system was compared with the isolated keratinocytes grown in tissue culture. The presence of intraepidermal lymphocytes correlated extremely well with keratinocyte ICAM-1 expression but not with keratinocyte HLA-DR expression in psoriasis, atopic dermatitis, lichen planus, and mycosis fungoides. The intensity of endothelial cell expression of ICAM-1 correlated with the degree of dermal inflammation. We conclude that IFN-gamma, once produced by activated T lymphocytes in the dermis, may be of importance in lymphocyte trafficking in the epidermis by the induction of keratinocyte ICAM-1 expression. The use of the short-term organ culture system, in which there is inducible ICAM-1 expression, provides an experimental bridge between purely in vitro and in vivo investigations to further our understanding of the molecular basis for lymphocyte apposition to keratinocytes in the skin.

Antigens, Surface↗
PubMed1989

T lymphocytes and monocytes bind to keratinocytes in frozen sections of biopsy specimens of normal skin treated with gamma interferon.

When 2 mm punch biopsy specimens of normal skin are incubated with gamma interferon (IFN-gamma), the keratinocytes are induced to express intercellular adhesion molecule-1 (ICAM-1). Lymphocytes and monocytes that express lymphocyte function-associated antigen-1 (LFA-1) bind to cultured keratinocytes expressing ICAM-1. We have developed an in vitro adherence assay using frozen sections of normal skin that have been incubated with IFN-gamma, and then overlaid by peripheral blood mononuclear leukocytes. Although peripheral blood mononuclear leukocytes do not bind to the epidermal keratinocytes of untreated skin sections, after exposure of the skin to IFN-gamma the peripheral blood mononuclear leukocytes prominently bind to the epidermal keratinocytes that express ICAM-1. The binding by peripheral blood mononuclear leukocytes is increased approximately twofold by activation with phorbol ester treatment. The temperature dependence and kinetics of this adherence reaction reveal no binding at 8 degrees C, good binding at 24 degrees C, and optimal binding at 37 degrees C, reaching a maximal extent by 60 minutes. The adherence reaction is blocked either by pretreating the peripheral blood mononuclear leukocytes with LFA-1 antibody or the IFN-gamma-exposed skin specimen with ICAM-1 antibody. The immunophenotypic analysis of the adherent peripheral blood mononuclear leukocytes to epidermal keratinocytes revealed that most cells activated by 12-O-tetradecanoyl-phorbol-13-acetate are T lymphocytes, with CD8+ T cells binding slightly better than CD4+ T cells, with a smaller population of monocytes. These results provide additional support for a role of LFA-1, ICAM-1, and IFN-gamma in modulating keratinocyte-lymphocyte interactions.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Monoclonal↗
PubMed1989

Gamma interferon induces different keratinocyte cellular patterns of expression of HLA-DR and DQ and intercellular adhesion molecule-I (ICAM-I) antigens.

With indirect immunofluorescence techniques we demonstrated that recombinant gamma-interferon induced the expression of the class II antigens HLA-DR and HLA-DQ as well as intercellular adhesion molecule-I (ICAM-I) on normal, cultured human keratinocytes grown in low-calcium, serum-free medium. Each antigen displayed a distinctive cellular staining pattern. HLA-DR was strongly localized to perinuclear zones with intense cell surface expression; HLA-DQ displayed a perinuclear accentuation, but with minimal cell surface staining, and ICAM-I was strongly expressed in a diffuse cytoplasmic pattern with intense cell surface expression. Keratinocytes grown in medium supplemented with 10% fetal calf serum underwent differentiation, with a diminished expression of all three antigens as compared to those grown in low-calcium, serum-free medium. These results confirm that gamma interferon can differentially regulate HLA-DR and HLA-DQ expression; that there are probably different biochemical metabolic pathways by which these three molecules are expressed on keratinocytes, and that the expression is also a function of the degree of keratinocyte differentiation. The strong cell surface expression of ICAM-I is suggested to be of major importance as the recognition molecule, by which T cells bind to gamma interferon exposed keratinocytes, and suggests an integral role for this molecule in epidermal lymphocyte trafficking.

Antigens, Surface↗
PubMed1989

Long-term cyclosporin for psoriasis.

Thirteen patients with severe persistent psoriasis, intolerant of, or unresponsive to, other current treatments have been treated with cyclosporin (Cys) for periods varying from 12-25 (mean 18) months. The dose ranged from 1-4 mg/kg/day (mean 2.8 mg). There was a 72% reduction in the mean PASI score at 4 weeks, and at the end of the study, an 81% reduction. Adjuvant therapy with topical steroids was used in 11 of the 13 patients after the first 3 months of Cys treatment to persistent patches on an intermittent basis with beneficial effect. Six patients developed mild to moderate hypertension, in three this was controlled by a reduction in the dose of Cys, and in the other three by hypotensive agents. The mean serum creatinine rose from 72 to 90 microM/l during the study. Hypertrichosis occurred in seven of the 13 patients. Low dosage Cys is an effective treatment for clearing psoriasis and maintaining improvement on a long-term basis.

