L. Fry

The effects of cyclosporin A on T lymphocyte and dendritic cell sub-populations in psoriasis

Sequential skin biopsies from six patients with severe psoriasis were studied during treatment with cyclosporin. Four of the patients cleared completely and the remaining two showed a marked improvement. A subset of dendritic cells, HLA‐DR+ but lacking the T6 antigen characteristically expressed by Langerhans cells (DR+ 6‐), was observed in lesional epidermis. They disappeared during treatment, before clinical improvement was apparent and at a rate which correlated with clearance of psoriasis. These cells were not found in normal or uninvolved psoriatic epidermis and their number in lesional skin appeared to be related to the clinical severity of the disease. Total numbers of CD4 and CD8, and HLA‐DR+ CD8 T cells were substantially reduced in both epidermis and dermis prior to clinical improvement. In contrast, there was generally no decrease in the number of HLA‐DR + CD4 T cells in the epidermis during resolution, whereas these cells were reduced by an average of 68% in the dermis. The beneficial effects of cyclosporin in psoriasis further support the hypothesis that T cells play a central role in the pathogenesis of psoriasis. The cellular changes observed in the skin during cyclosporin treatment may help to elucidate the effects of this drug on immunoregulatory mechanisms in man.

Restricted T-cell receptor Vβ gene usage in the skin of patients with guttate and chronic plaque psoriasis

A strong association between acute guttate psoriasis and group A, β‐haemolytic streptococcal infections is well established. Furthermore, streptococcal M proteins and toxins have been shown to act as superantigens, stimulating subpopulations of T lymphocytes expressing particular Vβ families.

Protective effect of gluten-free diet against development of lymphoma in dermatitis herpetiformis.

A retrospective study of 487 patients with dermatitis herpetiformis showed that lymphoma developed in eight patients, the expected incidence being 0.21 (standardized registration ratio 3810). All lymphomas occurred in patients whose dermatitis herpetiformis had been controlled without a gluten‐free diet (GFD) or in those who had been treated with a GFD for less than 5 years. The results are suggestive of a protective role for a GFD against lymphoma in dermatitis herpetiformis and give further support for advising patients to adhere to a strict GFD for life.

Increased incidence of malignancy in dermatitis herpetiformis.

A retrospective study of 109 patients with dermatitis herpetiformis showed that malignant tumours had developed in seven patients, the expected incidence being 2.93, giving a relative risk of 2.38. In three of the seven patients the malignancy was a lymphoma, giving a relative risk of 100 for this tumour (expected incidence 0.03). In six of the seven patients who developed malignancies small-intestinal biopsy specimens were macroscopically abnormal, giving a relative risk of 4.22 in this group, which is similar to that reported in adult coeliac disease. Patients treated with a gluten-free diet appeared to have a reduced risk of developing malignancy compared with those taking a normal diet (relative risk with gluten-free diet 1.01 and with normal diet 3.09). A small subgroup of eight patients with linear IgA dermatitis herpetiformis were also studied: three developed malignant disease and in one the tumour was a lymphoma.

25 years' experience of a gluten‐free diet in the treatment of dermatitis herpetiformis

Gluten‐free diets have been used in the treatment of patients with dermatitis herpetiformis in our department since 1967. Of the 212 patients with dermatitis herpetiformis attending between 1967 and 1992, 133 managed to take the diet, and 78 of these achieved complete control of their rash by diet alone. Of the remaining 55 patients taking a gluten‐free diet, all but three were taking partial diets; over half of these patients managed to substantially reduce the dose of medication required. Of the 77 patients taking a normal diet, eight entered spontaneous remission, giving a remission rate of 10%; a further two patients who had been taking gluten‐free diets were found to have remitted when they resumed normal diets. Loss of IgA from the skin was observed in 10 of 41 (24%) patients taking strict gluten‐free diets. These patients had been taking their diets for an average of 13 years (range 5–24 years), and their rash had been controlled by diet alone for an average of 10 years (range 3–16 years).

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.

Group A streptococcal antigen-specific T lymphocytes in guttate psoriatic lesions.

