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Biomedical subjects

L Fry

Publications and source records attributed to L Fry.

At least 55 records · Page 3Linked to original sources
PubMed1995

Psoriasis: a T-cell-mediated autoimmune disease induced by streptococcal superantigens?

Psoriasis is a T-cell-mediated disease that can be triggered by infection with group A beta-haemolytic streptococci. It is proposed that psoriatic skin lesions are initiated by exotoxin-activated T cells, and persist because of specific T cells that react both with streptococcal M protein and a skin determinant, possibly a variant of keratin. As discussed here by Helgi Valdimarsson and colleagues, cytokines released by the superantigen (SAg)-stimulated T cells could induce or enhance the expression of the crossreactive autoantigen, leading to the rescue and activation of autoreactive T cells. In this way, the SAg-determined T-cell receptor V beta phenotype would be maintained by T cells in psoriatic lesions.

Autoimmune Diseases↗
PubMed1995

Lack of proliferative response by gluten-specific T cells in the blood and gut of patients with dermatitis herpetiformis.

The majority of patients with Dermatitis Herpetiformis (DH) have a gluten-sensitive enteropathy which may be triggered by a T cell-mediated immune response to gluten. Using a proliferative assay, the responses to gluten fraction III, recall antigens and mitogens of peripheral blood mononuclear cells (PBMC) and gut T cell lines (TCL) isolated from patients with Dermatitis Herpetiformis (DH) and normal controls were studied. In most cases, neither PBMC nor gut T cell lines (which were predominantly CD3+, CD4+, TCR alpha beta +) from either controls or patients proliferated in response to gluten fraction III alone. However, the addition of 10 U/ml IL-2 to PBMC cultures containing gluten fraction III resulted in a marked increase in proliferation in 9/19 DH patients and 7/11 controls compared to IL-2 alone. Furthermore, gluten-induced upregulation of IL-2 receptor (CD25) expression was demonstrated on PBMC from 4/4 patients with DH and 2/3 controls after 7 days' culture with antigen. A similar effect by exogenous IL-2, or the same concentration of IL-4, was observed in 8/11 (P = 0.02) and 5/6 respectively DH, and 3/4 normal gut T cell lines. No difference was observed in the response of DH and control PBMC to Tetanus toxin, Candida albicans and PPD; both normal and DH gut T cell lines were unresponsive to these antigens. However, the addition of IL-2 increased the response to Candida albicans by DH gut T cell lines. Moreover, the response of DH gut T cell lines to PHA (P < 0.001), Concanavalin A and anti-CD3 were markedly reduced compared to PBMC from the same patients. These findings suggest that gluten-specific T cells present in the blood and gut of normal and DH individuals are activated by but do not proliferate in response to specific antigen.

Candida albicans↗
PubMed1995

Dermatitis herpetiformis.

Dermatitis herpetiformis (DH) is a relatively rare skin disorder with an estimated incidence of 1:10,000 in the UK. It is characterized by urticarial plaques and blisters on the elbows, buttocks, and knees, although other sites may also be involved. The eruption tends to be persistent: only 10-15% of patients have spontaneous remission over a 25-year study period. The disease is characterized by the presence of IgA deposits in the upper dermis of uninvolved skin and the diagnosis should not be made in the absence of these deposits. Two-thirds of patients have a small intestinal enteropathy with villous atrophy as seen in coeliac disease (CD). However, the remaining third also show evidence of a gluten sensitivity in the intestine, as judged by increased lymphocytic infiltration of the epithelium. Villous atrophy also ensues after gluten challenge in those patients with previous normal villous architecture. The initial treatment of the rash is with one of the following three drugs, dapsone, sulphapyridine or sulphamethoxypyridazine. However, the rash also clears with gluten withdrawal. It must be stressed, however, that the average time to achieve significant reduction in drug requirements is 6 months and it can be over 2 years before drugs are no longer required. On re-introduction of gluten the eruption recurs. Patients with DH have a high incidence of auto-immune disorders, thyroid disease, pernicious anaemia, and insulin-dependent diabetes, and should be screened for those diseases on a yearly basis. As with coeliac disease there is also an increased incidence of lymphoma and a gluten-free diet appears to protect patients from this complication. The mechanism by which gluten causes the skin lesions has still to be elucidated, but current investigations implicate lymphocytes and cytokines in the pathogenesis. The original hypothesis of an antigen-antibody reaction in the skin with complement activation causing the skin lesions, may not be correct.

Adolescent↗
PubMed1995

Failure of intradermal skin testing with gluten to produce delayed hypersensitivity reactions in patients with dermatitis herpetiformis.