Adult↗
PubMed1989

Characterization of factor XIIIa positive dermal dendritic cells in normal and inflamed skin.

The immunocytochemical identification and characterization of indigenous dermal dendritic cells (dermal dendrocytes) using a rabbit polyclonal antibody to clotting enzyme factor XIII subunit A (FXIIIa) was carried out on normal and inflamed human cutaneous tissue. The immunophenotype of FXIIIa positive dendritic cells was analysed with a panel of 18 monoclonal antibodies using immunoperoxidase and double immunofluorescence staining techniques. The antibody against FXIIIa detected highly dendritic dermal cells located particularly in the upper reticular and papillary dermis. Double fluorescence microscopy showed that FXIIIa positive cells were bone marrow derived (HLe-I+) and co-expressed monocyte, macrophage or antigen presenting cell markers (HLA-DR+, LFA-I+, HLA-DQ+, OKM5+, Mo I+, Mono-I+, Leu M3+). No labelling was obtained with cell markers for Langerhans cells (CDI), T lymphocytes (CD2), granulocytes (LeuMI) fibroblasts (Te7), intercellular adhesion molecule-I (ICAM-I) or endothelial cells (Factor VIII related antigen). Gamma interferon induced increased expression of HLA-DR and co-expression of ICAM-I on FXIIIa+ dermal dendritic cells in normal skin in organ culture. Moreover, in benign inflammatory dermatoses such as atopic eczema and psoriasis there was an increased number of FXIIIa+, DR+, ICAM-I+ cells in the upper dermis and foci of FXIIIa+ cells in the epidermis closely associated with lymphocytes. FXIIIa positive cells in human skin represent a specific population of bone-marrow dermal dendritic cells, distinct from Langerhans cells, that share some features common to mononuclear phagocytes (monocyte/macrophages). In addition, the detection of HLA-DQ on 48% of FXIIIa+ cells and the lack of OKMI in combination with high OKM5 expression suggests an antigen-presenting cell phenotype.

Adult↗
PubMed1989

The spindle-shaped cells in cutaneous Kaposi's sarcoma. Histologic simulators include factor XIIIa dermal dendrocytes.

Kaposi's sarcoma is a neoplasm that develops as multifocal lesions, often involving the skin, characterized by a complex histologic picture including numerous vascular spaces, perivascular and interstitial spindle-shaped cells, and extravasated erythrocytes, lymphocytes, and plasma cells. Using an antibody against factor XIIIa, which identifies dermal dendrocytes, numerous factor XIIIa-positive dermal dendrocytes were detected among the spindle-shaped cells in 12 acquired immune deficiency syndrome (AIDS)-associated, and five non-AIDS-associated Kaposi's sarcoma lesions. The factor XIIIa-positive dermal dendrocytes were also increased in histologic simulators of Kaposi's sarcoma such as dermatofibroma, angiomatoid malignant fibrous histiocytoma, granuloma annulare, and early wound healing, but were absent in keloids. The increased number of dermal dendrocytes, which are often in an angiocentric configuration and which also express CD4, lymphocyte function associated antigen-1 (LFA-1), and Leu M3 in Kaposi's sarcoma, may be important to the angioproliferative response. The results suggested that the spindle-shaped cells that are present in a variety of cutaneous lesions are dermal dendrocytes and belong to the reticuloendothelial system, unlike other mesenchymal cell types such as the endothelial cell. Apparently a diverse array of stimuli, including human immunodeficiency virus type-1 (HIV-1) infection and trauma, can stimulate the accumulation of factor XIIIa expressing dermal dendrocytes in the skin. These cells can then participate in different stages of a variety of cutaneous alterations including Kaposi's sarcoma, dermatofibroma, granuloma annulare, and early wound healing. Thus, the factor XIIIa-positive dermal dendrocyte is a common cellular denominator among diverse clinical entities that share some histologic features.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Keratinocyte intercellular adhesion molecule-1 (ICAM-1) expression precedes dermal T lymphocytic infiltration in allergic contact dermatitis (Rhus dermatitis).