A strong association exists between guttate psoriasis and group A, β‐haemolytic streptococcal infections. To demonstrate the presence of streptococcal‐specific T cells in psoriatic skin, T‐cell lines (TLs) were established from biopsies of lesions from five patients with guttate psoriasis, and compared with TLs from five patients with eczema, five with lichen planus, two with pityriasis rosea and three with nickel contact dermatitis. TLs from purified protein derivative (PPD)‐induced delayed hypersensitivity sites in three normal individuals were also studied. All five of the psoriatic TLs responded in a proliferation assay to heat‐killed isolates of group A streptococci, compared with only one eczema, two lichen planus and one pityriasis rosea. The response of one nickel contact dermatitis and two PPD TLs to group A streptococci was markedly less than to nickel and PPD, respectively. One of the psoriatic TLs was cloned in the presence of type 5 streptococcal M protein. The nine clones obtained were all CD3+, CD4+, CD45RO+, TCR α,β+, γ,δ−. However, they were all unreactive with antibodies to TCR V β 5, 6, 8 or 12. Eight of the nine clones reacted, to a varying extent, to one or two of three preparations of group A streptococci expressing different M proteins. The streptococcal response of four consistently reactive clones from this patient was HLA‐DR‐restricted and inhibited by anti‐HLA‐DR antibody in a dose‐dependent manner. On stimulation these four clones secreted high levels of γ‐interferon and detectable levels of IL‐2, IL‐10 and granulocyte/macrophage colony stimulating factor (GM‐CSF) depending upon the nature of the stimulus, but no IL‐4 or TNF‐α production was detected.

Lymphocytic infiltration of epithelium in diagnosis of gluten-sensitive enteropathy.

The macroscopic appearance of the mucosa of the small intestine and the lymphocytic infiltration of the epithelium were studied in 27 patients with dermatitis herpetiformis and in 11 control subjects. The mucosa was abnormal in appearance in 13 of the patients and normal in 14 patients and in all the controls. In 25 (93%) of the patients the intraepithelial lymphocyte count was significantly raised compared with the controls. The increased lymphocytic infiltration of the epithelium in the patients probably represented an underlying immunological reaction of the small intestine to gluten, since the infiltration lessened in five out of six patients after a year on a gluten-free diet and in all of four patients after three years on a gluten-free diet. Increased lymphocytic infiltration of the epithelium of the small intestine seems a surer sign of gluten sensitivity than the macroscopic appearance of the mucosa, and a diagnosis of gluten-sensitive enteropathy may no longer be excluded when the mucosa appears normal. Further evidence of the significance of increased lymphocytic infiltration is that patients with normal-looking mucosa but with raised intraepithelial lymphocyte counts often had low serum folate levels.

Different HLA associated gene combinations contribute to susceptibility for coeliac disease and dermatitis herpetiformis.

Forty two white patients of British or Irish descent with coeliac disease and 28 with dermatitis herpetiformis were typed for class I HLA-A, B, and C, and class II DR and DQ antigens. In coeliac disease there was a significant increase in the frequencies of A1, B8, DR3, DR7, and DQw2 compared with controls but no increase of DR2. In dermatitis herpetiformis there were similarly increased frequencies of A1, B8, DR3, and DQw2. In contrast with coeliac disease, however, the frequency of DR7 (18%) was no different from the control group but there was an increased frequency of DR2.

Cross-reactivity between streptococcal M surface antigen and human skin

Summary Psoriasis can be triggered by haemolytic streptococcal infections. As M protein is a major pathogenic surface antigen in these streptococci, the cross‐reactivity between streptococcal M protein surface antigens and human epidermis was investigated. The conserved component common to the few M proteins investigated consists of an alpha‐helical ‘coiled‐coil’ configuration, similar to sub‐units of human keratin. The amino acid sequence of protein M6, one of the M proteins that has been fully sequenced, was compared with that of 4721 ubiquitous peptides, by computer‐assisted analysis using a protein‐sequence data bank. Of all human proteins in the data bank 50‐Da keratin type 1 showed the closest homology with protein M6. Further evaluation revealed that this homology mainly involved the heptapeptide repeat patterns, which form the alpha‐helical “coiled‐coil” structure, in both M6 and 50‐kDa keratin.