Sequential studies of gliadin antibodies in patients with dermatitis herpetiformis

Summary Sequential studies of circulating gliadin antibodies (IgG, IgA, IgM, IgD) were performed in 24 patients with dermatitis herpetiformis (DH) by an ELISA. Three groups of patients were studied: (a) 14 patients who responded to a gluten-free diet and were able to stop their drug therapy, (b) 5 patients who did not respond to a gluten-free diet, (c) 5 patients with normal jejunal biopsies, who did not receive a gluten-free diet. Most of the serum gliadin antibodies detected were of IgG class, but in several patients IgA gliadin antibodies were found in addition. When the patients were on a normal diet, 63% had elevated IgG gliadin antibody titres (titres which exceeded the maximum titre of the controls by one dilution) and there were no significant differences between the three groups. When the patients were followed up, there was a significant fall in the gliadin antibody titres in those who responded to a gluten-free diet compared to the two other groups of patients. Thus assays of IgG gliadin antibodies might be helpful in some patients in judging the complicance of patients on a gluten-free diet.     

Antiendomysial antibody — useful serological indicator of dermatitis herpetiformis

Summary Antiendomysial antibodies (EmA) of the IgA class are directed against reticulin components of the primate smooth muscle and are markers of gluten-sensitive enteropathy. These antibodies occur in essentially all active cases of celiac disease and in about 70% of dermatitis herpetiformis (DH) patients. IgA deposits in the dermal papillae of the skin are the hallmark of DH and are employed routinely in establishing its diagnosis. The incidence of IgA deposits in skin varies depending upon the site and type of biopsy specimen taken.We studied sera and skin biopsy specimens for EmA and for IgA deposits in the skin from 11 DH patients. EmA were detected in the sera of 10 of the 11 cases. Of these 11 patients, 9 were positive for IgA deposits in their skin, as revealed by direct immunofluorescence (IF). The immune deposits were detected in the normal, and not in the lesional skin. DH cases that were initially negative on biopsy and serum positive for EmA were found to be positive when a repeat biopsy of the normal skin was performed. Thus, serological studies in conjunction with direct IF studies of the normal skin are useful in making a diagnosis of DH.Presented at the Society for Investigative Dermatology Meeting, Washington, DC, May 2, 1986     

IgA anti-endomysial antibody detection in the serum of patients with dermatitis herpetiformis following gluten challenge

Summary This study reports the appearance of IgA-class anti-endomysial antibodies in the serum of 8 out of 12 patients with dermatitis herpetiformis who were challenged with gluten after a number of years of control of the rash with a strict gluten-free diet. Although there was no evidence for the antibodies having any pathogenic role in the rash of dermatitis herpetiformis, their presence may be related to the deterioration in the gluten-sensitive enteropathy.     

Distribution of monkey esophagus antigens reactive with IgA-class antibodies in the sera of dermatitis herpetiformis patients

Summary Antibodies of IgA class reactive to the lining of the smooth muscle bundles, i.e., endomysium (EmA), are present in the sera of patients with dermatitis herpetiformis and coeliac disease. These antibodies can be detected on monkey esophagus, a substrate of choice for pemphigus and pemphigoid antibodies. The amount of antigen reactive with IgA-EmA is greatest in the lower portion of the esophagus and decreases towards the uppermost part.This work was supported in part by the Summerhill Foundation and by the Polish Academy of Medicine     

疱疹样皮炎的血清学研究进展

疱疹样皮炎是一种与肠病有关的谷胶敏感性皮肤病,皮损表现为瘙痒性的红斑、丘疹、水疱,直接免疫荧光所见的IgA在真皮乳头层颗粒状沉积对疱疹样皮炎诊断有重要价值。尽管病理学检查和直接免疫荧光一直被认为是疱疹样皮炎诊断的金标准,但对于一些症状不典型或取材位置不当无法确诊的病例,血清学检查有着不可替代的作用,血清学检查对于疱疹样皮炎患者的疗效评估和随访均具有重要价值。随着对疱疹样皮炎发病机制的不断认识,新的血清学检测技术也在不断进步,同时通过血清学检查对DH患者血清中多种抗体水平的分析,为疱疹样皮炎发病机制的研究提供了更多线索。     

Serum antibodies to wheat germ agglutinin and gluten in patients with dermatitis herpetiformis

Summary It has been speculated that gluten may play a role in the pathogenesis of dermatitis herpetiformis (DH) because it can act as a lectin. The lectin activity of gluten preparations was recently identified as wheat germ agglutinin (WGA). IgG and IgA serum antibodies to WGA and gluten were therefore measured in patients with DH and coeliac disease (CD) by an enzylac-linked immunosorbent assay (ELISA). Compared with healthy controls, both patients categories had increased IgG and IgA activities to WGA and gluten, the CD group showing the highest antibody levels. DH patients with subtotal villous atrophy tended to have higher activities than those with no villous changes or only minor changes. No significant difference in the gluten-to-WGA ratio of IgA or IgG antibodies was found when DH patients were compared with CD patients. If WGA plays a pathogenetic role in DH, then DH patients must have dermal characteristics, as yet undefined, that explain the initiation of their skin disease.     