The ability of small molecules such as urushiol, present as a wax on the poison ivy leaf surface, to cause allergic contact dermatitis (rhus dermatitis) has fascinated immunologists for decades. Current dogma suggests that these epicutaneously applied catechol-containing molecules serve as haptens to conjugate with larger proteins via reactive o-quinone intermediates. These complexes are then recognized as foreign antigens by the immune system and elicit a hypersensitivity reaction. Phorbol ester can directly induce cultured keratinocyte (KC) intercellular adhesion molecule-1 (ICAM-1) expression via a protein kinase C (PK-C)-dependent mechanism. As urushiol is also a known PK-C agonist, we asked if topical application of a poison ivy/oak mixture could directly induce epidermal KC ICAM-1 expression. During the pre-erythematous phase of this reaction (4 to 20 hours), epidermal KCs expressed ICAM-1; this "initiation phase" preceded the appearance of activated memory T lymphocytes in the papillary dermis, and thus appeared to be nonlymphokine mediated. A near-contiguous cellular-adhesion molecular network was identified by ICAM-1 staining of basal KCs, dermal dendrocytes, and endothelial cells. During the second 24-hour period with the onset of erythema and edema, there was an "amplification phase" of more intense KC ICAM-1 expression coupled with relatively weak KC HLA-DR expression that coincided with dermal and epidermal T-cell infiltration. This suggests the presence of lymphokines, such as gamma interferon, during the amplification phase because of KC HLA-DR expression. On cultured KCs, urushiol directly induced ICAM-1 expression but not HLA-DR. Thus, in addition to functioning as an antigenic hapten, urushiol directly induces KC ICAM-1 expression. The KC ICAM-1 expression may then alter the dynamic trafficking of memory T cells in the epidermis, so as to initiate cutaneous inflammation in a nonantigen specific manner. This initiation phase is followed by T-cell infiltration and consequent lymphokine production that significantly amplifies the original stimulus. Thus much can still be learned about the molecular pathophysiology of this common type of cutaneous inflammation.

Adult↗
PubMed1988

Intestinal permeability in dermatitis herpetiformis.

Differential absorption of D-xylose and 3-0-methyl-D-glucose, and unmediated intestinal permeation (simple diffusion) of lactulose and L-rhamnose, have been investigated in 20 patients with dermatitis herpetiformis. Both iso-osmolar and hyperosmolar test solutions were employed and the results were compared with those obtained from a group of healthy adult volunteers. The findings in each patient have been correlated with small intestinal histology. The majority of patients with villous atrophy had abnormally raised intestinal lactulose permeation and lactulose/rhamnose permeability ratios, whereas patients with normal small intestinal morphological grading did not differ significantly from the healthy control group in this respect. There was a high incidence of delayed plasma D-xylose absorption peaks in dermatitis herpetiformis irrespective of small intestinal histological findings. These results imply that abnormal intestinal permeability in dermatitis herpetiformis is the result of gluten-induced damage to the mucosa rather than an inherent primary defect. It is therefore improbable that the rash in this condition is purely a manifestation of increased intestinal permeation of antigen.

3-O-Methylglucose↗
PubMed1988

Immunofluorescent studies in ocular cicatricial pemphigoid.

Twenty nine patients with cicatrizing conjunctivitis were studied; 17 with a clinical diagnosis of cicatricial pemphigoid, five with a clinical diagnosis of pseudopemphigoid caused by long-term application of topical medication and seven who had a cicatrizing conjunctivitis from other causes. Biopsies from clinically uninvolved bulbar conjunctiva were taken for direct immunofluorescence and blood was taken for indirect immunofluorescence using normal human conjunctiva, oral mucosa and skin as substrates. On direct immunofluorescence, in vivo bound immunoglobulins were found along the basement membrane in 10 of the 17 patients with cicatricial pemphigoid, one of the five with pseudopemphigoid and two of the seven with a cicatrizing conjunctivitis associated with other diseases. Circulating anti-basement membrane zone antibodies were found only when conjunctiva was used as a substrate. These were present in seven of the patients with cicatricial pemphigoid, three of those with pseudopemphigoid and two of those with a cicatrizing conjunctivitis caused by other diseases. These results indicate that direct immunofluorescence is a useful, but not absolute diagnostic marker for ocular cicatricial pemphigoid. The results in the pseudopemphigoid group argue that this is an immunologically mediated disorder indistinguishable from spontaneous cicatricial pemphigoid and probably triggered by the drugs. The presence of circulating antibodies should allow for precise identification of the antigen involved in cicatricial pemphigoid using SDS electrophoresis and Western blot analysis.

Adult↗
PubMed1988

The prevalence of thyroid autoantibodies in dermatitis herpetiformis.

The prevalence of IgG class thyroglobulin and microsomal antibodies, estimated using a sensitive ELISA, was 48% in 115 patients with dermatitis herpetiformis, which was significantly greater than the prevalence of 16% in 107 unselected controls without dermatitis herpetiformis. IgA class thyroid antibodies were found in 29% of dermatitis herpetiformis patients. Overt thyroid disease had been diagnosed in six (5%) of the dermatitis herpetiformis group and a further six patients had elevated TSH levels. The presence of thyroid antibodies was not associated with particular HLA-DR antigens. These results demonstrate the frequent occurrence of thyroid antibodies in dermatitis herpetiformis, although thyroid failure is less commonly associated with this condition. Immune response genes outside the HLA-DR region may be involved in the immune hyper-responsiveness seen in dermatitis herpetiformis which is reflected in the high prevalence of thyroid autoimmunity.

Adolescent↗