ABC of dermatology. Autoimmunity and skin disease.
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Biomedical subjects
Publications and source records attributed to D J Gawkrodger.
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Keratinocytes expressed major histocompatibility complex class II antigens during the development of irritant contact dermatitis, and during the induction of contact hypersensitivity, as well as in established allergic contact dermatitis. A battery of anti-class II monoclonal antibodies, some of which are specific for class II subregion products (DP, DQ, DR), was used in an immunohistochemical study of the sequential changes in the allergic challenge reactions to dinitrochlorobenzene (DNCB) and nickel, the irritant response to anthralin, and the induction of sensitization to DNCB. The induction of keratinocyte class II expression paralleled the influx of Leu-3a+ T cells into the skin and had occurred by 24 or 48 h in each type of reaction. Differential expression of class II subregion products on keratinocytes was noted: DR was the most frequently expressed molecule, followed by DP and DQ, although in the irritant response, DP expression was not observed. The importance of these observations can be decided only by functional studies.
An eczematous flare-up reaction, occurring at a previously involved site, which followed oral challenge with 5.6 mg of nickel in a 29-year-old nickel-sensitive woman, was biopsied and studied by immunohistochemistry. The cellular infiltrate in the dermis and epidermis at 8 days was predominantly of Leu 3a phenotype (helper/inducer T lymphocytes), with smaller numbers of Leu-2a-reactive (suppressor/cytotoxic) T lymphocytes. Many infiltrating cells were DR-positive. No increase in epidermal Leu-6-positive Langerhans cells was seen but Leu-6-reactive cells were noted in the dermal infiltrate. Keratinocytes showed some expression of class II antigen (mainly DR). In comparison with the 48-hour allergic patch test reaction, the eczematous flare-up site showed no increase in epidermal Langerhans cell numbers nor infiltration with macrophages, but the responses were similar since both showed a superficial T cell reaction in the skin.
Pompholyx in nickel-sensitive subjects can be induced by orally-administered nickel, but only by a high dose. Ingestion of 5.6 mg nickel consistently worsened the pompholyx, often with a mild toxic erythema or patch test site flare, but lower doses of nickel failed to excite reactions more frequently than did a placebo, in a double-blind study. The metabolism of nickel is complex and there was considerable variation between three normal individuals in their absorption and excretion of an orally-administered nickel load. Patients may show similar variability which could be of importance clinically, although in only one of five subjects with acute eczema was the serum nickel raised, and then only marginally. The exact role of dietary nickel in perpetuating the hand dermatitis of sensitive subjects remains unclear.
Data on 134 consecutive nickel-sensitive subjects attending our contact dermatitis clinic were analysed. The female to male ratio was 8 to 1, with a mean age at presentation of 35 years for women and 53 years for men. Hand dermatitis occurred in 49% of patients and in 70% of men. It was usually preceeded by jewellery or metal contact dermatitis for some months or years. Although office workers made up the largest occupational group, cleaners, housewives, catering staff, nurses and hairdressers were represented among the women. Several of the men had had heavy occupational exposure to nickel. Cobalt co-sensitivity occurred in 29% of subjects. Sensitivity to 3 or more allergens was found in 32% of those studied but was seen in 2/3 of the men. The prevalence of a personal history of atopy was not raised. A majority of women had had their ears pierced: in 2/3 the nickel dermatitis followed this procedure but in a third it had occurred before. Female sex, jewellery contact and wetwork occupations all predispose to the development of nickel sensitivity.
A simple micro-computer program was used to analyse the results of testing 501 consecutive patients attending a patch test clinic. 64% of males and 71% of females had positive tests; 17% of males and 12% of females had occupational dermatitis; 16% of males and 15% of females had irritant contact dermatitis; and 13% of males and 19% of females had a history of atopic eczema.
Skin disorders were reported in 33% of catering staff and 35% of women cleaners who returned a questionnaire, and were employed in a large hospital. Hand dermatitis occurred in 15% of the caterers and 12% of the cleaners. In the majority, the dermatitis was irritant in origin and related to their wet work occupations. Cleaners had a high prevalence of jewellery dermatitis. Limited patch testing revealed a majority positive to nickel, but a third were negative, indicating that jewellery reactions often but not invariably predict nickel sensitivity. Few subjects were atopic, but some psoriatic patients with hand problems were encountered. Most workers were able to carry on in their occupations despite having hand dermatitis.
Monoclonal antibodies consistently demonstrated the presence of MHC class II antigens (HLA-DR,-DP and -DQ) on keratinocytes in normal human epidermis. Reactivity was normally greatest on the keratinocytes of the intraepidermal portion of sweat ducts or the external root sheath of hair follicles, but staining was noted on the surface of some interappendageal keratinocytes in most subjects. The patterns were varied but distinctive and depended on the antibody used. The functional importance of the MHC class II antigens expressed on normal keratinocytes remains to be investigated.