Dermatitis herpetiformis (DH) is characterized by a rash and a gluten-sensitive enteropathy (GSE) indistinguishable from that of coeliac disease. T-cell-mediated mechanisms have been implicated in the pathogenesis of GSE. It seems feasible that intradermal injection of gluten, in patients known to have GSE, could lead to an influx of T cells sensitized to gluten, with subsequent development of a delayed hypersensitivity-type reaction. Six patients with DH and three normal subjects had intradermal injections of 'Frazer's fraction III' (FFIII; the partial peptic tryptic digest of gluten which is known to be antigenic) and phosphate-buffered saline (PBS) as a control. Skin biopsies were taken at PBS and FFIII injection sites at 48 h. In addition, two of the patients with DH had biopsies taken of FFIII injection sites at 6 h. Monoclonal antibodies and the avidin-biotin-peroxidase technique were used to stain for T cells in the skin biopsies. A monoclonal antibody to a neoepitope exposed in the terminal complement complex and an immunofluorescent method were used to detect the presence of terminal complement component in biopsies taken from two of the control subjects and two of the patients. Both patients and control subjects developed a weal and flare within a few minutes of injecting the FFIII, and this persisted for up to 6 h. No skin reaction was present in either the patients or the control subjects at 48 h. No skin reaction was visible at any time following injection of PBS.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies↗
PubMed1995

Confirmation of genetic heterogeneity in familial psoriasis.

Psoriasis affects approximately 2% of the European population and is often familial. Linkage of a subset of psoriasis families to loci on chromosome 17q has recently been reported. We have studied members of a large multiply affected family from the north east of England and analysed genotypes for markers from 17q, including the polymorphic microsatellite markers AFM210xa5, AFM163yg1, AFM044xg3, AFMa353yg1, and AFM217yd19. Two point and multipoint analysis clearly show exclusion of linkage between the telomeric region of 17q and psoriasis in this family. This confirms the genetic heterogeneity of psoriasis and the existence of at least one other major psoriasis locus.

Chromosomes, Human, Pair 17↗
PubMed1994

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). The advantages of a gluten-free diet in the management of patients with dermatitis herpetiformis are: (i) the need for medication is reduced or abolished; (ii) there is resolution of the enteropathy, and (iii) patients experience a feeling of well-being after commencing the diet. Thus, we propose that a gluten-free diet is the most appropriate treatment for patients with dermatitis herpetiformis.

Adolescent↗
PubMed1994

T lymphocytes in lesional skin of patients with dermatitis herpetiformis.

Ten patients with dermatitis herpetiformis had biopsies taken from involved and uninvolved skin. Monoclonal antibodies and the avidin-biotin peroxidase staining technique were used to stain for T cells and Langerhans cells in skin sections. A significant increase in the number of CD3-positive T cells was observed in the upper dermis of involved compared with uninvolved skin (P < 0.0005). Most of the T cells in involved skin were CD45RO-positive memory cells; CD4-positive T cells exceeded the number of CD8-positive T cells by a ratio of 4:1. In addition, CD1a-positive dendritic cells were observed within the clumps of T cells in involved dermis in nine of the 10 patients, but were absent from the dermis of uninvolved skin. Double immunofluorescent staining demonstrated that approximately 20-40% of the CD3-positive T cells were activated, and expressed the HLA-DR antigen. These findings suggest that activated T cells are involved in the pathogenesis of dermatitis herpetiformis skin lesions.

CD3 Complex↗
PubMed1994

Decreased T cell reactivity to trypsinized group A, type M22 streptococci in psoriasis.

The proliferative responses of peripheral blood mononuclear cells from patients with guttate and chronic plaque psoriasis to streptococcal M protein were investigated using whole and trypsinized group A M22-positive streptococci. Peripheral blood mononuclear cell responses to whole type M22 group A streptococci were significantly increased in guttate, but not chronic plaque, psoriasis patients compared to 17 non-psoriatic controls (p < 0.05; n = 17). A significant reduction of this response was observed in both guttate (p < 0.001; n = 17) and chronic plaque (p < 0.01; n = 27) psoriatic patients, but not in the control group, after repeated trypsinization to remove M protein from the streptococci. Furthermore, the difference between the peripheral blood mononuclear cell response to untrypsinized and trypsinized streptococci was significantly greater in the guttate patients than in the controls (p < 0.02). This preliminary study has shown an increased reactivity of T lymphocytes with specificity for trypsin-sensitive protein expressed by type M22 streptococci in the peripheral blood of patients with psoriasis.

