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Linear IgA bullous dermatosis (LABD) and dermatitis herpetiformis (DH) represent the major subtypes of IgA mediated autoimmune bullous disorders. We sought to understand the disease etiology by using serum proteomics. We assessed 92 organ damage biomarkers in LABD, DH, and healthy controls using the Olink high-throughput proteomics. The positive proteomic serum biomarkers were used to correlate with clinical features and HLA type. Targeted proteomic analysis of IgA deposition bullous disorders vs. controls showed elevated biomarkers. Further clustering and enrichment analyses identified distinct clusters between LABD and DH, highlighting the involvement of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Comparative analysis revealed biomarkers with distinction between LABD and DH and validated in the skin lesion. Finally, qualitative correlation analysis with DEPs suggested six biomarkers (NBN, NCF2, CAPG, FES, BID, and PXN) have better prognosis in DH patients. These findings provide potential biomarkers to differentiate the disease subtype of IgA deposition bullous disease., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Pruritus is one of the leading symptoms of dermatitis herpetiformis (DH), however, studies on the pathogenesis of pruritus are scarce. Currently, skin mast cells (MCs) have been indicated to play a role in pruritus in autoimmune bullous disease., Objective: To study the role of mast cells and related mediators involved in the pathogenesis of pruritus in DH., Materials & Methods: The number of MCs and expression of histamine and thymic stromal lymphopoietin (TSLP) was investigated in lesions of 29 DH cases and 15 healthy skin donors by immunohistochemistry. Fourteen patients were assessed for severity of pruritus based on the Numeric Rating Scale and Pruritus Grading System. The levels of histamine and TSLP in the serum of 18 DH patients and 15 healthy controls were also investigated., Results: A significant increase in the number of MCs and degranulation was observed in DH lesions, which positively correlated with intensity of pruritus. In addition, skin TSLP but not histamine was shown to correlate with intensity of pruritus. No significant difference in expression of serum TSLP or histamine was observed between DH patients and healthy controls., Conclusion: These results suggest that skin MCs and TSLP might be involved in the pathogenesis of pruritus in DH which should be further clarified in future studies.

Dermatitis herpetiformis (DH) is an extraintestinal manifestation of coeliac disease (CD). Patients with DH have an elevated risk of development of another autoimmune blistering skin disease, bullous pemphigoid (BP). In this study we investigated whether patients with DH and CD (mean age for both 49 years) have circulating autoantibodies against BP180, the major BP autoantigen. ELISA tests showed that only a few DH (3/46) and CD (2/43) patients had BP180-NC16A IgG autoantibodies. Immunoblotting found that more than half of the DH samples contained IgG autoantibodies against full-length BP180. Epitope mapping with 13 fusion proteins covering the BP180 polypeptide revealed that in DH and CD patients, IgG autoantibodies did not target the NC16A or other epitopes typical of BP but recognized other intracellular and mid-extracellular regions of BP180. None of the analyzed DH and CD patients with either ELISA or immunoblotting positivity had IgG or IgA reactivity against the cutaneous basement membrane in indirect immunofluorescence analysis or skin symptoms characteristic of BP. Although only a minority of middle-aged DH patients had IgG autoantibodies against the immunodominant epitopes of BP180, our results do not exclude the possibility that intermolecular epitope spreading could explain the switch from DH to BP in elderly patients., (Copyright © 2020 Nätynki, Tuusa, Hervonen, Kaukinen, Lindgren, Huilaja, Kokkonen, Salmi and Tasanen.)

Background and objectives : Dermatitis herpetiformis (DH) is a blistering dermatosis, which shares common immunologic features with celiac disease (CD). The aim of the present study was to explore the performance of a panel of CD-related antibodies and IL-17A in Bulgarian patients with DH. Materials and Methods: Serum samples from 26 DH patients at mean age 53 ± 15 years and 20 healthy controls were assessed for anti-tissue transglutaminase (anti-tTG), anti-deamidated gliadin peptides (anti-DGP), anti-actin antibodies (AAA), and IL-17A by enzyme linked immuno-sorbent assay (ELISA), as well as anti-tTG, anti-gliadin (AGA), and anti-Saccharomyces cerevisiae antibodies (ASCA) using immunoblot. Results: The average serum levels of anti-tTG, anti-DGP, AGA, AAA, and the cytokine IL-17A were at significantly higher levels in patients with DH compared to the average levels in healthy persons which stayed below the cut-off value ( p < 0.05). Anti-DGP and anti-tTG antibodies showed the highest diagnostic sensitivity and specificity, as well as acceptable positive and negative predictive value. None of the healthy individuals was found positive for the tested antibodies, as well as for ASCA within the DH group. All tests showed good to excellent correlations (r = 0.5 ÷ 0.9, p < 0.01). Conclusions: Although the diagnosis of DH relies on skin biopsy for histology and DIF, serologic testing of a panel of celiac-related antibodies could be employed with advantages in the diagnosing process of DH patients. Furthermore, DH patients who are positive for the investigated serologic parameters could have routine monitoring for gastrointestinal complications typical for the gluten-sensitive enteropathy.

