Cyclosporin A does not inhibit epidermal growth at therapeutic levels.
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Biomedical subjects
Publications and source records attributed to L Fry.
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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.
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.
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.
The class I and class II HLA serologically defined antigens and DQ alpha and DX alpha restriction fragment length polymorphism (RFLP) in 23 patients with linear IgA disease (LAD) were determined and their frequencies compared with those in a group of patients with dermatitis herpetiformis (DH) and healthy controls. In LAD there was a significant increase in HLA-B8 and DR3 and a larger increase in the DQw1-DR2/DRw6 related DQ alpha 6.2 kb and 6.8 kb RFLP. In DH there was a significantly increased frequency of HLA-A1, B8, DR3, and DQw2 with a concomitant increase in the DR3-DQw2 related DQ alpha 4.6 kb RFLP. The difference in DR3 frequencies and the increased frequency of DQw1 rather than DQw2 in LAD indicates that different susceptibility genes operate in the two diseases.
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To determine whether psoriatic keratinocytes differ from normal keratinocytes in their response to gamma interferon, epidermal cell suspensions from normal and from lesional and uninvolved psoriatic skin were cultured in the presence of gamma interferon and the induction of HLA-DR expression and inhibition of cell growth were measured. The addition of 10(2) units of gamma interferon/ml during a 7-day culture period significantly increased mean HLA-DR+ cell numbers in 21 epidermal suspensions of normal from 3.9 to 24.1% (P less than 0.0001), uninvolved psoriatic from 8.4 to 33.1% (P less than 0.0001), and to a lesser extent lesional psoriatic biopsies from 12.6 to 18.3% (P less than 0.01). However, the increase in HLA-DR+ cell numbers in these latter cultures was significantly less than that observed in either normal or uninvolved psoriatic epidermal cell cultures (P less than 0.0001). Furthermore, [3H]thymidine incorporation was substantially decreased by gamma interferon in 16 out of 22 (73%) cultures of normal epidermal cells; this decrease was statistically significant (P less than 0.01). In contrast, only 4 out of 11 (36%) lesional and 9 out of 21 (43%) uninvolved psoriatic epidermal cultures showed comparable inhibition of proliferation. These findings suggest that psoriatic keratinocytes have an altered response to gamma interferon; this could explain the infrequency of keratinocyte HLA-DR expression in psoriatic plaques in vivo and may also contribute to the increased epidermal proliferation that characterizes this disease.
T lymphocyte and dendritic cell subpopulations were counted in three biopsies each of endogenous eczema and pityriasis rosea and two of lichen planus and compared with previous findings in psoriatic lesions. In common with psoriasis, proportionately more CD4 T cells than CD8 T cells were DR+ in both epidermis and dermis of all lesions. In addition, total numbers of epidermal dendritic cells were significantly increased in endogenous eczema and pityriasis rosea, and variably in lichen planus lesions. Interestingly, a DR+T6- subpopulation of dendritic cells was present in varying proportions in all three skin lesion types. Electron microscopy of DR+T6- dendritic cells from psoriatic lesions, using an immunogold staining technique, showed the cells to be of the Langerhans' cell lineage. DR+T6- dendritic cells are a subpopulation of Langerhans' cells which are not specific to psoriasis, but present in the lesions of other benign, inflammatory skin conditions in which CD4 T cells are preferentially activated.
T lymphocyte and dendritic cell subpopulations were counted in untraumatized, uninvolved skin of 27 patients with psoriasis. Eight of the patients proved to be Koebner-positive, as determined by tape stripping and punch biopsy, and 19 Koebner-negative. In the epidermis the CD4/CD8 T cell ratio was significantly higher in the Koebner-positive vis-à-vis Koebner-negative patients (median CD4/CD8 = 1.68 and 0.75, respectively: p less than 0.05). This resulted from a small increase in CD4 and a larger decrease in CD8 epidermal T cells in the Koebner-positive group. However, numbers of epidermal dendritic cells did not differ significantly between the two groups. In the dermis the CD4/CD8 T cell ratio was also higher in the Koebner-positive than in Koebner-negative patients (median of 3.56 and 2.57, respectively). These findings demonstrate that the tendency of uninvolved skin of psoriatic individuals to become lesional after trauma is associated with a predominance of CD4 over CD8 T cells in the epidermis.
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The distribution and activation of T-lymphocyte subsets in the small intestinal mucosa of coeliac disease and dermatitis herpetiformis subjects on a normal diet has been studied and compared to normal controls. Double-labelling immunofluorescence techniques with monoclonal antibodies were used on cryostat tissue sections. Intestinal epithelial cells demonstrated staining for HLA-DR, the intensity being proportional to the degree of enteropathy. In both patients and controls nearly all (97%) intra-epithelial lymphocytes were of the CD8 subset and not activated as judged by HLA-DR expression. In the lamina propria there was an approximate 50-fold increase in T cells in the patients as compared with the controls. Whilst the ratio of total CD4 to total CD8 cells was unchanged, the CD4 subset was preferentially activated in the patients. Thus in the normal controls the median ratio of activated CD4 cells to activated CD8 cells was 1.67 whilst for dermatitis herpetiformis and coeliac disease it was 3.42 and 6.07 respectively. These findings suggest that the lamina propria is a site of vigorous T-cell activity in gluten-sensitive individuals and is consistent with the view that the enteropathy of dermatitis herpetiformis and coeliac disease is the result of a delayed-type hypersensitivity against gliadin.
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It has previously been reported that gliadins bind to reticulin in tissue sections. Three lines of evidence are reported in this study which indicate that the gliadins bind to reticulins because they are lectins which bind to sugars expressed on glycoproteins in reticulin and other sites. First, immunofluorescence studies on tissue sections showed that although gliadin binding is largely confined to areas rich in reticulin, it is, nonetheless, also seen in one or two other sites devoid of reticulin. Second, by using fluorescein-labelled lectins of known specificity, it has been shown that the areas to which gliadins bind in tissue sections (including those sites devoid of reticulin) are rich in particular sugars. Third, it has been shown that one of these sugars, alpha-D-mannose, partially inhibited gliadin binding to tissue sections.