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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.

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.

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.

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.

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.

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: 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.

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 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.

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.

Polymorphonuclear leukocyte chemotaxis was investigated in 15 patients with dermatitis herpetiformis and was found not to be significantly increased when compared with the polymorphonuclear leukocyte chemotaxis of 15 normal healthy controls. These results indicate that accumulations of polymorphonuclear leukocytes found in the skin of patients with dermatitis herpetiformis are not due to an increased responsiveness of polymorphonuclear leukocytes to a chemotactic factor.

We have developed a triple sandwich enzyme immunoassay to detect circulating gluten in human sera. With human sera containing known amounts of added gluten as controls, the assay was sensitive in the range of 0.75 to 75 micrograms of gluten per ml of serum. Forty-one control subjects were compared to 21 patients with dermatitis herpetiformis and 11 patients with celiac disease. The dermatitis herpetiformis and celiac disease patients had significant elevation of serum gluten values over the control subjects. Circulating gluten antigenemia is a previously unrecognized feature which may be important in understanding the pathogenesis of dermatitis herpetiformis and celiac disease.

In order to study the development of atrophic gastritis, gastric secretory function was examined by a standard pentagastrin test 24 to 78 months after a previous examination (Ex I). The study included 12 patients with dermatitis herpetiformis (DH), 6 patients with functional signs of atrophic gastritis previously, and 8 healthy controls. The surrent examination (Ex II) also included microbiological culture of gastric juice and estimation of gastrin(s), parietal cell and thyroidal antibodies. Most of the controls had increased their maximum acidity and maximum acid output (MAO) between the examinations. This may indicate an altered potency of pentagastrin in recent years. Conversely, 5 of the 6 patients with atrophic gastritis showed a further reduction of maximum acidity and MAO, indicating progressive parietal cell atrophy. In the DH-group, two tendencies were observed: 6/12 patients had an increased MAO at Ex II. They had had lower mean age and higher mean MAO at Ex I, as compared with the remaining 6 patients who had a decreased MAO at Ex II. The latter group more often had parietal cell antibodies.

A woman, aged 66, fulfilled all the usual criteria of dermatitis herpetiformis. Subsequently, she developed circulating IgA and IgM basement membrane zone antibodies, a labile erythrocyte sedimentation rate (ESR), and the clinical picture changed to one of bullous pemphigoid. Her labile ESR was obviously caused by a factor related to the erythrocytes. Direct Coombs test was positive.

Polymorphonuclear leucocyte chemotaxis was investigated in 6 patients with active dermatitis herpetiformis in the untreated state and when under control with Dapsone. Control studies were undertaken in 7 healthy volunteers. No significant difference in chemotaxis was demonstrated between the active, treated and control groups. Furthermore, when Dapsone in physiological concentrations was added separately in all three groups there was no additional effect on chemotaxis. These results clearly show that polymorphonuclear leucocytes from active untreated dermatitis herpetiformis have normal chemotactic activity compared with those from the same patients in the treated state and controls. Additional Dapsone did not alter these findings.

Skin and serum zinc measurements have been made in patients with leprosy with and without trophic skin ulceration and in several other groups. Serum zinc concentrations were decreased in leprosy irrespective of the presence or absence of skin ulceration. Serum zinc concentrations in leprosy were also unrelated to smears positive for Mycobacterium leprae and to the clinical type of leprosy. Since a decrease of the serum zinc was also found in patients with dermatitis herpetiformis and pulmonary tuberculosis it seems likely that the decreased serum zinc in leprosy is a nonspecific metabolic consequence of chronic skin and internal disease. The mean skin zinc concentration in leprosy did not differ significantly from the corresponding value in control subjects, the lack of agreement between serum and skin concentrations being possibly related to the presence of nonexchangeable keratin-bound zinc in skin. Though the clinical significance of lowered serum zinc concentrations in leprosy is uncertain therapeutic trials of zinc treatment in leprosy with trophic skin ulceration seem justifiable.

Seventeen patients with dermatitis herpetiformis were tested for gastric hydrochloric acid secretion. Seven were found to be achlorhydric. Atrophic gastritis in these patients probably had an auto-immune pathogenesis, as judged by elevated serum gastrin level, high prevalence of antibodies against gastric parietal cells and antrum sparing of the gastric atrophy. This type of atrophic gastritis is considered to indicate a precursor state to pernicious anemia.

The low levels of glutathione-peroxidase in blood from patients with dermatitis herpetiformis increased after 5 months selenium and vitamin E treatment. In this double-blind study no significant clinical improvement was, however, noted.