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Dermatitis herpetiformis is a cutaneous form of celiac disease manifesting as an itching rash typically on the elbows, knees and buttocks. It is driven by the ingestion of gluten-containing cereals and characterized by granular deposits of immunoglobulin A in the papillary dermis. These antibodies target transglutaminase (TG) 3 and in the majority of patients they are also found in circulation. The circulating antibodies disappear and skin symptoms resolve as a result of gluten-free diet but the cutaneous anti-TG3 IgA deposits may persist for several years. In dermatitis herpetiformis, plasma cells secreting antibodies against TG3 are located in the intestinal mucosa similarly to those producing TG2 antibodies characteristic for celiac disease. In fact, both TG2- and TG3-specific plasma cells and gluten responsive T cells are found in dermatitis herpetiformis patients but the interplay between these cell populations is unknown. The small bowel mucosal damage in celiac disease is believed to be mediated by co-operation of cytotoxic intraepithelial T cells and the inflammatory milieu contributed by gluten-reactive CD4+ T cells, whereas the skin lesions in dermatitis herpetiformis appear to be devoid of gluten reactive T cells. Thus, how celiac disease-type intestinal T and B cell responses develop into an autoimmune condition affecting the skin is still incompletely understood. Finally, the skin and small bowel lesions may reappear upon reintroduction of gluten in patients treated with gluten-free diet but virtually nothing is known about the long-lived B cell and memory T cell populations activating in response to dietary gluten in dermatitis herpetiformis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kemppainen, Salmi and Lindfors.)

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 is a rare, chronic autoimmune disorder characterized by intense pruritic papules and vesicles, which can be associated with celiac disease and other autoimmune disorders. Its histologic characteristic is the accumulation of neutrophils within the papillary dermis with granular deposition of immunoglobulin A (IgA) observed under direct immunofluorescence. Herein, we report a 58-year-old woman who presented with a vesicular rash on the buttocks. The patient reported a recent history of genital herpes, Entamoeba histolytica colitis, recurrent hives, and eczema. A representative biopsy demonstrated features of spongiotic dermatitis and focal papillary dermal neutrophilic aggregates. Direct immunofluorescence revealed fibrillary IgA deposition in the papillary dermis, granular C3 deposition at the dermal-epidermal junction, and dermal papillae. The overall clinical, histologic, and DIF findings were consistent with those of dermatitis herpetiformis. The fibrillar IgA pattern is rare and easily overlooked by the unwary. Pathologists should be aware of this rare pattern, especially when the histologic findings are not classic.

Background: Indian data on dermatitis herpetiformis (DH) is not available. The aim of this study was to investigate the demographic and clinicopathological characteristics of patients with DH and to study its association with other autoimmune diseases., Methods: All data were collected from case record forms of patients registered in immunobullous disease clinic of our institute. The diagnosis was based on characteristic clinical and immuno/histopathological features., Results: A total of 65 patients were included, which constituted 9.47% of the registered patients in the immunobullous disease clinic over 3.5 years. The male to female ratio was 1.4 : 1; the average age was 44.35 ± 15.52 years. Direct immunofluorescence showed granular IgA deposits at the papillary tips in 83.07% and basement membrane zone in 12.3% patients. Sixteen (24.1%) patients had associated celiac disease, and 15 (23.07%) patients had other autoimmune comorbidities such as hypothyroidism. Forty percent of patients on strict gluten-free diet achieved remission in 2 years, while 35.4% had frequent relapses as they continued gluten intake., Conclusions: Dermatitis herpetiformis is not a rare disease in northern India as previously believed. The clinical, histological, and immunopathological characteristics of Indian DH patients are similar to those reported in Caucasian populations. The limitations of our study include an absence of genetic testing for HLA-DQ2 or DQ8, nonavailability of kits for detecting IgA specific for epidermal transglutaminase (IgA eTG), and short follow-up period., (© 2018 The International Society of Dermatology.)

In healthy skin, epidermis and dermis are anchored together at the dermal-epidermal junction (DEJ), a specialized basement membrane pivotal for skin integrity and function. However, increased inflammation in the DEJ is associated with the disruption and separation of this junction and sub-epidermal blistering. Granzyme B (GzmB) is a serine protease secreted by immune cells. Dysregulated inflammation may lead to increased GzmB accumulation and proteolysis in the extracellular milieu. Although elevated GzmB is observed at the level of the DEJ in inflammatory and blistering skin conditions, the present study is the first to explore GzmB in the context of DEJ degradation in autoimmune sub-epidermal blistering. In the present study, GzmB induced separation of the DEJ in healthy human skin. Subsequently, α6/β4 integrin, collagen VII, and collagen XVII were identified as extracellular substrates for GzmB through western blot, and specific cleavage sites were identified by mass spectrometry. In human bullous pemphigoid, dermatitis herpetiformis, and epidermolysis bullosa acquisita, GzmB was elevated at the DEJ when compared to healthy samples, while α6/β4 integrin, collagen VII, and collagen XVII were reduced or absent in the area of blistering. In summary, our results suggest that regardless of the initial causation of sub-epidermal blistering, GzmB activity is a common final pathway that could be amenable to a single targeted treatment approach.

