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F Wojnarowska

Publications and source records attributed to F Wojnarowska.

At least 19 recordsLinked to original sources

Melanomas in renal transplant recipients.

BACKGROUND: It is well documented that renal transplant recipients are at increased risk of developing skin cancers, in particular squamous cell carcinomas. Less extensively reviewed in the literature is the increased incidence of malignant melanoma. We have reviewed 10 patients in the Oxford renal transplant population who developed 12 melanomas following transplantation. OBJECTIVES: To determine the incidence and characteristics of melanoma in renal transplant recipients. METHODS: We reviewed the case notes and pathology of all patients who developed melanoma within the Oxford Renal Transplant Unit. The clinical details were recorded including date of transplant, immunosuppressive therapy, interval between transplant and melanoma, site of occurrence, history of sun exposure, type of clinician diagnosing the melanoma, history of other skin malignancies and outcome. From the histopathology we documented various prognostic factors. RESULTS: Ten patients developed 12 melanomas (one patient had three melanomas) from a population of 1874 transplanted patients. The total number of transplant years was 11 942.2. The incidence of melanoma in our population was 12 per 11 942.2 transplant years, which is approximately 8 times greater than the standardized rate for this region. We found that the mean interval between transplant and melanoma was approximately 11 years (median 8.5). A dermatologist was the diagnosing clinician in at least 67% of cases. Melanomas occurred on the trunk in the majority of cases (58%), followed by the upper limb (25%). All patients apart from one are alive with no recurrence of their melanoma. One patient died as a result of metastatic melanoma. The mean follow-up period following melanoma was 3.7 years. In all patients apart from the patient who died, the melanomas were < 1 mm Breslow thickness. That patient's melanoma was 4.5 mm thick. There was no precursor naevus in eight of the 12 melanomas. In two there was a precursor dysplastic naevus. In the cases in vertical growth phase the tumour-infiltrating lymphocyte response was absent in four cases and nonbrisk in one patient. CONCLUSIONS: In the Oxford transplant population studied melanomas occurred at approximately 8 times the rate in the general population. This is the highest rate reported in the literature. The patients had a better outcome than reported previously. This may be due to detection at a relatively early stage. Renal transplant recipients attend dedicated dermatology clinics in Oxford, which may have contributed to the early diagnosis and good outcome.

Adult↗

Cytokine alterations in lichen sclerosus: an immunohistochemical study.

BACKGROUND: Although the histology of lichen sclerosus is characteristic, the precise nature of the inflammatory changes and the signals provoking them is uncertain. OBJECTIVES: To delineate the inflammatory changes in lichen sclerosus more accurately by studying cytokine changes. METHODS: An immunohistochemical study of 12 specimens of genital lichen sclerosus and one specimen of extragenital lichen sclerosus was undertaken using monoclonal antibodies to interferon (IFN)-gamma, IFN-gamma receptor, tumour necrosis factor (TNF)-alpha, interleukin (IL)-1alpha, IL-2 receptor (CD25), intercellular adhesion molecule-1 (ICAM-1) and its ligand CD11a. Control specimens were seven specimens of normal vulva obtained during gynaecological procedures, three specimens of normal skin, adjacent uninvolved thigh from three of the patients with lichen sclerosus, five specimens of nonvulval psoriasis, four specimens of nonvulval lichen planus and two specimens from chronic wounds. RESULTS: The lichen sclerosus specimens demonstrated slightly increased staining for IFN-gamma within the epidermis compared with the normal vulva and nonvulval skin. There was increased dermal staining for IFN-gamma both within the pale zone of the upper dermis and within the inflammatory zone below this. We confirmed our previous demonstration that in lichen sclerosus HLA-DR immunostaining is increased in association with vascular endothelium, the inflammatory cell infiltrate and around the keratinocytes. The areas of the epidermis with the strongest immunostaining for HLA-DR generally also had the strongest staining for IFN-gamma. In the lichen sclerosus specimens the zone of inflammation also demonstrated increased immunostaining for TNF-alpha, IL-1alpha, IFN-gamma receptor, CD25, CD11a and ICAM-1 while the zone of sclerosus demonstrated a smaller increase in immunostaining for IFN-gamma receptor, TNF-alpha, CD11a and ICAM-1, and the epidermis demonstrated increased staining for ICAM-1. CONCLUSIONS: The increased staining for IFN-gamma, TNF-alpha, IL-1alpha, IFN-gamma receptor, CD25, CD11a and ICAM-1 suggest that the cytokine response in lichen sclerosus shares characteristics of the cytokine response in lichen planus and chronic wounds.