Adolescent↗
PubMed1993

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

A strong association exists between guttate psoriasis and group A, beta-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 alpha, beta+, gamma, delta-. However, they were all unreactive with antibodies to TCR V beta 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 gamma-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-alpha production was detected. This study has demonstrated, for the first time, that T lymphocytes specific for group A streptococcal antigens can be consistently isolated from guttate psoriatic lesions. The role of streptococcal-specific T cells in the pathogenesis of psoriasis remains to be determined.

Antigens, Bacterial↗
PubMed1993

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

A strong association between acute guttate psoriasis and group A, beta-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 V beta families. We have therefore studied the possible role of streptococcal superantigens in psoriasis by staining peripheral T lymphocytes and skin sections from patients with guttate or chronic plaque psoriasis for the expression of nine TCR V beta families, using a range of monoclonal antibodies. A marked over-representation of V beta 2+ T lymphocytes was observed in the dermis and epidermis of patients in both groups, when compared with T lymphocytes in their peripheral blood. A less marked dermal increase in V beta 5.1+ T lymphocytes was also observed in these patients. These findings are consistent with the involvement of a superantigen, possibly streptococcal, in the pathogenesis of psoriasis.

Acute Disease↗
PubMed1993

The role of cytokines in the generation of skin lesions in dermatitis herpetiformis.

The infiltration of polymorphonuclear neutrophils (PMN) into the upper dermis which characterizes the skin lesions of dermatitis herpetiformis (DH) has never been satisfactorily explained. This study has shown that lesional skin of patients with DH has increased expression of endothelial leucocyte adhesion molecules (ELAM) in the deep dermis, combined with a markedly increased staining for interleukin 8 (IL-8) in the basal epidermal layer. Dendritic cells which stained for granulocyte macrophage colony stimulating factor (GM-CSF) were also observed at the dermo-epidermal junction, and this phenomenon was more pronounced in lesional than in uninvolved DH skin. ELAM, IL-8 and GM-CSF are known to promote infiltration and activation of PMN, and it is suggested that these cytokines may play a key role in the generation of DH lesions.

Adult↗
PubMed1993

Renal function and biopsy findings after 5 years' treatment with low-dose cyclosporin for psoriasis.

Renal biopsies were performed in eight patients with chronic plaque psoriasis who had been treated with low-dose cyclosporin (CyA) (range 1-6 mg/kg/day; average dose 3.3 mg/kg/day) for an average period of 5 years. In six of the eight patients biopsies showed features consistent with CyA nephrotoxicity. Tubular atrophy and arteriolar hyalinosis were present in all six, four had an increase in interstitium, and two showed an increased incidence of glomerular obsolescence. Two of the patients showed all of these features, two patients had three features, and the remaining patients had two features. Renal function was assessed by glomerular filtration rate (GFR) and serum creatinine. Both a fall in the GFR and a rise in the serum creatinine correlated with the severity of the features of CyA nephrotoxicity seen on biopsy. However, the best predictor of the biopsy findings was a failure of renal function to show significant improvement when CyA was discontinued for a month. CyA has been discontinued in two of the eight patients who had the most severe features of CyA nephrotoxicity on renal biopsy. In both patients there has been improvement of renal function after 1 year of follow-up.

Adult↗
PubMed1993

Dermatitis herpetiformis--an autoimmune disease due to cross-reaction between dietary glutenin and dermal elastin?

Dermatitis herpetiformis (DH), is associated with skin eruptions and granular depositions of IgA in the papillary dermis, but this is not a feature of coeliac disease (CD). The specificity of the IgA in the skin is unknown. High molecular weight glutenin (HMW-g), a component of gluten, has been shown to have structural similarities to human elastin. This paper reports immunoadsorption studies which suggest that human serum may contain antibodies which cross-react with HMW-g and elastin. DH patients had significantly lower levels of IgA antibodies to HMW-g and to elastin than both CD patients and healthy controls. Furthermore, introduction of a gluten-free diet (GFD) was associated with a further reduction in the amount of IgA antibodies to elastin in the DH patients. This diet-associated decrease of elastin antibodies was restricted to the IgA isotype. A significant correlation was observed between IgA antibodies to HMW-g and elastin in healthy controls and CD patients, while no such correlation was found in patients with DH. These findings could indicate that HMW-g induces production of antibodies to elastin, which are deposited in the skin, and that when the antigenic stimulus is removed, these antibodies are further reduced due to continuous dermal deposition. It is postulated that DH may be an autoimmune disease due to cross-reactivity between dietary glutenin and dermal elastin.