Background: Elafin is a serine protease inhibitor that has various epithelial cell regulatory and immunomodulatory effects including inactivation of neutrophil elastases. This later role originated the interest of elafin in certain neutrophil-rich dermatoses. Interestingly, it has been speculated that elafin has a protective role by slowing the deamidation process of gliadin in celiac disease (CD), despite the typical absence of neutrophils in intestinal histologic samplings. Dermatitis herpetiformis (DH) is a chronic recurrent vesicular dermatitis associated with gluten hypersensitivity and also characterized by a neutrophilic infiltrate and granular immunoglobulin A deposits in papillary dermis., Materials and Methods: We selected 31 formalin-fixed paraffin-embedded skin specimens of DH that demonstrated typical immunopathologic findings and probed them with rabbit polyclonal immunoglobulinG antielafin antibodies through standard immunohistochemistry analysis. Negative controls consisted of normal skin from elbow and knee surgical re-excisions specimen lacking residual tumor. Positive controls included skin biopsies of active plaque psoriasis, Sweet syndrome, and pyoderma gangrenosum., Results: Similar to what has been previously reported in intestinal sampling of patients with active CD, abnormal expression of elafin was noted in virtually all probed skin biopsies of DH patients with active cutaneous disease., Conclusion: Under normal circumstances, keratinocytes overexpress elafin to downregulate a neutrophil mediated inflammatory response. The deficient expression of elafin in the aforementioned probed DH specimens correlates with previous similar elafin underexpression in intestinal samples of active CD. These histological findings suggest that these 2 gluten mediated disorders carry an abnormal elafin underexpression during disease activity.

Dermatitis herpetiformis (DH), bullous pemphigoid (BP), and pemphigus vulgaris (PV) are autoimmune bullous skin conditions with eosinophilic and neutrophilic infiltrations. While cytokines are crucial for the affinity and activation of different leukocyte cells in the inflammation and blister formation, there are no studies concerning a role of IL-36. The goal of the study was to analyze whether interleukin 36 is involved in pathogenesis of DH, BP, and PV. And the second aim of the study was the estimation of correlation between Il-36 and IL-17 and titers of specific antibodies in these diseases. Expression of IL-36 and IL-17 was detected in serum in all DH, BP, and PV samples. Serum levels of IL-36 and IL-17 α were statistically higher in DH, BP, and PV groups as compared to the control group. IL-36 α levels were statistically higher in DH patients, as compared to patients with PV and BP. Our results showed that IL-36 may be helpful in the diagnostic and monitoring of the activity of the disease. IL 36 may play a relevant role of enrolling eosinophils and neutrophils in DH, BP, and PV and finally provoke tissue injury.

A family of eleven proteins comprises the Janus kinases (JAK) and signal transducers and activators of transcription (STAT) signaling pathway, which enables transduction of signal from cytokine receptor to the nucleus and activation of transcription of target genes. Irregular functioning of the cascade may contribute to pathogenesis of autoimmune diseases; however, there are no reports concerning autoimmune bullous diseases yet to be published. The aim of this study was to evaluate the expression of proteins constituting the JAK/STAT signaling pathway in skin lesions and perilesional area in dermatitis herpetiformis (DH) and bullous pemphigoid (BP), as well as in the control group. Skin biopsies were collected from 21 DH patients, from 20 BP patients, and from 10 healthy volunteers. The localization and expression of selected STAT and JAK proteins were examined by immunohistochemistry and immunoblotting. We found significantly higher expression of JAK/STAT proteins in skin lesions in patients with BP and DH, in comparison to perilesional skin and the control group, which may be related to proinflammatory cytokine network and induction of inflammatory infiltrate in tissues. Our findings suggest that differences in the JAK and STAT expression may be related to distinct cytokines activating them and mediating neutrophilic and/or eosinophilic infiltrate.

There has been no previous systematic study of bullous skin diseases with granular basement membrane zone deposition exclusively of C3. In this study we collected 20 such patients, none of whom showed cutaneous vasculitis histopathologically. Oral dapsone and topical steroids were effective. Various serological tests detected no autoantibodies or autoantigens. Direct immunofluorescence for various complement components revealed deposition only of C3 and C5-C9, indicating that no known complement pathways were involved. Studies of in situ hybridization and micro-dissection with quantitative RT-PCR revealed a slight reduction in expression of C3 in patient epidermis. These patients may represent a new disease entity, for which we propose the term "granular C3 dermatosis". The mechanism for granular C3 deposition in these patients is unknown, but it is possible that the condition is caused by autoantibodies to skin or aberrant C3 expression in epidermal keratinocytes.

We propose a biochemical mechanism for celiac disease and non-celiac gluten sensitivity that may rationalize many of the extradigestive disorders not explained by the current immunogenetic model. Our hypothesis is based on the homology between the 33-mer gliadin peptide and a component of the NMDA glutamate receptor ion channel - the human GRINA protein - using BLASTP software. Based on this homology the 33-mer may act as a natural antagonist interfering with the normal interactions of GRINA and its partners. The theory is supported by numerous independent data from the literature, and provides a mechanistic link with otherwise unrelated disorders, such as cleft lip and palate, thyroid dysfunction, restless legs syndrome, depression, ataxia, hearing loss, fibromyalgia, dermatitis herpetiformis, schizophrenia, toxoplasmosis, anemia, osteopenia, Fabry disease, Barret's adenocarcinoma, neuroblastoma, urinary incontinence, recurrent miscarriage, cardiac anomalies, reduced risk of breast cancer, stiff person syndrome, etc. The hypothesis also anticipates better animal models, and has the potential to open new avenues of research., (© 2016 WILEY Periodicals, Inc.)