Coeliac disease and dermatitis herpetiformis (DH) are characterized by autoantibodies targeting transglutaminase (TG)2 and TG3, respectively. Previous studies show that TG2 antibodies are produced in the gut and can be assessed in organ culture of small-intestinal biopsies from patients with coeliac disease. Thus far, no studies have investigated TG3 antibodies in organ culture of biopsies from patients with DH, or exploited the method in DH. The aim of this study was to investigate TG3 and TG2 antibody responses in serum and small-intestinal biopsies from patients with DH with active disease, and from those in remission. The majority of patients with DH were negative for both serum and organ culture medium TG2-targeting antibodies. Surprisingly, patients with active DH secreted TG3 antibodies into the culture medium despite seronegativity. In patients secreting high levels of TG3 antibodies into the culture medium, we also detected TG3-antibody-positive cells in the small-intestinal mucosa. These findings suggest that TG3 antibodies can be investigated in the organ culture system and that their secretion occurs in the small intestine, especially in active DH.

Inflammation-induced heat shock proteins (HSPs) and hypovitaminosis D have been reported to impact immune responses and to be associated with autoimmune diseases including celiac disease (CD), a gluten-sensitive enteropathy mediated by autoantibodies against tissue transglutaminase (TG2). Recently, we provided evidence for a role of autoantibodies to HSPs in patients with dermatitis herpetiformis (DH), an inflammatory skin disease induced by underlying latent CD. In this study, we aimed at investigating the humoral autoimmune response to HSPs and vitamin D status in CD patients (n=15) presenting without the cutaneous disease manifestation. In comparison with healthy controls (n=15), circulating autoantibodies against HSP40, HSP60, and HSP90 were increased in these patients, and these autoantibodies, including anti-HSP70, correlated with serum anti-TG2 autoantibodies. Deficient and insufficient vitamin D serum levels were found in 8 out of 15 CD patients and 11 out of 15 healthy controls, and the vitamin D status showed no relationship with levels of circulating anti-TG2 or anti-HSP autoantibodies in the patients. Our results preliminarily suggest a pronounced anti-HSP autoimmune response in CD that is linked to pathophysiological processes in the gut independently of both a potential concomitant disease-related extra-intestinal inflammatory manifestation in the skin and the vitamin D status. Future studies on larger groups of patients are needed to confirm the present data and to further clarify whether autoimmunity towards HSPs is primarily related to underlying CD or skin inflammation in DH patients., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Goals: We analyzed from our prospectively collected series of patients with dermatitis herpetiformis (DH) whether small-bowel histologic findings are changing and how serum tissue transglutaminase (TG2) IgA antibodies correlate to mucosal damage., Background: DH is an extraintestinal manifestation of celiac disease presenting with itchy blistering rash and pathognomonic IgA deposits in the skin. Prominent gastrointestinal symptoms are rare, and small-bowel findings range from severe villous atrophy (SVA) and partial villous atrophy (PVA) to normal mucosa with inflammatory changes., Methods: The cohort included 393 patients (214 male and 179 female) with DH having small-bowel biopsies performed at Tampere University Hospital since 1970. The small-bowel findings were calculated in the three 15-year periods, and in the last period they were correlated with serum IgA class TG2 antibody levels measured by enzyme-linked immunosorbent assay., Results: The prevalence of SVA decreased significantly (P=0.032), from 42% in the first study period to 29% in the last study period. A concomitant increase was seen in PVA, from 33% to 41%, and normal villous architecture, from 25% to 30%. The patients with SVA (P<0.001) and PVA (P=0.046) had significantly higher TG2 antibody levels than those with normal villous architecture., Conclusions: This long-term study in patients with DH disclosed a significant decrease in the occurrence of SVA. Serum IgA TG2 antibody levels correlated to damage in the small bowel. The trend toward milder small-bowel histology in DH suggests that a similar pattern could occur in the pool of undiagnosed celiac disease from which DH develops.

Itch which is one of the major, subjective symptoms in a course of bullous pemphigoid and dermatitis herpetiformis makes those two diseases totally different than other autoimmune blistering diseases. Its pathogenesis is still not fully known. The aim of this research was to assess the role of IL-31 in development of itch as well as to measure its intensity. Obtained results, as well as literature data, show that lower concentration of IL-31 in patients' serum may be correlated with its role in JAK/STAT signaling pathway which is involved in development of autoimmune blistering disease. Intensity of itch is surprisingly huge problem for the patients and the obtained results are comparable with results presented by atopic patients.

Background: Recently, high prevalence of cryofibrinogenaemia has been observed in plasma of untreated dermatitis herpetiformis (DH) patients, and the pathological IgA and TG3 deposits in the papillary dermis were found to co-localize with fibrin and fibrinogen., Objective: To study the fibrinolytic potential in plasma of untreated, dapsone and or/gluten-free diet treated DH patients as well as the in vitro effect of dapsone on the fibrinolytic profile., Method: Plasma samples of 23 DH patients, 19 healthy subjects and 5 pemphigus vulgaris patients were investigated by a turbidimetric-clot lysis assay. Out of them 5 DH plasma samples representing different fibrinolytic parameters, and 3 healthy controls were selected for parallel fibrin clot preparation. The clot fibrin structure was examined by scanning electron microscopy (SEM), and the diameters of 900 fibrin fibres were determined in each clot., Results: A significantly prolonged clot lysis time was detected in untreated DH patients. The turbidity values of DH plasma clots indicated an altered fibrin structure that was also confirmed by SEM: significantly thicker fibrin fibers were observed in untreated, TG3 antibody positive DH patients compared to healthy controls, whereas the fiber diameters of dapsone-treated patients were similar or thinner than the control values. In line with the structural changes of fibrin, the fibrinolytic profile of 5 DH patients under dapsone treatment approached the control values., Conclusion: This study revealed that the fibrinolytic potential was impaired in the plasma of untreated DH patients, whereas dapsone corrected the fibrinolytic defect. These data suggest a pathogenic role for plasma-derived factors in the development of skin symptoms and add a new aspect to the long-known beneficial, symptomatic effect of dapsone in active DH., (Copyright © 2016 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.)