Despite qualitative similarities there were subtle differences between the nickel allergic and dithranol irritant dermatitis reactions. In both responses, dermal and epidermal cellular infiltrates developed, which were predominantly of Leu 3a phenotype with lesser numbers of Leu 2a positive cells. Dermal infiltrates were larger in the allergic response, but epidermal invasion was greater in the irritant reaction. In the allergic challenge response, Leu 3a reactive cells appeared in the dermis and epidermis by 4 h. At 48 h, both reactions showed skin infiltration by Leu M3 positive macrophages, and had increased numbers of cells in the epidermis expressing class II antigens. The number of Leu 6 reactive Langerhans cells in the epidermis was almost halved at 48 h in the irritant reaction, but Langerhans cell counts were increased by a third between 24 and 48 h of the allergic response. Ultrastructural studies showed disruption of the Langerhans cell mitochondrial cristae at 8 h in the irritant reaction, with few identifiable epidermal Langerhans cells at 48 h. At 1 h in the allergic response, electron microscopy identified two populations of Langerhans cells; the majority showed an electron-dense cytoplasm with vacuoles, and the rest appeared normal. Peripolesis was noted in both types of reaction.
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In twenty-eight men with dermatitis herpetiformis (DH) the mean serum testosterone levels were within normal limits, but high levels were found in three patients with partial villous atrophy and two who had normal jejunal biopsies. The introduction of a gluten-free diet in patients with villous atrophy produced a statistically significant fall in the testosterone level in those able to discontinue their drug treatment but not in those noticing no change or only a reduction in drug requirements. The serum levels of luteinizing hormone or follicle-stimulating hormone were increased in nine patients; only one of these had a raised testosterone level and six were over 60 years of age. Four out of twenty married males with DH had no children, a figure higher than expected. Three of these men had elevated gonadotrophin levels although none had an increased serum testosterone. Thus, raised levels of testosterone and gonadotrophin were found in only a minority of men with DH, in contrast to the more marked changes previously reported in males with coeliac disease.
Werner's syndrome is a rare condition of autosomal-recessive inheritance, showing some features of accelerated aging. We describe the clinical findings and laboratory studies in a 29-year-old man with this disorder, who presented because of a leg ulcer. Skin fibroblasts from our patient were difficult to culture and proliferated more slowly than those of controls. They produced less glycosaminoglycans than those of controls but synthesized more collagen, which was normal in type. The patient's urinary glycosaminoglycan level was slightly elevated, with hyaluronic acid as a major component. His peripheral blood lymphocytes showed no chromosomal instability and responded normally to mutagens.
Plasma growth-hormone levels in 12 fasting psoriatics were 4.4 +/- 1.4 mU/l (mean +/- SEM), compared to 2.7 +/- 1.7 in 5 patients with eczema and 1.2 +/- 0.3 in 6 normal subjects. The differences in mean values were not statistically significant and were due to exceptionally high levels of growth hormone in five patients with psoriasis and one patient with eczema. In the psoriatic group the exceptional patients were not distinguished by age or the area of involved skin but they tended to be leaner than those with low plasma-growth hormone levels. We conclude that raised plasma growth hormone cannot be the cause of psoriasis but might be a secondary effect of the skin disease in some patients.
Serial biopsies during the first 24 hours after dinitrochlorobenzene (DNCB) challenge in fifteen sensitized patients have shown that DNCB associates with Langerhans cells within I hour of application, and has reached the dermis around the appendages by 6 hours.
A young woman with inactive discoid lupus erythematosus (LE) gave birth in three successive pregnancies to four male infants who showed cutaneous, and in one case cardiac, signs of neonatal LE. The mother had Ro and La antibodies although the anti-nuclear factor (ANF) was not consistently detectable. Three of the infants received phototherapy for neonatal jaundice. Maternal discoid LE may give rise to neonatal LE, and successive siblings can be affected.
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We describe a long term study of 76 patients with dermatitis herpetiformis. Unlike patients with coeliac disease, where the peak incidence was during the first and fourth decades, no dermatitis herpetiformis patients presented in the first decade; also, there was a male preponderance in dermatitis herpetiformis which contrasts with the excess of females in coeliac disease. The apparent prevalence of dermatitis herpetiformis was 11 per 100 000 in our population; approximately one fifth of that of coeliac disease. Jejunal villous atrophy was present in 78% of our dermatitis herpetiformis patients, and a single jejunal biopsy was as effective at detecting this as the multiple biopsy technique. A majority of patients were able to stop, or radically reduce their dapsone or sulphapyridine treatment after the institution of a gluten free diet. Spontaneous remission of the skin lesion occurred in only two patients not receiving a gluten free diet. Gastric parietal or thyroid antibodies were detected in 38% of patients, and three cases of thyroid disease and two cases of pernicious anaemia were detected. Lymphoma developed in two patients, one being intestinal in origin. We conclude that a gluten free diet is of therapeutic benefit in dermatitis herpetiformis and that spontaneous remission is uncommon in those not on a diet. Despite patchiness of the enteropathy, a single jejunal biopsy is quite adequate to diagnose the presence of upper intestinal villous atrophy.