Objevtive: To investigate the expression of transient receptor potential lvanilloidreceptor 4 (TRPV4) protein in pemphigus vulgaris (PV), bullous pemphigoid (BP), dermatitis herpetiformis (DH), and epidermolysis bullosa acquisita (EBA), and explore the role of TRPV4 in the pathogenesis of these diseases., Methods: TRPV4 protein in normal skin tissues and lesions of PV, BP, DH, and EBA were detected with immunohistochemistry., Results: The positivity rate of TRPV4 protein expression was 61.90% in PV, 81.81% in BP, 72.22% in DH, and 68.42% in EBA. TRPV4-positive rates in these lesions were significantly lower than the rate in normal skin tissues (93.33%) and also differed significantly among these lesions (PV

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.)

Regulatory T cells (Tregs) play a crucial role by maintaining the peripheral tolerance and inhibiting autoimmunity. In recent years, numerous autoimmune and immune-mediated diseases have been shown to present significant number depletion and/or function impairment of this subset. In the present study, we present a brief overview of the results obtained by our group in association with the centers belonging to the Italian Immunopathology Group, as to the expression levels and biological significance of circulating regulatory CD4+CD25+brightFOXP3+ T cells in a variety of immune-mediated skin diseases (such as psoriasis, scleroderma, bullous pemphigoid and GvHD), together with preliminary results achieved in patients with inflammatory bowel disease-related dermatoses. This review shows that this series of different cutaneous diseases characterised by an immune-mediated pathogenesis, share a significant down-regulation of circulating FOXP3+ Treg cells, whilst the treatment and the achievement of clinical response are generally associated with an opposite phenomenon with up-regulation of Treg cells. Future studies are mandatory to identify the effective role of these modifications in the disease pathogenesis as well as its relationship with the clinical response.

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.

The initial development and maintenance of tolerance to dietary antigens is a complex process that, when prevented or interrupted, can lead to human disease. Understanding the mechanisms by which tolerance to specific dietary antigens is attained and maintained is crucial to our understanding of the pathogenesis of diseases related to intolerance of specific dietary antigens. Two diseases that are the result of intolerance to a dietary antigen are celiac disease (CD) and dermatitis herpetiformis (DH). Both of these diseases are dependent upon the ingestion of gluten (the protein fraction of wheat, rye, and barley) and manifest in the gastrointestinal tract and skin, respectively. These gluten-sensitive diseases are two examples of how devastating abnormal immune responses to a ubiquitous food can be. The well-recognized risk genotype for both is conferred by either of the HLA class II molecules DQ2 or DQ8. However, only a minority of individuals who carry these molecules will develop either disease. Also of interest is that the age at diagnosis can range from infancy to 70-80 years of age. This would indicate that intolerance to gluten may potentially be the result of two different phenomena. The first would be that, for various reasons, tolerance to gluten never developed in certain individuals, but that for other individuals, prior tolerance to gluten was lost at some point after childhood. Of recent interest is the concept of non-celiac gluten sensitivity, which manifests as chronic digestive or neurologic symptoms due to gluten, but through mechanisms that remain to be elucidated. This review will address how animal models of gluten-sensitive disorders have substantially contributed to a better understanding of how gluten intolerance can arise and cause disease.

Bullous pemphigoid (BP) and dermatitis herpetiformis (DH) are chronic subepidermal bullous diseases, which progress together with an itch and an inflammatory reaction. These symptoms may be the cause of a phenomenon described in the literature as a neurogenic skin inflammation. Neuropeptides are one of the mediators which take part in this process. The aim of our study was to indicate the expression of selected neuropeptides - CRF (corticotropin releasing factor), CGRP (calcitonin gene-related peptide), NKB (neurokinin B), SP (substance P) and the receptor for endothelin B (ETRB) - in the skin of patients suffering from BP or DH. A significantly increased expression of CRF was found in the specimen collected from the skin lesions of patients with BP and DH as well as a significantly increased expression of receptor for endothelin B in the patients with DH by the immunohistochemical method. The results obtained give evidence of a possible participation of CRF and receptor for endothelin B in the pathogenesis of the itch in the dermatitis herpetiformis as well as CRF in bullous pemphigoid.