Background: Transglutaminase (TG)2 is the autoantigen in celiac disease, but also TG3 antibodies have been detected in the serum of celiac disease patients., Aims: To investigate the correlations between serum TG3 antibodies and clinical and histological manifestations of celiac disease and to assess gluten-dependency of TG3 antibodies., Methods: Correlations between serum TG3 antibody levels measured from 119 adults and children with untreated coeliac disease and the demographic data, clinical symptoms, celiac antibodies, histological data and results of laboratory tests and bone mineral densities were tested. TG3 antibodies were reinvestigated in 97 celiac disease patients after 12 months on a gluten-free diet (GFD)., Results: TG3 antibody titers were shown to correlate with the age at celiac disease diagnosis. Further, negative correlation with TG3 antibodies and intestinal γδ+ cells at diagnosis and on GFD was detected. Correlations were not detected with the clinical manifestation of celiac disease, TG2 or endomysial autoantibodies, laboratory values, severity of mucosal villous atrophy, associated diseases or complications. TG3 antibody titers decreased on GFD in 56% of the TG3 antibody positive patients., Conclusion: Serum TG3 antibody positivity in celiac disease increases as the diagnostic age rises. TG3 antibodies did not show similar gluten-dependency as TG2 antibodies., (Copyright © 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Objective: Dermatitis herpetiformis (DH) is a cutaneous form of celiac disease affecting ∼ 17% of celiac disease patients. The aim was to determine how often celiac disease precedes the development of DH, and what is the impact of gluten-free diet (GFD) in this phenotype change., Material and Methods: Our prospectively collected DH series from 1970 comprised 514 patients. We analyzed all DH patients who at least 2 years earlier had been diagnosed with celiac disease. DH diagnosis was confirmed by showing immunoglobulin A deposits in dermis. Serological and small bowel mucosal findings were analyzed, and the strictness of GFD treatment before and after the diagnosis of DH was evaluated., Results: Twenty (4%) DH patients had a prior diagnosis of celiac disease. The median time interval between celiac disease and DH detection was 9.5 years. Before DH appeared 4 patients had been on a normal gluten-containing diet, 10 had dietary lapses on a GFD, and 6 were on a strict GFD. Celiac autoantibodies were positive in 7 out of 19 patients, and 5 out of 7 undergoing small bowel biopsy had partial villous atrophy. Following DH diagnosis the rash was controlled after a median of 6 months on a strict GFD., Conclusions: Patients with celiac disease may develop DH by time. This is most often an indicator of poor adherence to GFD, and a rigorous dietary intervention is necessary. In the majority of cases, DH will be detected without prior celiac disease diagnosis, but the physicians should recognize this phenotype alteration.

Dermatitis herpetiformis (DH) and bullous pemphigoid (BP) are skin diseases associated with eosinophilic and neutrophilic infiltrations. Although chemokines are critical for the selective accumulation and activation of various leukocyte subsets in the inflammatory process, there are few findings concerning inflammatory cells and production of coagulation factors in blistering diseases. Skin biopsies were taken from 14 patients with DH, 27 with BP, and 20 control subjects. The localization and expression of tissue factor (TF) in skin lesions and perilesional skin were studied by immunohistochemistry and confirmed by Western Blot. Moreover the plasma concentrations of TF were measured by immunoassays. D dimers, fibrinogen, and selected coagulation parameters were measured by routine methods. Expression of TF in the epidermis and in inflammatory influxed cells in dermis was detected in skin biopsies from BP patients. Examined TF expression was detected in perilesional skin of all BP patients too. The expression of TF was not observed in biopsies from healthy people and DH patients. The findings of the study show an increased expression of tissue factor in the lesional and perilesional skin of patients with bullous pemphigoid. The difference in chemokine pattern expression and variations in the cellular infiltration in BP and DH cause variable expression of TF.

Background: Dermatitis herpetiformis (DH) and celiac disease (CD) are considered as autoimmune diseases that share a defined trigger (gluten) and a common genetic background (HLA-DQ2/DQ8). However, the pathogenesis of DH is not fully understood and no data are available about the immune regulation in such a disease., Objective: The aim of this study was to assess if alterations in the pattern of the immune response and, in particular, impairments of regulatory T (Tregs) cells may contribute to the phenotypic differences between DH and CD., Methods: We investigated the presence of Tregs cell markers, in the skin, the duodenum and the blood of patients with DH by immunohistochemistry, confocal microscopy and flow cytometry. As controls, we included patients with bullous pemphigoid, patients with CD without skin lesions, as well as healthy subjects (HS)., Results: In the skin of DH patient, we found a significantly lower proportion of FOXP3(+) Tregs and IL-10(+) cells than in HS (p < 0.001 for both cell populations). In duodenal samples, no differences where found in the proportion of Tregs between patients with DH and patients with CD without skin manifestations. Finally, the frequency of CD25(bright)FOXP3(+) cells within the CD4(+) subset was significantly reduced in CD patients either with or without DH with respect to HS (p = 0.029 and p = 0.017, respectively)., Conclusions: Our findings suggested that a reduction of Tregs may play a major role in the skin, leading to a defective suppressive function and thus to the development of the lesions. By contrast, no differences could be detected about Tregs between patients with DH and patients with CD in the duodenum, suggesting that the mechanisms of the intestinal damage are similar in both diseases., (Copyright © 2014 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.)