Aged↗

Interventions for bullous pemphigoid.

BACKGROUND: Bullous pemphigoid is the most common autoimmune bullous disease in the West. Oral steroids are considered the standard treatment. OBJECTIVES: To assess the effects of treatments for bullous pemphigoid. SEARCH STRATEGY: We searched the Skin Group Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE to March 2003 and bibliographies from identified studies. SELECTION CRITERIA: Randomised controlled trials of treatments for patients with immunofluorescence confirmed bullous pemphigoid. DATA COLLECTION AND ANALYSIS: Two reviewers evaluated the studies in terms of the inclusion criteria, five extracted data independently; disagreements were resolved by discussion. Statistical pooling of the data was inappropriate because of heterogeneity of treatments. MAIN RESULTS: We found seven randomised controlled trials with a total of 634 patients. All studies involved different comparisons, none included a placebo group. Different doses, different formulations of corticosteroids and the addition of azathioprine failed to show significant differences in measures of disease control. However, patients who took azathioprine were able to almost halve the amount of prednisone required for disease control. Plasma exchange plus prednisone achieved significantly better disease control than prednisone alone; this favourable effect was not apparent in another study. The latter study also compared plasma exchange or azathioprine plus prednisone, but failed to show significant differences for disease control or mortality, although total adverse events at six months almost reached statistical significance in favour of plasma exchange plus prednisone. Comparing tetracycline plus nicotinamide with prednisolone, no significant difference for disease response was shown. A very potent topical corticosteroid was compared to oral prednisone in patients with moderate and extensive disease. In patients with extensive disease, the topical steroid group showed significantly better survival and disease control, and less severe complications, while no significant differences for these outcomes were seen in patients with moderate disease. Most of the reported deaths were in patients taking high doses of oral corticosteroids. AUTHORS' CONCLUSIONS: Very potent topical steroids are effective and safe treatments for bullous pemphigoid; their use in extensive disease may be limited by side effects and practical factors. Starting doses of prednisolone greater than 0.75 mg/kg/day do not seem to give additional benefit, lower doses may be adequate for disease control; this could reduce the incidence and severity of adverse reactions. The effectiveness of the addition of plasma exchange or azathioprine to corticosteroids has not been established. Combination treatment with tetracycline and nicotinamide may be useful; this needs further validation.

Azathioprine↗

Sulfamethoxypyridazine-responsive pemphigoid nodularis: a report of two cases.

Pemphigoid nodularis is a chronic and uncommon variant of bullous pemphigoid. The condition is characterized by the presence of prurigo nodularis-like lesions, possible history of blistering, and immunohistochemical findings of bullous pemphigoid. These patients are often unresponsive to conventional therapy with potent topical and systemic steroids and different immunosuppressive agents used alone or in combination. We describe two cases of pemphigoid nodularis treated successfully with sulfamethoxypyridazine without any adverse effects.

Anti-Bacterial Agents↗

Activation/inactivation of the classical pathway of complement in non-lesional skin of patients with systemic lupus erythematosus.