The role of the process of apoptosis is investigated in the pathogenesis of many autoimmune diseases; however at present, there is not much information about its role in dermatitis herpetiformis. Skin biopsies were taken from 18 DH patients and from 10 healthy subjects. The localization and expression of Bax, Fas, FasL, TRAIL, TRAIL-R in skin lesions, and perilesional skin were studied by immunohistochemistry. Expression of Bax, Fas, and Fas ligand was detected in the keratinocytes in skin biopsies from DH patients. Expression of TRAIL and TRAIL receptor was confirmed in epidermis, infiltration cells, and some fibroblasts. The expression of examined molecules in biopsies from healthy people was observed only in single cells. There were statistically significant differences between lesional, perilesional, and healthy skin of control group in Bax expression analysis and between lesional skin and control group in Fas, FasL, and TRAIL expression. There were statistically significant differences between control group and perilesional skin in Bax and FasL expression. Our results show that selected proapoptotic molecules may take part in pathogenesis of dermatitis herpetiformis, but the role of apoptosis in this process is not clear.

Dermatitis herpetiformis (DH) and bullous pemphigoid (BP) are autoimmune diseases characterized by destruction of the basement membrane zone (BMZ) and anchoring fibres by autoantibodies and infiltration. Adhesion molecules can take part in these phenomena. Skin biopsies were taken from 13 patients with DH, 21 with BP, and from 10 healthy subjects. The localization and expression of E and L selectins and beta1, beta3, beta4 integrins were studied by immunohistochemistry. Expression of selectins was detected mainly in the skin leukocytes in all samples. Expression of beta1, beta3 integrins was detected mainly in basal keratinocytes. Expression of beta 4 integrin was irregular and detected mainly in the blister. Our results suggest that integrins and selectins may play an important role in the destruction of BMZ in DH and BP. The elucidation of the role of adhesion molecules in the pathogenesis of bullous diseases may be helpful in the development of new targeted therapies.

The majority of patients with dermatitis herpetiformis (DH) have small intestinal enteropathy that may result in bone loss. The objective of this study was to evaluate bone mineral density (BMD) in DH and to examine whether dietary treatment or degree of the small intestinal lesion correlate with BMD. Twenty-five patients with DH (18 men) were investigated. Detailed dietary assessment and duodenal biopsies were performed on all patients before entry into the study. BMD at lumbar spine and femur was determined by DXA scan. Bone biomarkers, vitamin D, and parathyroid status were assessed. Twenty patients had enteropathy. None of the patients had hypovitaminosis D or secondary hyperparathyroidism. Resorption and formation markers were within normal limits. BMD Z-scores were not significantly different from expected (-0.38; CI, -0.84 to 0.07) and femur (0.46; CI, -0.06 to 0.97). There was no relationship between BMD Z-scores and the severity of the degree of enteropathy. We conclude that enteropathy of differing severity is present in 80% of patients with DH, but this is not associated with bone disease.

Although the specific IgA autoantibody responsible for the pathogenesis of dermatitis herpetiformis (DH) is unknown, the presence of IgA is considered essential in the pathogenesis of DH. To date, no cases of IgA deficiency have been reported in DH. In contrast, IgA deficiency is found in 2% to 3% of patients with celiac disease, a rate 10 to 15 times higher than the normal population. We report 2 patients with DH who also have partial IgA deficiency. We evaluated the sera of these patients for the presence of IgA autoantibodies to endomysium, tissue transglutaminase, epidermal transglutaminase, and gliadin. Both patients were found to have IgA endomysial and tissue transglutaminase antibodies, and serologic markers for DH. Corresponding IgG autoantibodies were not useful serologic markers of DH in the setting of IgA deficiency, as they often are in celiac disease. We then screened 98 DH sera for total IgA levels and identified 1 additional case with IgA deficiency. In conclusion, DH may develop in patients with partial IgA deficiency, indicating that pathogenically directed IgA antibodies are likely sufficient for cutaneous IgA deposition in this disease.

Dermatitis herpetiformis (DH) is a subepidermal autoimmune disease characterized by skin and intestinal lesions consistent with coeliac disease. There are also some data that metalloproteinases (MMPs) are involved in the development of skin lesions in DH, however their exact role in this process is not fully understood. The aim of the study was to investigate whether MMPs and their inhibitors are involved in pathogenesis of DH. Skin biopsies were taken from 13 patients with active DH and from 10 healthy subjects. The localization and expression of MMPs and TIMPs were examined by immunohistochemistry. MMPs expression was detected in basal keratinocytes and in the whole epidermis in all of the DH subjects. Neutrophils in microabscesses and in blister fluid were also positive for MMPs. Expression of TIMPs was moderate or weak in all examined biopsies. Our results allow us to conclude that imbalance between these enzymes takes an important role in the pathogenesis of DH.

Background: Dermatitis herpetiformis may be regarded as the cutaneous counterpart of coeliac disease. These conditions are related to the ingestion of gluten and both are characterised by circulating antibodies against tissue transglutaminase., Aims: To study the distribution of tissue transglutaminase in the skin of dermatitis herpetiformis patients and controls, and to investigate whether the dermal IgA deposits, diagnostic for dermatitis herpetiformis, are related to tissue transglutaminase expression in the skin., Methods: A series of 11 patients with dermatitis herpetiformis had a 4 mm punch biopsy taken from the uninvolved perilesional skin. A group of 16 controls, undergoing surgical removal of benign nevi, gave perilesional skin. Biopsies were covered with OCT and frozen at -80 degrees C. After washing, skin biopsy sections were incubated with an IgG anti-tissue transglutaminase mouse monoclonal antibody. After washing, sections were incubated with anti-mouse IgG., Results: The anti-tissue transglutaminase monoclonal antibody specifically recognised the basal epidermal cells. This staining was no different between patients and controls., Conclusion: Our results suggest that tissue transglutaminase can be recognised in the basal epidermal layer both of patients with dermatitis herpetiformis and controls. Since this distribution does not correspond to the distribution of dermal IgA deposits, it is concluded that dermatitis herpetiformis dermal IgA deposits are not due to antibodies directed against cutaneous tissue transglutaminase.