Heat shock proteins (Hsp) are highly conserved immunomodulatory molecules upregulated when cells are exposed to stressful stimuli, such as inflammation. Their involvement in various autoimmune diseases, including autoimmune bullous diseases and celiac disease, has been increasingly recognized. To further study the role of Hsp in autoimmune bullous diseases, we have investigated for the first time the humoral autoimmune response to Hsp40, Hsp60, Hsp70, and Hsp90 in patients with dermatitis herpetiformis (DH; n = 26), bullous pemphigoid (BP; n = 23), and pemphigus vulgaris (PV; n = 16), the first representing a cutaneous manifestation of celiac disease. While in patients with active BP and PV, serum levels of autoantibodies against these Hsp did not differ from the corresponding age- and gender-matched healthy controls (n = 9-14); circulating autoantibodies against Hsp60, Hsp70, and Hsp90 were found to be increased at the active disease stage of DH. Further analysis of this latter patient subgroup showed that these anti-Hsp autoantibodies decreased in parallel with serum autoantibodies against epidermal and tissue transglutaminase during remission of skin lesions following a gluten-free diet, revealing significantly positive correlations. Although further studies on larger groups of patients will be needed to confirm the present data, our results support the notion that autoantibodies against Hsp60, Hsp70, and Hsp90 deserve attention in the study of the mechanisms that promote the development and maintenance of DH and possibly also the underlying celiac disease as well as potential novel disease biomarkers.

Bullous pemphigoid (BP) and dermatitis herpetiformis (DH) are skin diseases associated with inflammation. However, few findings exist concerning the role of mast cells in autoimmune blistering disease. Skin biopsies were taken from 27 BP and 14 DH patients, as well as 20 healthy individuals. Immunohistochemistry was used to identify the localization and mast cell expression of TNFα and MMP9 in skin lesions and perilesional skin. The serum concentrations of TNFα, MMP9, chymase, tryptase, PAF, and IL-4 were measured by immunoassay. TNFα and MMP9 expression in the epidermis and in inflammatory influxed cells in the dermis was detected in skin biopsies from patients. Although these mediators were found to be expressed in the perilesional skin of all patients, the level was much lower than that in lesional skin. Increased serum PAF levels were observed in BP patients. Mast cells may play an essential role in activating inflammation, which ultimately contributes to the tissue damage observed in BP and DH. Our findings suggest that differences in the pattern of cytokine expression directly contribute to variations in cellular infiltration in DH and BP.

Background: Dermatitis herpetiformis (DH) is a rare gluten-sensitive blistering itchy skin disease, strictly related to coeliac disease (CD). Direct immunofluorescence, demonstrating IgA granular deposits localized either in the dermal papillae or along the dermo-epidermal junction, is currently the gold standard for diagnosis of DH. It has been shown that DH immunocomplexes contain epidermal transglutaminase (eTG) and that sera from patients with DH contain antibodies specifically directed against eTG., Objectives: We studied the usefulness of serum eTG antibodies in discriminating between DH, CD and other gastrointestinal and dermatologic diseases., Methods: eTG antibodies were tested in 308 adult patients' sera: 44 patients with untreated dermatitis herpetiformis (UDH), 99 patients with untreated coeliac disease (UCD), 70 dermatological controls and 95 gastrointestinal controls., Results: In UDH eTG antibody levels were significantly higher than in DH patients on gluten-free diet, UCD, gastrointestinal controls and dermatological controls. In UCD eTG antibodies strongly correlated with tissue transglutaminase (tTG) antibodies, whereas in UDH no significant correlation was observed., Conclusion: Serum IgA eTG antibody determination can efficiently distinguish UDH from other dermatological itchy diseases and is highly sensitive to gluten-free diet., (© 2012 The Authors. Journal of the European Academy of Dermatology and Venereology © 2012 European Academy of Dermatology and Venereology.)

Aim: The aim of this paper to report the main clinical and immunopathological findings of our case series of 159 patients with dermatitis herpetiformis (DH)., Methods: All DH patients that were diagnosed from 1995 to 2012 at the Section of Dermatology of the University of Florence were included in the study. Clinical data were collected for each patient. Moreover, histopathological examination on both the skin and the small bowel, direct immunofluorescence on perilesional skin as well as the search for anti-endomysium and anti-tissue transglutaminsase antibodies (tTG) were performed., Results: A total of 159 patients with a male predominance were enrolled. About 36% of the patients were below the age of 20. The most frequent clinical features seen in our DH patients were represented by figurate erythema, wheals, papules and scratching lesions, while the knees, elbows and buttocks were the most commonly involved sites. All the 22 patients that underwent a bowel biopsy showed the typical alterations found in celiac disease. Moreover, 100% of the patients showed granular IgA deposits at the papillary tips. Finally, anti-endomysium and anti-tTG antibodies were present in 90% and 96% of the patients, respectively., Conclusion: We reported one of the largest case series of patients with DH from a single center. Our study confirmed most of the data from the Literature, and in particular the association of DH to histologically proven CD in all the biopsied cases. Another interesting finding of our study is the high prevalence of DH within pediatric patients, that is usually underreported.