BACKGROUND: The link between the lupus band and pathogenesis remains controversial, because immunoglobulins and complement components, including the membrane attack complex, can be found in both lesional and non-lesional skin of patients with systemic lupus erythematosus (SLE). The expression of proteins that regulate complement has not been previously investigated in the skin of patients with SLE. AIM: The aim of this study is to compare the expression of protectin (CD59), which demonstrates the activation of the classical pathway of complement, in non-lesional skin obtained from patients with SLE with its expression in normal skin. This may help us explain the link between the lupus band and pathogenesis of cutaneous lupus erythematosus. METHODS: An indirect immunofluorescence technique was performed in order to provide unequivocal evidence for the activation of complement via the classical pathway and to compare the expression of CD59 in non-lesional skin from patients with SLE with normal skin samples obtained from healthy people. RESULTS: The activation of the classical pathway of complement was demonstrated in non-lesional skin in more than 90% of SLE patients investigated in this study. Staining intensity of the complement regulatory protein CD59 was markedly increased in the majority of non-lesional skin samples obtained from patients with SLE, compared to that from normals. CONCLUSIONS: CD59 is overexpressed in non-lesional skin in which complement activation has occurred. It seems likely that an increased and continuous CD59 expression may be important for maintaining the integrity of the skin BMZ during inflammatory responses involving complement activation in SLE skin. Alahlafi A, Wordsworth P, Wojnarowska F. Activation/inactivation of the classical pathway of complement in non-lesional skin of patients with systemic lupus erythematosus.

CD59 Antigens↗

The basement membrane zone and dermal extracellular matrix in erosive lichen planus of the vulva: an immunohistochemical study demonstrating altered expression of hemidesmosome components and anchoring fibrils.

Histopathology demonstrates disruption of the basal layer of the epidermis in lichen planus (LP) and altered expression of basement membrane zone (BMZ) components occurs in cutaneous and oral LP. This is the first study in erosive LP of the vulva to investigate the expression of components of the BMZ and extracellular matrix by indirect immunofluorescence. Six biopsies from lesional vulval erosive LP were compared with two biopsies from normal vulva and five biopsies from normal skin. In erosive vulval LP there was widespread disruption of several BMZ components compared to normal skin. The hemidesmosome antigens were disrupted and attenuated, or absent. Expression of lamina lucida proteins and anchoring filaments also showed some alteration. Lamina densa components were altered and in particular there was very marked thickening, streaking and fragmentation of the anchoring fibrils. Some dermal extracellular matrix proteins were increased. This study has demonstrated widespread damage to the BMZ in erosive LP of the vulva, in particular the hemidesmosomes (alpha6beta4 integrin, BP230, BP180) and anchoring fibrils (collagen VII). This suggests an alteration in antigenic expression in the BMZ that may lead to exposure of epitopes and thus make these proteins vulnerable to attack by autoantibodies.

Autoantigens↗

Cytokeratin expression in pili annulati hair follicles.

Pili annulati is a rare autosomal inherited hair shaft abnormality of unknown pathogenesis in which clinical examination reveals alternating light and dark bands leading to a shiny appearance of the hair due to cavities within the cortex of the hair shaft. This is the first investigation of the proposed cytokeratin defect in pili annulati hair follicles. Four cryopreserved pili annulati and four control scalp specimens were analysed using immunohistochemistry for different 'hard' trichocytic and 'soft' epithelial cytokeratins including K1, K6, K10, K14, K16, K17, K18, K19, Ha1 and Hb1. There was no difference in staining intensity and quality of staining pattern seen in pili annulati and control scalp specimens. These results suggest that pili annulati is not caused by a defect of the cytokeratins investigated in this study.

Adult↗

Erosive lichen planus of the vulva: weak circulating basement membrane zone antibodies are present.

The objective of this study was to investigate whether circulating basement membrane zone (BMZ) antibodies are present in erosive lichen planus (LP) of the vulva. In total, 56 consecutive women with biopsy-confirmed erosive LP of the vulva were recruited from a vulval clinic in a district general hospital and teaching hospital in Oxfordshire. Indirect immunofluorescence (IgG and IgA) was performed on 56 sera, and 15 were tested to IgG subclasses (1-4). Immunoblotting was carried out on salt-split and urea-extracted epidermal skin extracts on 11. The main outcome measure was the presence or absence of staining at the BMZ. Of the 56 sera, 34 (61%) had weak (neat or 1 : 5) epidermal-binding BMZ antibodies (25 had IgG, 5 had IgA, 4 had both IgG and IgA). All 15 sera tested to IgG showed epidermal binding to one or more IgG subclasses: IgG1 (7 sera), IgG2 (7), IgG3 (7) and IgG4 (0). Immunoblotting identified IgG antibodies to bullous pemphigoid (BP)180 (10/11) and BP230 (2/11). The majority (61%) of patients with vulval erosive LP had circulating serum IgG BMZ antibodies, chiefly reacting with BP180. There was subclass restriction of the IgG response to IgG1, 2 and 3. The significance of these antibodies is uncertain, but they may be a marker for the disease.