Intraepithelial gammadelta T cells are increased in the inflamed small bowel and are also found in increased numbers in cutaneous lesions from patients with dermatitis herpetiformis (DH). Thus, these cells might play an important role in the pathogenesis of the disease. We investigated the T-cell receptor (TCR) delta repertoire in involved and non-involved skin and compared it with the TCR delta repertoire of the inflamed duodenum and peripheral blood of the same patients. An identical TCR delta repertoire in the small bowel and in the cutaneous lesions would suggest a migration of antigen-specific gammadelta T cells from the intestine to the skin which cross-react with cutaneous antigens. T-cell receptor DV1-DV3 transcripts were amplified by reverse transcriptase (RT)-PCR and analyzed by complementarity determining region 3 (CDR3) size spectratyping and nucleotide sequencing. Our results indicate that the cutaneous TCR delta repertoires were oligoclonal and identical dominant gammadelta T-cell clones were present in the involved and non-involved skin. Furthermore, the TCR delta repertoire of the skin was distinct from that in the small bowel. The peripheral blood exhibited a restricted TCR delta repertoire, which differed from that in the intestine and skin. Thus, cutaneous gammadelta T cells are not specifically expanded within the involved skin and are unlikely to be derived from the inflamed duodenum.

Background: The dermal and perivascular infiltrate in dermatitis herpetiformis (DH), which is mainly composed of CD4+ lymphocytes, neutrophils and eosinophils, is believed to play an important part in the pathogenesis of the disease. Previous studies suggest that cytokines such as interleukin (IL) -8, granulocyte-macrophage colony-stimulating factor, IL-4 and IL-5 could be involved in the pathogenesis of DH. These cytokines appear to drive tissue infiltration and maturation of eosinophils. Part of the effect of T-helper (Th) 2-type cytokines (IL-4, IL-5) on eosinophils could be mediated by eotaxin, which is a highly specific chemotactic protein induced by various cytokines [IL-4, IL-13, tumour necrosis factor (TNF) -alpha and interferon-gamma]., Objectives: To evaluate the expression of eotaxin and its inducers, IL-13 and TNF-alpha, in DH. METHODS We examined lesions collected from 10 DH patients with active disease. Sections from each specimen were incubated with anti-IL-13, anti-TNF-alpha and anti-eotaxin antibodies. Chloroacetyl esterase reaction was performed to show mast cell infiltration., Results: Eotaxin was mainly expressed at the tips of the dermal papillae, within the microabscesses. Positivity was also found in the lymphomonocytic infiltrate in the dermis. IL-13 was expressed in the dermal infiltrate and TNF-alpha was found in the inflammatory infiltrate and in dermal vascular cells., Conclusions: These findings confirm the importance of the lymphomonocytic infiltrate and of Th2 cytokines in the pathogenesis of this disease, suggesting that tissue infiltration in DH is mediated by cell-specific chemokines such as eotaxin and not only by non-specific chemokines such as IL-8.

Dermatitis herpetiformis is a gluten-sensitive skin disease with intestinal lesions and malabsorption symptoms less severe than those found in celiac disease. While several studies have shown the occurrence of osteopenia in celiac disease, bone mass and metabolism have never before been evaluated in dermatitis herpetiformis. Therefore, in 16 untreated patients, 16 sex- and age-matched untreated celiac patients, and 16 sex- and age-matched healthy volunteers, lumbar and femoral bone mineral density were measured and bone and mineral metabolism and nutritional status were evaluated. All these parameters were significantly altered in the two groups of patients and although the degree of these alterations was milder in patients with dermatitis herpetiformis than in celiac patients, the presence of subtotal villous atrophy in patients with dermatitis herpetiformis was associated with the presence of more severe alterations. Bone mineral density was significantly correlated with nutritional status, and patients showing bone loss were characterized by a body mass index lower than 20. Alterations of bone mass and mineral metabolism complicate dermatitis herpetiformis when severe intestinal lesions coexist. A low nutritional status may be predictive of the presence of bone loss.

Although possessing a morphologically similar small bowel abnormality to patients with isolated gluten-sensitive enteropathy (GSE), patients with dermatitis herpetiformis (DH) have few gastrointestinal symptoms and exhibit blistering skin lesions and cutaneous IgA deposits. To determine whether clinical discrepancies between these gluten-sensitive conditions might be the result of different patterns of small bowel cytokine expression, duodenal biopsies were obtained from eight DH patients and nine isolated GSE patients. Biopsies were evaluated for interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) expression by reverse-transcriptase polymerase chain reaction (message) and immunohistochemistry (protein). In DH patients, most of whom had no gut symptoms, IFN-gamma mRNA expression was significantly less than in isolated GSE patients with symptomatic gut disease. Conversely, IL-4 mRNA expression in DH patients was greater than that found among isolated GSE patients. These findings suggest that the different clinical phenotypes of gluten sensitivity may be caused by variation in cytokine expression in the small bowel response to gluten.