Adult↗
PubMed1993

Normal response to tumor necrosis factor-alpha and transforming growth factor-beta by keratinocytes in psoriasis.

Normal and chronic plaque psoriatic keratinocyte cultures were tested for their in vitro response to 2-200 ng/ml TNF-alpha and 0.1-10 ng/ml TGF-beta in a serum-free culture system. All normal and lesional psoriatic epidermal cell cultures showed a dose- and time-dependent inhibition of growth in response to TNF-alpha and TGF-beta. Inhibition in individual cultures was first seen at a concentration of 2 ng/ml for TNF-alpha and 0.1 ng/ml for TGF-beta at day 2, but became significant at 20 ng/ml and 1 ng/ml for TNF-alpha and TGF-beta respectively at days 2-6. This effect was statistically significant at days 3-4 for the group of normal (TNF-alpha and TGF-beta, n = 10, p < 0.01) and psoriatic cultures (TNF-alpha, n = 9, p < 0.01; TGF-beta, n = 7, p < 0.05). Epidermal cells from normal and psoriatic skin were inhibited to the same extent at the same optimal concentrations by each cytokine. Inhibition was abolished by the addition of specific antibody to each cytokine, whilst antibody to a different cytokine had no effect. Nuclear and/or nuclear membrane staining was observed with antibody to the p55 TNF receptor both in cultured keratinocytes and in the upper epidermal layers of both normal and psoriatic skin. In contrast, plasma membrane and cytoplasmic expression of the p55 TNF receptor was observed on macrophages and lymphocytes infiltrating psoriatic dermis. This study has shown that the growth of normal and psoriatic keratinocytes was equally inhibited by TNF-alpha and TGF-beta in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Psoriasis: immunopathology and long-term treatment with cyclosporin.

Psoriasis is a disorder of abnormal keratinocyte proliferation mediated by T lymphocytes. Initiation of psoriasis is associated with an influx and activation of CD4 T lymphocytes into the dermis and epidermis, and resolution with an influx and activation of CD8 T lymphocytes within the epidermis. As a result of these observations it was postulated that cyclosporin (CsA) should prove to be an effective treatment for psoriasis. A total of 82 patients with psoriasis have been treated with CsA. Thirty patients with moderate disease were treated for periods up to 12 weeks, and comprised a short-term study. Two groups have been treated with long-term CsA. A group of 18 patients have been treated for greater than 1 year but less than 3 years, (mean 2.1) and a group of 10 patients for 4.0-5.5 (mean 5) years. A total of 15% of patients can be maintained on less than or equal to 2 mg/kg/day; 55% on 3 mg/kg/day, 80% on 4 mg/kg/day, and 92% on 5 mg/kg/day. Hypertension occurred in 17% of patients in the short-term study, 29% in the 2.1-year group and 44% in 5-year group. Blood pressure returned to normal in all hypertensive patients when CsA was discontinued for 1 month. Nephrotoxicity was assessed by serum creatinine levels and glomerular filtration rate (GFR) and renal biopsy in the 5-year group. In the short-term group there was no significant rise in the serum creatinine.(ABSTRACT TRUNCATED AT 250 WORDS)

Creatinine↗
PubMed1992

Expression of interferon-gamma receptors in normal and psoriatic skin.

Psoriatic keratinocytes have a reduced antiproliferative response to interferon (IFN)-gamma, and HLA-DR expression is usually not observed on keratinocytes in psoriatic plaques despite the presence of activated T cells. We have therefore compared the expression of IFN-gamma receptors in psoriatic skin with that of normal human skin. Using mouse monoclonal antibodies and immunoperoxidase staining on cryostat cut sections, we detected IFN-gamma receptors on keratinocytes throughout the epidermal layers except stratum corneum in normal skin (n = 11). Biopsy specimens from involved psoriatic skin (n = 17) consistently showed a staining pattern that differed from that of normal skin in that only the lower part of epidermis reacted with the antibodies to IFN-gamma receptors, whereas the upper layers showed no or minimal staining. Expression of IFN-gamma receptors in uninvolved psoriatic skin (n = 16) did not differ from that of healthy controls. Forty-five percent of the biopsies from lesional psoriatic skin displayed ICAM-1 positive keratinocytes, and only two specimens had a limited expression of HLA-DR reactive keratinocytes. The decreased binding of antibodies against the IFN-gamma receptors in the upper part of psoriatic epidermis might be secondary to abnormal maturation of psoriatic keratinocytes or a primary defect involving abnormal modulation of IFN-gamma receptors.

Adult↗