Adult↗

Coexistence of psoriasis and linear IgA disease in a patient with recent herpes zoster infection.

We report the case of a 29-year-old man with chronic plaque psoriasis who developed linear IgA disease following herpes zoster infection. There has only been one previous report describing the coexistence of psoriasis and linear IgA disease, which was confirmed by immunopathological studies. In our patient, immunoblotting studies identified IgA antibodies binding to BP180 and BP230 antigens, and IgG autoantibodies binding weakly to the BP180 antigen. This is an interesting case that we believe is an example of epitope spreading in the development of autoimmune subepidermal bullous diseases.

Adult↗

Mucosal vulval lichen planus: outcome, clinical and laboratory features.

BACKGROUND: Mucosal lichen planus of the vulva is a rare but increasingly recognized condition. It has potentially severe complications such as fusion of the labia and vagina; the risk of developing squamous cell carcinoma (SCC) may be increased. An association between hepatitis B and C infection and skin or oral lichen planus appears to exist in certain geographical areas. OBJECTIVE: To investigate the course of mucosal vulval lichen planus, its response to treatment and associated laboratory features. SUBJECTS AND METHODS: Forty-four women with mucosal vulval lichen planus were studied between 1997 and 2000 and laboratory data were collected. RESULTS: Thirty of 44 patients had additional oral lesions, only nine had cutaneous findings compatible with lichen planus. We did not find an association with antibodies to hepatitis B or C virus in this British study population. All women were treated with potent to very potent topical corticosteroids; however, in the majority of patients symptoms persisted. In seven (16%) patients vulval lichen planus was in remission after a disease duration between 2 and 18 years (mean 10.6 years). One patient developed a vulval SCC. CONCLUSIONS: Screening for hepatitis B and C in women with mucosal vulval lichen planus in the UK seems unnecessary. We recommend long-term follow-up, and that all non-healing ulcerative and papular lesions should be biopsied.

Adrenal Cortex Hormones↗

Decreased antioxidant enzyme expression and increased oxidative damage in erosive lichen planus of the vulva.

The aim of this study was to investigate whether increased oxidative stress occurs in erosive lichen planus of the vulva. Skin biopsies from six patients with untreated, histologically confirmed erosive lichen planus of the vulva were examined immunohistochemically using antibodies against antioxidant enzymes. The protein-bound lipid peroxidation products malondialdehyde (MDA) and 4-hydroxynonenale (4-HNE) and the oxidative DNA damage marker 8-hydroxy-2'-deoxyguanosine (8-OHdG) were investigated. Protein carbonyls as markers of protein oxidation were visualised using the dinitrophenylhydrazone (DNPH) method. Normal vulval tissues from 12 subjects served as controls. In vulval lichen planus tissue the enzymatic antioxidant defence was found to be significantly decreased in the epidermal layers. Furthermore, a significant increase of lipid peroxidation products and oxidative DNA damage was found within the epidermis. Protein oxidation occurred predominantly in the papillary dermis. This is the first study to demonstrate a decreased antioxidant defence and increased oxidative damage to lipids, DNA and proteins in lichen planus. These oxidative modifications point to pathophysiological alterations mainly within the basal cell layers of the epidermis and at the dermoepidermal junction. Further studies are warranted to investigate the potential role of oxidative stress in the development of autoimmunity in this disease.

8-Hydroxy-2'-Deoxyguanosine↗

Skin cancers in renal-transplant recipients occur more frequently than previously recognized in a temperate climate.