Accumulation of inflammatory cells such as macrophages may lead to degeneration of connective tissue matrix in various skin diseases. Macrophage metalloelastase, is a matrix metalloproteinase (MMP-12) capable of degrading elastin as well as various basement membrane components. To investigate the role of human macrophage metalloelastase in skin, we assessed by in situ hybridization and immunohistochemistry 66 specimens representing skin diseases characterized either by changes in elastic fibers or by pronounced infiltrations of extravasating and migrating macrophages. CD68 immunostaining was performed to identify the human macrophage metalloelastase-positive cells and Weigert's Resorcin-Fuchsin staining to reveal the status of elastic fibers. We found abundant expression of human macrophage metalloelastase mRNA in macrophages in areas devoid of normal elastic fibers in granulomatous skin diseases sarcoidosis, necrobiosis lipoidica diabeticorum, and granuloma annulare. Positive cells for human macrophage metalloelastase protein could be detected in the same regions as well as positive immunostaining for urokinase plasminogen activator. Of the other matrix metalloproteinases capable of degrading elastin, 92 kDa gelatinase colocalized with human macrophage metalloelastase, while 72 kDa gelatinase was produced by surrounding fibroblast-like cells. Furthermore, human macrophage metalloelastase was expressed by macrophages in areas with disrupted basement membrane, as assessed by type IV collagen staining, in pityriasis lichenoides and dermatitis herpetiformis. Specimens of anetoderma, acrodermatitis chronica atrophicans and pseudoxanthoma elasticum showed no signal for human macrophage metalloelastase. Matrilysin was not detected in any of the samples investigated. Our study suggests that human macrophage metalloelastase may contribute to elastin degradation occurring in granulomatous skin diseases and may aid macrophage migration through the epidermal and vascular basement membranes in inflammatory disorders.

Background: We investigated whether wheat starch-based gluten-free products are safe in the treatment of gluten intolerance., Methods: The study involved 41 children and adults with coeliac disease and 11 adults with dermatitis herpetiformis adhering to a gluten-free diet for 8 years on average. Thirty-five newly diagnosed coeliac patients at diagnosis and 6 to 24 months after the start of a gluten-free diet and 27 non-coeliac patients with dyspepsia were investigated for comparison. Daily dietary gluten and wheat starch intake were calculated. Small-bowel mucosal villous architecture, CD3+, alphabeta+, and gammadelta+ intraepithelial lymphocytes, mucosal HLA-DR expression, and serum endomysial, reticulin, and gliadin antibodies were investigated., Results: Forty of 52 long-term-treated patients adhered to a strict wheat starch-based diet and 6 to a strict naturally gluten-free diet; 6 patients had dietary lapses. In the 46 patients on a strict diet the villous architecture, enterocyte height, and density of alphabeta+ intraepithelial lymphocytes were similar to those in non-coeliac subjects and better than in short-term-treated coeliac patients. The density of gammadelta(+)cells was higher, but they seemed to decrease over time with the gluten-free diet. Wheat starch-based gluten-free flour products did not cause aberrant upregulation of mucosal HLA-DR. The mucosal integrity was not dependent on the daily intake of wheat starch in all patients on a strict diet, whereas two of the six patients with dietary lapses had villous atrophy and positive serology., Conclusion: Wheat starch-based gluten-free flour products were not harmful in the treatment of coeliac disease and dermatitis herpetiformis.

Recent BP230-knockout experiments with subsequent blistering and recently identified plectin/HD1 mutations in epidermolysis bullosa simplex patients suggest that defective expression of BP230 and plectin/HD1 may predispose to blister formation in human skin. We have studied the expression of the epithelial adhesion complex as well as the basement membrane and anchoring fibril antigens in uninvolved dermatitis herpetiformis skin to find out if alterations can be detected in these structures predisposing to the blister formation typical of the disease. Ten uninvolved dermatitis herpetiformis skin specimens, which all showed clear granular deposits of IgA under the basement membrane in direct immunofluorescence and five normal skin specimens, were studied by indirect immunofluorescence technique. Six uninvolved dermatitis herpetiformis skin specimens showed distinctly decreased immunoreaction for BP230 and four uninvolved dermatitis herpetiformis skin specimens showed distinctly decreased immunoreaction for plectin/HD1. All five skin controls showed strong immunoreactions for BP230 and plectin/HD1. Other hemidesmosomal proteins including BP180 and integrin alpha6beta4, as well as basement membrane proteins laminin-5, laminin-1, nidogen and type IV collagen, and the anchoring fibril protein type VII collagen showed a normal strong expression. Our results suggest that alterations in BP230 and plectin/HD1 may contribute or predispose to blister formation in dermatitis herpetiformis skin.