Dermatitis herpetiformis (DH) and bullous pemphigoid (BP) are skin diseases associated with eosinophilic and neutrophilic infiltrations. Although cytokines are critical for the inflammatory process, there are single findings concerning concentration of IL-17 in bullous diseases. The goal of this study was to assess IL-17 expression in DH and BP patients. Skin biopsies were taken from 10 DH, 14 BP patients and from 10 healthy subjects. The localization and expression of IL-17 was studied by immunohistochemistry and the serum concentration was measured by immunoassays. Expression of IL-17 in the epidermis and in influxed cells in dermis was detected in skin biopsies. Expression of IL-17 was statistically higher in epidermis and infiltration cells in specimens from BP than from DH patients. Examined interleukin expression was detected in perilesional skin of all patients but it was much lower than in lesional skin. The expression of IL-17 was not observed in biopsies from healthy people. Serum level of IL-17 was statistically higher in BP and DH groups as compared to control group. Our results provide the evidence that IL-17 may play an essential role in activating and recruiting eosinophils and neutrophils, which ultimately contribute to the tissue damage in DH and BP.

Background: Dermatitis herpetiformis (DH) is a cutaneous manifestation of celiac disease (CD), the latter being identified by circulating autoantibodies against native gliadin (nGli), tissue transglutaminase (tTG), endomysium, or a combination of these. Recently, a novel serologic assay using deamidated gliadin-analogous fusion peptides (GAF3X) showed high diagnostic sensitivity in patients with CD., Objective: The aim of this study was to explore the anti-GAF3X enzyme-linked immunosorbent assay (ELISA) and to compare it with a panel of classic CD-related serologic tests in patients with DH., Methods: Antibodies against nGli, GAF3X, and tTG were determined by separate ELISA tests and against endomysium by indirect immunofluorescence microscopy in 45 patients with DH and 52 control patients (30 patients with bullous pemphigoid and 22 patients with linear IgA disease). A total of 24 patients with DH underwent intestinal biopsies to confirm underlying CD., Results: Antibodies to nGli were detected in 26 (58%) (IgA) and 24 (53%) (IgG), to GAF3X in 38 (84%) (IgA) and 36 (80%) (IgG), to tTG in 35 (78%) (IgA), and to endomysium in 32 (71%) (IgA) patients with DH. Combined testing of IgA and IgG antibodies to GAF3X detected 7 of 10 (70%) IgA-anti-tTG-negative patients with DH and together with the IgA-anti-tTG ELISA showed the highest serologic hit rate (93%) for CD., Limitations: Intestinal biopsies were not performed in all patients with DH., Conclusion: The novel anti-GAF3X ELISA shows a higher sensitivity to detect CD-associated autoantibodies in patients with DH compared with tests using nGli, tTG, or endomysium as substrates., (Copyright © 2011 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.)

Patients with dermatitis herpetiformis (DH) have a gluten-sensitive enteropathy and while on gluten-containing diets have elevated levels of serum IL-8. We hypothesized that the mucosal immune response to gluten is responsible for the elevated serum IL-8. Six DH patients were studied while on a gluten-free diet (GFD), whereas four continued on a normal diet. Patients were followed for a mean 2.2 years and serum IL-8 was analyzed. Small bowel biopsies from five DH patients on normal diets, two DH patients on GFD, and six subjects with no small bowel abnormalities were analyzed for IL-8 mRNA. Serum IL-8 levels normalized in five of six patients on GFD and decreased in one, whereas serum IL-8 levels showed no statistically significant change in DH patients on normal diets. Small bowel biopsies from DH patients on normal diets had increased expression of IL-8 mRNA compared to normal subjects, whereas patients on a GFD showed no significant increase in small bowel mRNA. No significant IL-8 mRNA was detected in normal skin biopsies from patients with DH. These observations suggest that the IL-8 in the serum of patients with DH originates from the small bowel as a mucosal immune response to gluten ingestion.

Background: Patients with gluten sensitivity, i. e. celiac disease and dermatitis herpetiformis have anti-endomysial antibodies recognizing transglutaminases, which are usually detected on appropriate tissue sections. It would be desirable to have available a reliable, tissue-independent serological diagnostic tool. We compared disease-specificity and sensitivity of tTG versus eTG-based detection systems for the diagnosis of anti-endomysial IgA-antibodies., Patients and Methods: We examined 204 serum samples in duplicates with commercial human ELISA-kits: 54 healthy blood donors, 20 celiac disease, 29 dermatitis herpetiformis and 101 with other autoimmune dermatoses., Results: The tTG-based ELISA proved to be very disease-specific (100 %) and sensitive for the diagnosis of gluten sensitivity (95 % celiac disease; 96.6 % dermatitis herpetiformis). The eTG-based ELISA was also perfectly specific (100 %), but only 15 % of celiac disease-sera and 44.8 % of dermatitis herpetiformis-sera yielded positive results., Conclusions: The human tTG-ELISA fulfills all criteria of a screening test and, because of being investigator-independent, inexpensive and highly reproducible, compares favorably with the current diagnostic gold standard (indirect immunofluorescence and biopsy) of celiac disease and dermatitis herpetiformis. The low sensitivity of the eTG-ELISA may have technical reasons, but could theoretically also be linked to disease activity or indicate the existence of an as yet undefined disease subset. Studies are currently under way to address these issues.