BACKGROUND: Renal-transplant recipients are at increased risk of developing skin cancers, especially squamous cell carcinoma. We have carried out a comprehensive epidemiologic review of skin cancers occurring in a population receiving transplants in Oxford over a 21-year period, where nearly all patients have remained under the care of the Oxford Transplant Centre. METHODS: Between 1975 and 1996, 1,360 renal transplants were performed in 1,115 patients. Skin cancer data were reviewed in 979 patients from this group who remained under the care of the Oxford Transplant Centre. The lesions included in the analysis were histologically confirmed basal cell carcinoma, Bowen's disease, squamous cell carcinoma, keratoacanthoma, malignant melanoma, Merkel cell tumor, and sebaceous carcinoma. RESULTS: One hundred eighty-seven (19.1%) transplant patients developed at least one skin malignancy. The rate of skin cancer was 141 per 1,000 person years at risk. Sixty-four percent of patients with skin cancer had multiple lesions (maximum 50). Squamous cell carcinoma was the most common skin cancer to develop and the most common first skin cancer to present. The mean time to presentation of the first skin cancer was 8 years. Six patients developed nodal metastases, and two patients died secondary to skin cancer. Risk factors identified were increasing age at transplantation, recipient sex, total time of exposure to immunosuppression, increased creatinine levels at 1 year, and graft relation. The cumulative incidence of skin cancer reached 61% at 20 years after transplantation. CONCLUSION: The data from this study suggest that more patients develop skin malignancies than previously reported from Europe. It is important to advise patients before transplantation in regard to skin complications, provide regular dermatological follow-up, and tailor immunosuppressive regimen to minimum doses to be compatible with good graft function.

Carcinoma, Squamous Cell↗

Does treatment of vulvar lichen sclerosus influence its prognosis?

OBJECTIVE: To record the clinical features, symptomatic response to topical steroids, and resolution of clinical signs in a large cohort of female patients with vulvar lichen sclerosus. DESIGN: Descriptive cohort study with a mean follow-up of 66 months. SETTING: The vulvar clinics of a teaching hospital and of a district general hospital in Oxfordshire, England. PATIENTS: Three hundred twenty-seven patients (74 girls and 253 women) with a definite clinical diagnosis of vulvar lichen sclerosus. Interventions The patients received topical steroids as part of their normal care. MAIN OUTCOME MEASURES: Symptomatic response to treatment (good, partial, or poor); response of the vulvar signs (total, partial, minor, or poor); and the presence or absence of moderate or severe scarring. RESULTS: The mean age at onset was 5.4 years in girls and 55.1 years in women and first-choice therapy was an ultrapotent topical steroid for 50% of the girls and 89% of the women. Response to treatment was recorded in 255 patients. In 244 patients (96%) symptoms improved with treatment, as 168 (66%) became symptom free and 76 (30%) showed partial response; 11 (4%) had poor response. Among the 253 patients in whom a response of the vulvar signs to topical steroid was recorded, 58 (23%) showed total response, with return to normal skin texture and color; and 173 (68%) showed partial, 18 (7%) showed minor, and 4 (2%) showed poor response. Moderate or severe scarring occurred less often in girls (P<.001). Squamous cell carcinoma developed in 6 women (2.4%). CONCLUSION: Topical ultrapotent steroid is an effective treatment for vulvar lichen sclerosus, giving relief of symptoms in most and completely reversing the skin changes in approximately one fifth of patients.

Administration, Cutaneous↗

The lupus band: do the autoantibodies target collagen VII?