Background: In autoimmune bullous skin diseases, accumulation of neutrophils and/or eosinophils in the affected skin represents a characteristic feature. So far, however, the induction of this granulocyte infiltration has not been elucidated., Objective: Regarding their biological effects, the chemokines interleukin 8 (IL-8) and RANTES (regulated upon activation normal T lymphocyte expressed and secreted) could play a role in this granulocyte accumulation., Methods: Immunohistochemical examination of lesional skin from patients with bullous pemphigoid, pemphigus, dermatitis herpetiformis and linear IgA disease was performed using a set of different antibodies against IL-8 and RANTES. Additionally, blister fluids were screened for soluble RANTES peptide using an ELISA., Results: No difference in chemokine expression was found in lesions of autoimmune bullous diseases compared to normal skin., Conclusion: In contrast to chronic inflammatory diseases like psoriasis and eczema, where keratinocyte IL-8 immunoreactivity was found to differ from normal skin, keratinocyte immunoreactivity is not altered in autoimmune bullous diseases.

We studied the temporal expression of interstitial collagenase, stromelysin-1 and -2, and urokinase plasminogen activator (uPA) mRNAs by in situ hybridization in eight patients with dermatitis herpetiformis. To induce blisters, 50% potassium iodide patch tests were performed, and serial biopsy specimens were taken at 4, 12, and 24 h. Additional samples were taken from occasional spontaneous blisters. Components of the basement membrane, laminin-5, laminin-1, and type VII collagen, were examined immunohistochemically in relation to matrix metalloproteinase expression. At 12 h, when no blisters were seen, uPA mRNA was present in basal keratinocytes in five of eight samples, whereas interstitial collagenase and stromelysin-1 mRNA were not detected. At this time, immunohistochemistry failed to show changes in the basement membrane. At 24 h, uPA, collagenase, and stromelysin-1 mRNAs were present in basal keratinocytes, suggesting an activation of latent forms of the two latter enzymes by the uPA-plasmin pathway. Signal for stromelysin-2 was not detected. Furthermore, disruptions of laminin-1 and type VII collagen were evident. The data suggest that stromelysin-1 and interstitial collagenase may contribute to the degradation of basement membrane in dermatitis herpetiformis. Intracellular staining for laminin-5 co-localized with collagenase mRNA in basal keratinocytes. Because laminin-5 is essential for adhesion of keratinocytes to basement membrane and for establishment of focal adhesions on migrating cells, its production may reflect a regenerative response after the destruction of basement membrane components.

Objective: To compare the deposition of IgA and C3 in the skin of patients with active dermatitis herpetiformis relative to the sites of disease., Design: In the phase 1 study, skin biopsy specimens were obtained from erythematous perilesional skin, nonerythematous perilesional skin, and never-involved skin. In the phase 2 study, specimens from the nonerythematous perilesional and uninvolved skin from the same anatomic region were sampled., Setting: The Dermatology Clinic at the University of Utah Health Sciences Center, Salt Lake City., Patients: Patients with known dermatitis herpetiformis: 19 patients in the phase 1 study and 15 patients in the phase 2 study. Suppressive medications were stopped for 48 to 72 hours after biopsy specimens were obtained. All patients had active disease at the time that biopsy specimens were taken., Main Outcome Measure: The intensity of IgA and C3 immunofluorescent staining in 6 sections from each skin biopsy specimen was graded by using a semiquantitative scale (0 to 3+) in a blinded fashion by a single observer., Results: Deposition of IgA was more intense in noninflamed perilesional skin in 11 of 19 patients compared with that in erythematous skin (P < .05). Erythematous skin was negative for IgA in 16% (3/19) of the specimens. Noninflamed perilesional skin showed more intense IgA deposition in 18 of 19 specimens compared with that in never-involved skin (P < .01); C3 was more intense in erythematous skin (P < .01). In the phase 2 study, skin from the same anatomic region revealed greater deposition of IgA near lesions in 12 of 15 patients (P < .001)., Conclusions: In patients with dermatitis herpetiformis, IgA is not uniformly distributed throughout the skin, and IgA is present in greater amounts near active lesions. The preferred biopsy site for the diagnosis of dermatitis herpetiformis is normal-appearing skin that is adjacent to an active lesion.

Background: In the pathogenesis of dermatitis herpetiformis the participation of some proteins of the extracellular matrix has not been elucidated so far. They are found more amply in the papillary derma where they are manifested most markedly as the mentioned type of dermatosis. The objective of the present work was to assess the participation of components of the extracellular matrix in the pathogenesis of diseases and the possibility of their detection to make a more accurate diagnosis., Methods and Results: In a group of 11 patients (mean age 39 +/- 17 years) with dermatitis herpetiformis the diagnosis was established on the basis of the clinical and histological finding. Fibronectin and collagens type I, III, IV, V were assessed in the skin using rabbit antisera (INPHARM Co. Moscow). An elevated level of collagen type III and V was found in the affected papillae and on the floor of the blisters in the papillary derma, collagen type IV on the vault of the blister and fibronectin deposits in the affected papillae which had a netlike structure., Conclusions: Based on the above findings assessment of fibronectin, collagens type III, IV and V in the affected skin can be considered an important supplementary examination in the histological diagnosis of dermatitis herpetiformis.