Background: Dermatitis herpetiformis (DH) is a rare bullous disease of autoimmune etiology. It is an intestinocutaneous syndrome, in which vesicopapular cutaneous lesions are accompanied by gluten-dependent enteropathy. The diagnosis of DH is based on immunopathological investigation of unaffected skin fragment (granular IgA deposits present at the tops of dermal papillae and IgA - EmA present in the serum)., Material/methods: The studied group consisted of 33 patients with dermatitis herpetiformis - 23 males and 10 females aged 22-78 (mean age 44.7). In all the patients, the following parameters of blood coagulation systems were determined in the plasma Levels of prothrombin fragments 1+2 (F(1+2)), levels of thrombin - antithrombin III (TAT) complexes, antithrombin III activity (AT III)., Results: In patients with dermatitis herpetiformis, the main level of F(1+2) fragments amounted to 9.08 nmol/l, as compared with 1.14 nmol/l in the control group (the difference statistically significant, p<0.0001). In DH patients, the levels of TAT complexes were over twice higher than among the controls and that difference also reached statistical significance (p<0.0001). Mean antithrombin III activity (AT III) in patients with DH reached 102.60% and was similar to that observed in the control group (104.68%)., Conclusions: In patients with dermatitis herpetiformis, increased levels of F(1+2) prothrombin fragments and TAT complexes indicate enhanced in vivo thrombinogenesis. No statistically significant differences of F(1+2), TAT and AT III levels in DH patients related to their sex, age and duration of the disease were observed.

Background: Dermatitis herpetiformis (DH) is a subepidermal bullous disease characterized by a neutrophilic and eosinophilic infiltrate, together with activated lymphocytes that show preferential polarization towards the Th2-like phenotype. To date, the role of neither soluble mediators, such as cytokines, nor serum levels of myeloperoxidase (MPO), eosinophil cationic protein (ECP) and tryptase (TRY) have been studied in the peripheral blood of DH. In this study we investigated 40 DH subjects for possible alterations in MPO, ECP, TRY, eotaxin, interleukin (IL) 4 and IL-5 concentrations to evaluate the role of neutrophils, eosinophils and mast cells in the induction of skin lesions. Sera from 20 healthy subjects were tested as controls., Methods: Eotaxin, IL-4 and IL-5 serum contents were determined by a solid-phase enzyme-linked immunosorbent assay. A double antibody radioimmunoassay was used to measure serum levels of MPO, ECP and TRY., Results: Normal levels of eotaxin and IL-4 were found in all DH subjects; increased IL-5 levels were found only in 1 subject. The MPO levels were significantly higher in DH subjects than in healthy controls (p < 0.01). There was also a significant difference between the serum ECP levels of DH and healthy controls (p < 0.05). TRY was not revealed in the serum of DH subjects., Conclusions: The determination of Th2-like cytokines and TRY serum levels is not important in quantifying the involvement of activated lymphocytes and mast cells in DH; however, the finding of high MPO and ECP serum levels seems to confirm that these products are good markers of the presence of activated neutrophils and eosinophils., (Copyright 2002 S. Karger AG, Basel)

A number of autoimmune subepidermal blistering diseases are characterized by the distinct autoantigens of the cutaneous basement membrane zone. Recently, a few cases with autoantibodies against a novel 200-kDa dermal protein have been reported. We collected nine cases of subepidermal blistering disease with IgG antibodies against this 200-kDa antigen. In this report, we describe the clinical and immunological appearances in these cases. Five cases showed bullous pemphigoid-like features, one case resembled dermatitis herpetiformis, and another case showed mixed features of bullous pemphigoid and linear IgA bullous dermatosis. It was interesting to note that psoriasis coexisted in four cases. By indirect immunofluorescence on 1 M NaCl split skin, IgG antibodies from all sera reacted with the dermal side of the split. By immunoblot analysis, IgG antibodies recognized a 200-kDa protein of dermal extract. IgG affinity-purified antibodies on the 200-kDa immunoblot membrane stained the dermal side of 1 M NaCl split skin. Various examinations suggested that the 200-kDa antigen is not identical to any chains of laminins-1, -5 or -6. This autoimmune subepidermal blistering disease against the dermal 200-kDa protein may form a new distinct entity, which often associates with psoriasis.

Dermatitis herpetiformis is a gluten-sensitive disease with a symmetrically distributed blistering over extensor surfaces. The association with celiac disease is further supported by the high rate of immunoglobulin A autoantibodies to endomysium in patients with dermatitis herpetiformis, which are highly specific and sensitive indicators of celiac disease. Therefore, we determined immunoglobulin A antibodies to tissue transglutaminase, the recently discovered endomysial autoantigen in celiac disease, in patients with dermatitis herpetiformis and controls. Sera of 61 patients with dermatitis herpetiformis, as characterized by granular immunoglobulin A deposits in the subepidermal basement membrane and known endomysial antibody titers (determined by indirect immunofluorescence) as well as 84 control sera of patients with dermal or intestinal diseases unrelated to dermatitis herpetiformis, were analyzed for circulating immunoglobulin A antibodies to tissue transglutaminase by enzyme-linked immunosorbent assay. Immunoglobulin A anti-tissue transglutaminase titers in patients with dermatitis herpetiformis were significantly elevated above the controls. Furthermore, the immunoglobulin A anti-tTG titers showed a positive correlation with semiquantitative endomysial antibody data. Compared with endomysial antibodies, determination of immunoglobulin A anti-tissue transglutaminase reached a specificity and sensitivity of 97.6% and 89.1%. Patients with dermatitis herpetiformis have elevated immunoglobulin A autoantibodies to tissue transglutaminase, confirming its pathogenic relation with celiac disease and further supporting the usefulness of this novel assay for screening and therapy control.