BACKGROUND: Circulating autoantibodies directed against basement membrane zone (BMZ) components from patients with bullous pemphigoid and epidermolysis bullosa acquisita have been used to identify their target antigen in the skin and to confirm pathogenicity. Although the pattern of immunofluorescence in those diseases is similar to the lupus band, little is known about the origin and pathogenesis of the lupus band. Identifying the binding sites of the lupus band could provide a clue to the nature of the autoantigen that stimulates autoantibody formation in the skin of patients with systemic lupus erythematosus (SLE) and might provide valuable insight into the factors that influence the localization and pathogenicity of the lupus band. OBJECTIVES: To investigate the relation between the lupus band and the main BMZ components and to identify the target epitopes of autoantibodies deposited in the skin of patients with SLE. METHODS: Colocalization of the main components of the skin BMZ in nonlesional SLE skin with the lupus band was investigated using conventional immunofluorescence and confocal laser scanning microscopy. The effect of collagenase and pepsin on the expression of the lupus band was correlated with the differential sensitivity of these proteases on the collagenous and noncollagenous (NC) domains of collagen VII. Reactivity of sera from patients with SLE to a complete recombinant human NC1 domain of type VII collagen was then investigated by enzyme-linked immunosorbent assay (ELISA). RESULTS: Near complete colocalization of the lupus band with collagen VII was found in this study, and chemical degradation of the skin attenuated the expression of the lupus band. Collectively, the NC1 domain of collagen VII was suggested as the target antigen of the lupus band, but none of the sera from patients with SLE reacted with recombinant NC1 domain-coated ELISA plates. Alternative explanations for the results of the colocalization of the lupus band with collagen VII are discussed. CONCLUSIONS: The lupus band colocalized with collagen type VII. The findings of this study ruled out the NC1 domain of collagen VII as a target antigen for circulating autoantibodies in SLE patients with no clinical evidence of blistering. Further studies are required to determine if other regions of collagen VII or another BMZ component is the target antigen for the immunoglobulins of the lupus band.

Autoantibodies↗

Alterations in the basement membrane zone in pili annulati hair follicles as demonstrated by electron microscopy and immunohistochemistry.

BACKGROUND: Pili annulati is a rare autosomal dominant inherited hair shaft abnormality in which clinical examination reveals alternating light and dark bands leading to a shiny appearance of the hair. The clinically light bands are the abnormal areas due to cavities within the cortex. The pathogenesis remains unknown. OBJECTIVES: To investigate the expression of the basement membrane zone (BMZ) components in pili annulati hair follicles of the scalp. METHODS: Transmission electron microscopy (TEM) was carried out on scalp sections of six individuals with pili annulati and six controls. Longitudinal sections of scalp tissues from four individuals with pili annulati and six normal controls were studied by immunohistochemistry with a panel of monoclonal antibodies to the following BMZ components: alpha(6)beta(4) integrin, laminin 5, LH39 antigen, laminin 1, collagen IV and collagen VII. RESULTS: Using TEM, pili annulati scalp specimens exhibited a reduplicated lamina densa in the region of the root bulb in comparison with the single thin electron-dense band in controls. Using immunohistochemistry, there was a wavy BMZ in pili annulati follicles with antibodies to components of the lamina lucida, lamina densa and anchoring fibrils, whereas the BMZ in control hair follicles was as a smooth linear band. The expression of the hemidesmosome-associated alpha(6)beta(4) integrin was linear in both pili annulati and control hair follicles. CONCLUSIONS: Our results suggest that the genetic defect may be a mutation in proteins involved in signalling and regulation of formation and degradation of the lamina densa and sublamina densa region resulting in abnormal assembly or remodelling of the BMZ.

Adult↗

Increased risk of skin cancer associated with the presence of epidermodysplasia verruciformis human papillomavirus types in normal skin.

BACKGROUND: Human papillomaviruses (HPVs) are found in normal skin and in benign and malignant skin conditions. Epidermodysplasia verruciformis (EV) HPV types are those most plausibly linked to the development of squamous cell carcinomas of the skin. OBJECTIVES: To assess the risk of nonmelanoma skin cancer (NMSC) associated with the presence of EV HPV in normal skin in immunocompetent (IC) individuals and renal transplant recipients (RTRs). METHODS: Using a degenerate and nested polymerase chain reaction technique, HPV DNA was sought in 124 normal skin samples from sun-exposed and nonsun-exposed sites, from 39 IC individuals and 38 RTRs, both with and without NMSC. Data were analysed using the Mantel-Haenszel test and by logistic regression analysis. RESULTS: HPV DNA was detected in 58/67 (87%) and 20/57 (35%) samples from renal transplant and IC patients, respectively. There was no difference in either the prevalence or spectrum of HPV types found in sun-exposed and nonsun-exposed normal skin. However, there was significant association between NMSC and the presence of EV HPV DNA. Multivariate analysis provided an odds ratio of 6.41 (95% confidence interval 1.79-22.9) for the association of EV HPV DNA in normal skin (irrespective of site) and NMSC status, even after stratifying for patient group and adjusting for the clustering effect of multiple sampling. Conversely, there was no association between skin cancer status and the presence of cutaneous or mucosal HPV types in either sun-exposed or nonsun-exposed skin. CONCLUSIONS: HPV DNA is widespread in normal adult skin, particularly in transplant patients. In our study, the presence of EV but not cutaneous HPV DNA in normal skin was significantly associated with NMSC status and may prove to be of predictive value for skin cancer risk. These data provide reason to focus on EV HPV types as causal agents in skin cancer.