Because dermatitis herpetiformis is characterized by neutrophilic inflammation and destructive changes in the basement membrane zone, we studied the in situ expression of interstitial collagenase and stromelysin-1 in 11 lesions. A prominent signal for collagenase mRNA was consistently detected in the basal keratinocytes of rete ridges surrounding the neutrophilic abscesses in 10 of 11 lesions, and the expression was independent of the age of the lesion and the migratory state of the basal keratinocytes. Expression of stromelysin-1 was detected in seven of 11 lesions and co-localized with collagenase. No expression of the 92-kDa gelatinase mRNA or matrilysin protein was found in the vicinity of neutrophilic accumulations or the damaged basement membrane. Urokinase-type plasminogen activator mRNA was found in basal keratinocytes in seven of nine samples. Collagenase, stromelysin-1, and urokinase-type plasminogen activator were not expressed in normal-appearing skin of patients with dermatitis herpetiformis. Our results suggest that in lesions of dermatitis herpetiformis, collagenase and stromelysin-1 may be induced in basal keratinocytes by neutrophil cytokines or by altered cell-matrix interactions through contact of keratinocytes with the matrix due to damaged basement membrane. Stromelysin-1, in particular, may contribute to formation of blisters by degrading basement membrane components.

A 59 year old man is presented with a diagnosis of dermatitis herpetiformis. Duodenal and skin biopsy specimens from blisters of both recent and late onset were collected before treatment. Electron microscopy, immunohistochemistry, and in situ hybridisation were performed to analyse the presence of activated eosinophils and the local synthesis of interleukin 5 (IL5). Parallel state of eosinophil activation and IL5 synthesis was found in the duodenal mucosa with total flat mucosa and in skin vesicles of recent onset. It is suggested that duodenal and cutaneous eosinophils can synthesise IL5 and then participate in small bowel and skin lesions.

Using standard immunohistochemical methods, routinely processed sections, and a polyclonal antibody to Type IV collagen, we have determined the location of Type IV collagen, a substance located in the lamina densa of basement membrane, in a spectrum of acquired subepidermal bullous diseases. Type IV collagen was attached to the blister roof in five cases of well-established epidermolysis bullosa acquisita and to the blister base in 25 cases of bullous pemphigoid, four cases of dermatitis herpetiformis and 12 cases of porphyria cutanea tarda. Immunohistochemical localization of Type IV collagen in epidermal-dermal basement membrane is a simple, rapid and reliable technique which can be utilized to exclude and possibly to confirm the diagnosis of epidermolysis bullosa acquisita in routinely fixed paraffin-embedded tissues.

The PGE2 and PGF2 alpha content of bullae developing spontaneously on the skin was investigated by radioimmunoassay in 12 patients with different skin diseases. The PGF2 alpha level was also established in the plasma and urine. In herpes gestationis, dermatitis herpetiformis and bullous erysipelas the PGE2 and PGF2 alpha content of the bullae considerably exceeded the plasma and urinary PG levels. The findings were thought to be in relation with the acute inflammation of the skin, the mechanism of bulla formation as well as with pruritus.

Skin lesions were produced by application of 50% potassium iodide to twelve patients with dermatitis herpetiformis (DH). Perivascular cellular infiltrates were found to be characteristic of developing lesions. The cells were mainly round cells; alpha-naphthyl acetate esterase staining revealed that in 24-h lesions the mean percentage of T-lymphocytes was 43%, that of mononuclear phagocytes 6% and that of non-T/non-M cells (mainly B-lymphocytes) 44%. The percentage of the latter was highest (mean 81%) in 6-h specimens, suggesting that these cells are participating in the early stages of lesion formation. The infiltrating cells in dermal papillae and within subepidermal vesicles were predominantly polymorphonuclear leukocytes (mean 86%) with some mononuclear phagocytes and non-T/non-M cells. Immunofluorescence examination confirmed that fibrin deposition is characteristic of the initial lesions of DH and showed that the same is true of fibronectin. Seven out of eight patients had fibronectin deposits in dermal papillae. IgA was found in all and C3 in most of the specimens and, with the exception of papillary vesicles and blister cavities, the intensity of IgA and C3 fluorescence showed no marked alterations during the development of lesions.

Juvenile dermatitis herpetiformis occurred in a 20-month-old girl. She had granular lgA, C3, and fibrin bound to the basement membrane zone of the skin by direct immunofluorescence and negative serum antibodies against the skin on indirect immunofluorescence. The HLA typing of peripheral lymphocytes was A1, Aw30, B8, Bw51 without clinical evidence of malabsorption syndrome. A rapid improvement was observed on dapsone therapy. These findings strongly suggest that juvenile dermatitis hepetiformis is a disease entity different from chronic bullous dermatosis of childhood.

Iron absorption has been studied in patients with dermatitis herpetiformis (DH). Four patients out of 20 had iron deficiency, defined as absence of or only traces of haemosiderin in bone marrow smears. These four had adequate absorption of ferrous iron. The iron deficiency in at least 3 of them was ascribed to increased iron loss. The results indicate that, although having a mild to moderate malabsorption syndrome, DH patients can be expected to exhibit adequate absorption of orally administered iron. Explanations of a negative iron balance other than defective absorption should therefore be sought.