For reasons that are unclear, patients with dermatitis herpetiformis (DH) have a lower than expected mortality rate from ischaemic heart disease. We have compared risk factors for ischaemic heart disease (lipids, fibrinogen levels, smoking history and social class) in 29 DH patients and 57 controls matched for age and sex. Patients with DH had significantly lower cholesterol, triglycerides, apolipoprotein B and fibrinogen and higher HDL2; they also smoked less and were of higher social class. The mechanisms underlying these observations merit further investigation. Intestinal abnormalities or gluten-free diet may account for differences in lipid fractions, and the immunomodulatory properties of cigarette smoke may protect against the development of DH.

The etiology and pathogenesis of Bell's palsy are still an enigma. Some studies have reported about the presence of cellular and humoral immune dysfunction in this disease. Recently, determination of soluble interleukin 2 receptor has proven to be a valuable clinical tool to detect dysregulation of T lymphocyte function. The concentrations of soluble interleukin 2 receptor alpha was determined in serum samples from 11 patients with Bell's palsy by an enzyme linked immunosorbent assay (ELISA). Concomitantly 8 age- and sex-matched healthy blood donor as well as six patients with dermatitis herpetiformis served as negative and positive controls, respectively. The concentration of soluble interleukin 2 receptor in serum samples from these patients was similar to that in samples from normal subjects. In contrast to this, patients with dermatitis herpetiformis showed higher values of interleukin 2 receptor. Our results showed that Bell's palsy is not accompanied by a massive activation of T cells.

Serum IgA class antigliadin antibodies (IgA-AGA) are increased in untreated patients with coeliac disease and dermatitis herpetiformis (DH), and it has been suggested that salivary IgA-AGA measurements could be used as a non-invasive screening test for gluten-sensitive enteropathy. In the present study salivary and serum IgA-AGA were measured by an ELISA test in 10 untreated patients with DH. The results were compared to IgA-AGA levels in nine patients with DH on a long-term gluten-free diet (GFD) and in 20 healthy control subjects on an ordinary diet. The mean serum but not salivary IgA-AGA concentrations were significantly higher in the untreated than in the patients with DH on a long-term GFD. When the 10 untreated patients with DH adhered to a GFD for 3 months, the rash disappeared and the mean serum IgA-AGA decreased to normal levels, but no change was found in the mean salivary IgA-AGA concentration. These results show that serum but not salivary IgA-AGA measurements are suitable for monitoring GFD treatment in patients with DH. The discrepancy between the serum and salivary IgA-AGA concentrations suggests that systemic and salivary IgA-AGA responses are controlled separately.

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.

We have previously shown that cimetidine, given concurrently for 2 weeks to patients on chronic dapsone therapy, reduced methaemoglobinaemia by inhibiting the formation of the toxic hydroxylamine metabolite of dapsone. The aim of the present study was to examine the effect of this combination on the benefit/toxic ratio of dapsone over a longer period. Eight patients (six dermatitis herpetiformis, one linear IgA disease, one folliculitis decalvans) on long-term dapsone 50-100 mg daily, took cimetidine 1.6 g daily concurrently for 3 months. At 3-weekly intervals, a clinical assessment was made, plasma dapsone and methaemoglobin were measured, and parameters of oxidative haemolysis were monitored. The dapsone level rose from 2298 +/- 849 ng/ml (mean +/- SD) at baseline to 3006 +/- 1131 ng/ml at week 3 of cimetidine (P < 0.01). This rise in plasma dapsone was sustained during cimetidine administration, falling to 2446 +/- 954 ng/ml when cimetidine was stopped (P < 0.02). The methaemoglobin fell from 5.5 +/- 2.2% (mean +/- SD) at baseline to 3.9 +/- 1.1% at week 3 (P < 0.01), and remained low until week 12, when there was a return to baseline values (P < 0.01). The haemoglobin did not change from the baseline of 12.7 +/- 0.3 g/dl (mean +/- SD), and other parameters of haemolysis were unaltered. There was a fall in the visual analogue score for headache (P < 0.05), but this was not associated with any deterioration in control of the skin disorders. Hence, long-term concurrent cimetidine results in increased plasma dapsone levels without increased haemolysis, and is accompanied by reduced methaemoglobinaemia for more than 2 months.(ABSTRACT TRUNCATED AT 250 WORDS)

Although IgA is present in the skin of patients with dermatitis herpetiformis (DH), the relationship of that IgA to the mucosal immune response is not known. The purpose of this study was to determine if IgA antibodies directed against tissue antigens, which are present in the serum of patients with DH, are also present in the gut secretions of these patients. Serum and gut secretions from 8 patients with DH and 5 control subjects were analyzed by indirect immunofluorescence for the presence of IgA antireticulin and antiendomysium antibodies. IgA antibodies against reticulin (3 of 8 patients) and endomysium (4 of 8 patients) were found in the serum of patients with DH. IgA antibodies were also present in the gut secretions of all of these patients, but not in subjects (patients with DH and controls) that did not have serum IgA antireticulin or antiendomysium antibodies. The presence of IgA antireticulin and antiendomysium in both the serum and gut secretions of DH patients suggests that these antibodies arise as a result of the mucosal immune response and that IgA of mucosal origin can persist in the serum of patients with DH.