Adult↗

Oxidative stress is implicated in the pathogenesis of lichen sclerosus.

BACKGROUND: Lichen sclerosus (LS) is a chronic inflammatory skin disease of unknown aetiology which can be associated with secondary malignancies. Recent evidence supports an autoimmune basis for this disorder, as demonstrated by autoantibodies to extracellular matrix protein 1 (ECM-1). The pathophysiological mechanisms leading to autoimmunity and carcinogenesis are poorly understood. OBJECTIVES: We hypothesized that oxidative stress, which has been demonstrated to be involved in the pathogenesis of several autoimmune and malignant disorders, contributes to these processes in LS. METHODS: Skin biopsies from 16 patients with untreated, histologically confirmed vulval LS were examined immunohistochemically using antibodies against the lipid peroxidation products malondialdehyde and 4-hydroxynonenale and against the oxidative DNA damage marker 8-hydroxy-2'-deoxyguanosine. Protein carbonyls as markers of protein oxidation were visualized using the dinitrophenylhydrazone method. Expression of antioxidant enzymes was investigated. Normal vulval tissue from 16 subjects served as control. RESULTS: In vulval LS tissue a significant increase of lipid peroxidation products was found particularly within the basal cell layers of the epidermis, thus colocalizing with ECM-1. Oxidative DNA damage was detected throughout LS biopsies. Intriguingly, protein oxidation was significantly increased within the dermis of LS lesions, indicating oxidative protein damage in the areas of sclerosis and inflammation. The enzymatic antioxidant defence in LS was found to be significantly disturbed. CONCLUSIONS: This is the first study to demonstrate oxidative damage to lipids, DNA and proteins in LS, revealing a novel pathophysiological mechanism which may contribute to sclerosis, autoimmunity and carcinogenesis. Therapeutic strategies using antioxidants might be a useful new approach in the treatment of LS and could also help to prevent secondary malignancies.

Aged↗

Rapid effector function of circulating NC16A-specific T cells in individuals with mucous membrane pemphigoid.

BACKGROUND: Mucous membrane pemphigoid (MMP) is a chronic blistering skin disease frequently associated with circulating autoantibodies directed to a number of antigens including the NC16A region of BP180. NC16A domain-specific T cells have been identified in the blood of individuals with bullous pemphigoid (BP), pemphigoid gestationis and linear IgA disease, but there are no data investigating the potential role for such T cells in the pathogenesis of MMP. OBJECTIVES: To test the hypothesis that NC16A-specific T cells exist in the peripheral blood of individuals with MMP. METHODS: We isolated peripheral blood mononuclear cells from 10 patients with MMP, 17 with BP and 10 healthy controls and examined the immunogenicity of overlapping peptides spanning the NC16A domain using interferon (IFN)-gamma enzyme-linked immunospot assay. RESULTS: Significant IFN-gamma production was observed in response to the NC16A peptides in two of the patients with MMP and two of the patients with BP but in none of the normal controls. These data suggest that in a minority of individuals with MMP, NC16A domain-specific T cells circulate at sufficiently high frequency to be detectable directly ex vivo and to show rapid effector function. CONCLUSIONS: Overall, these findings are the first to examine the potential role for antigen-specific autoreactive T cells in the pathogenesis of MMP, and confirm that in some individuals the NC16A domain may be an important target antigen.

Autoantigens↗