The relationship between adenovirus type 12 (Ad12), celiac disease (CD) and dermatitis herpetiformis (DH) was evaluated by enzyme-linked immunosorbent assay (ELISA). Diagnostic phase serum samples from 44 children with CD, 16 children with DH and 60 matched controls were studied for serum antibodies to synthetic peptides derived from an early E1b protein of Ad12 and A gliadin. Both the patient groups had significantly (p < 0.001) higher IgG antibody levels to the Ad12 E1b peptide than the controls. The difference was especially pronounced for girls (p < 0.005). Antipeptide IgG antibodies to Ad12 E1b and A gliadin posed a synergistic increase in the CD and DH risk suggesting that infection with Ad12 is associated with CD and DH.

The anti-inflammatory influence of dapsone may involve suppression of neutrophil chemotaxis to selected attractants, but other actions of the drug are likely also involved. We have discovered that dapsone may suppress migration of neutrophils to extravascular sites through inhibition of adherence functions required for neutrophil recruitment. Neutrophil adherence mediated by integrins (CD11/CD18 or Mac-1 family receptors) was measured in vitro in terms of binding of stimulated cells to albumin-coated wells of microtiter plates, using phorbol myristate acetate (PMA) and N-formylmethionyl-leucyl-phenylalanine (FMLP) as stimuli. Adherence was assessed by staining attached cells with crystal violet dye and measuring the dye concentration at OD590 using an automated plate reader. The role of integrins in this assay was confirmed by the ability of anti-integrin antibody to suppress stimulated neutrophil adherence. The OD590 value for cells adhering to albumin in the absence of stimulus and dapsone averaged 0.2 +/- 0.04 (SEM) over five experiments. In the presence of 0.1 microM PMA or 10(-6) M FMLP, the OD590 values averaged 0.88 +/- 0.1 and 0.75 +/- 0.12, respectively. Dapsone did not affect unstimulated neutrophil adherence but, when present with stimulus, produced a dose-related inhibitory effect on adherence. Fifty percent inhibitory doses were approximately 150 micrograms/ml dapsone for both stimuli. Sulfapyridine reproduced the inhibitory effect of dapsone, but two structurally related compounds, hydrochlorothiazide and furosamide, did not. The observed ability of dapsone to inhibit neutrophil chemotaxis under agarose to FMLP and interleukin-8 may also be explained by interference with integrin-mediated adherence required for motility in this assay system. To consider if dapsone might have a similar inhibitory influence on neutrophil adherence in vivo, we tested the stimulated adherence function of neutrophils isolated from three individuals on dapsone therapy for dermatitis herpetiformis. Stimulated adherence of patients' cells averaged less than 40 percent of the control value. Suppression of leukocyte integrin function may therefore also contribute to the ability of dapsone to inhibit neutrophil infiltration in neutrophilic dermatoses.

Objective: This study looked at whether oral vitamin C and vitamin E would protect the erythrocyte from oxidant damage caused by dapsone in patients with dermatitis herpetiformis., Design: Fifteen consecutive patients with dermatitis herpetiformis taking dapsone therapy received, in addition, 800 U/d of vitamin E for 4 weeks; then 1000 mg of vitamin C per day for 4 weeks, and, finally, combined vitamin E and vitamin C therapy for 4 weeks. Hemolysis indexes were assessed at baseline and after each 4-week period., Results: Statistical analysis of the results suggests that oral administration of 800 units of vitamin E daily for 4 weeks confers partial protective effect against dapsone-induced hemolysis in patients with dermatitis herpetiformis., Conclusion: Partial protection against dapsone-induced hemolysis by orally administered vitamin E, if confirmed as being clinically relevant by further trials, may allow clinicians to continue dapsone therapy orally in patients who develop significant hemolysis. Prophylactic vitamin E to minimize potential hemolysis at the initiation of dapsone therapy may also be appropriate.

Zinc concentration was determined in epidermis, papillary dermis and serum in patients with dermatitis herpetiformis, acne or psoriasis and in two small groups of patients with ichthyosis vulgaris and Darier's disease. Except in ichthyosis vulgaris the zinc level in epidermis was decreased in all these disorders. The mean serum zinc concentration was, however, significantly decreased only in men with dermatitis herpetiformis. There was no correlation between the concentration of zinc in epidermis or dermis and that in serum. The decreased epidermal zinc concentration indicates that many of the patients have a zinc deficiency in spite of a "normal" serum zinc value. Supplementation of zinc might therefore be of value in patients with these disorders.

The chemotactic response of polymorphonuclear leucocytes to the blister roof, the blister fluid and the floor of the bulla, the underlying papillary dermis with the basement membrnae, were studied by a modified Boyden-assay in four patients with dermatitis herpetiformis. In the same way experimental suction blisters of the peri-lesional skin were investigated. The blister roofs showed no chemotactic activity contrary to the blister fluid and especially the underlying papillary dermis which attracted polymorphonuclear leucocytes in a high degree.