IgG/IgA pemphigus with IgG and IgA antidesmoglein 1 antibodies detected by enzyme-linked immunosorbent assay

Pemphigus is an autoimmune mucocutaneous bullous disease characterized by autoantibodies against the cell surfaces of epidermal keratinocytes. Six cases with deposition of both IgG and IgA on keratinocyte cell surfaces have been reported in the recent literature. We provisionally termed these cases IgG/IgA pemphigus. We describe a 42-year-old Japanese woman with clinical and histopathological features resembling herpetiform pemphigus who demonstrated in vivo bound and circulating anticell surface autoantibodies of both IgG and IgA classes on immunofluorescence examination. Enzyme-linked immunosorbent assay using baculovirus-expressed recombinant desmoglein (Dsg) 1 and Dsg 3 showed that both IgG and IgA antibodies reacted with Dsg1. The reactivity was completely adsorbed with preincubation of serum with Dsg1 baculoprotein, further confirming the exclusive reactivity of both IgG and IgA antibodies with Dsg1. This is the second case of IgG/IgA pemphigus in which the human target antigens for both IgG and IgA antibodies have been unequivocally identified. This study provides further evidence that IgG/IgA pemphigus is a distinct disease entity.     

Detection of circulating antibodies to purified keratinolytic proteinase in sera from guinea pigs infected with Microsporum canis by enzyme-linked immunosorbent assay

Summary A keratinolytic proteinase (KPase) which is regarded as an important factor in the pathogenesis of dermatophytosis was isolated and purified from Microsporum (M.) canis culture filtrates. Enzyme-linked immunosorbent assay (ELISA) was used to determine the occurrence of circulating antibodies to this enzyme in sera samples from guinea pigs with superficial fungal infections caused by M. canis. Of sera samples from guinea pigs infected with M. canis, 75% were reactive within 10 weeks, however, those ELISA values were relatively low compared with those from guinea pigs immunized with KPase. The presence of circulating antibodies was first detected 2 weeks post inoculation with M. canis, corresponding to the period when the lesions were most severe. The titers of the ELISA antibodies reached a peak at 4 weeks; at that time the lesions had disappeared completely.     

Elevation of IgA anti-epidermal transglutaminase antibodies in dermatitis herpetiformis

Background  Dermatitis herpetiformis (DH) is a papulovesicular eruption caused by ingestion of gluten. It is characterized by the deposition of IgA in the dermal papillae. IgA antibodies directed at tissue transglutaminase (TG2) are elevated in gluten-sensitive diseases including DH and coeliac disease (CD). More recently, antibodies directed at epidermal transglutaminase (TG3) were identified in patients with DH, and this may be the dominant autoantigen in this disease.
Objectives  To measure IgA antibodies to TG3 and TG2 in patients with DH and CD, and control populations.
Methods  Serum IgA antibodies against TG2 and TG3 were measured from adults with DH, adults and children with CD, patients with psoriasis, adult Red Cross blood donors, and paediatric controls.
Results  Patients with DH and CD had elevated levels of IgA anti-TG2 antibodies compared with control populations. The levels in the patients with DH and adults with CD were similar. IgA anti-TG2 antibodies were higher in the children with CD compared with adults with DH and CD, and with control populations. Patients with DH and adults with CD had elevated levels of IgA anti-TG3 antibodies compared with children with CD and control populations. There was a trend towards higher levels in the patients with DH compared with adults with CD.
Conclusions  IgA antibodies to TG3 are elevated in patients with DH and adults with CD. The progressive expansion of the epitope-binding profile of IgA antitransglutaminase antibodies in patients with CD may explain the development of DH in patients with undiagnosed CD during their adult life.     

Failure to detect specific gluten antigens associated with the immune aggregates in the skin in dermatitis herpetiformis

Summary The univolved skin of 10 patients with dermatitis herpetiformis (DH) was examined for the presence of gluten antigens with the immunofluorescence technique using a rabbit anti-gliadin antiserum, human antibodies to wheat and to reticulin conjugated to fluorescein-isothiocyanate (FITC) and class-specific anti-human lgA immunoglobulin.In all patients, IgA deposits were found in the tips of the dermal papillae of the uninvolved skin. With the anti-wheat and anti-reticulin conjugates, as well as with the rabbit anti-gliadin antiserum, no specific immunofluorescence was observed in any of the skin specimens. Skin biopsy sections of three DH patients were treated with an acid solution (pH 3.2) in an effort to dissociate antigen-antibody complexes that might be present. After the elution procedure the sections showed undiminished IgA fluorescence, and retesting with the anti-wheat- and antireticulin antisera again gave negative results. The skin eluates, two of which contained IgA, had no antibodies to wheat or reticulin.These findings do not give support to the hypothesis that the antigens in the suspected immune complexes in the DH skin consist of gluten.

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Zusammenfassung Die nicht angegriffene Haut von 10 Patienten mit Dermatitis Herpetiformis (DH) wurde auf die Anwesenheit von Gluten-Antigenen mit der Immunfluorescenztechnik untersucht unter Anwendung eines Antigliadin-Antiserums in einem Kaninchen erzeugt, menschliche Antikörper gegen Weizen sowie gegen Retikulin verbunden mit Fluorescein-Isothiocyanate (FITC) und mit spezifisch klassifiziertem anti-menschlichem IgA-Immunglobulin.In allen Patienten fanden sich IgA-Niederschläge in den Spitzen der Dermalpapillen der nicht angegriffenen Haut vor. Sowohl mit den Antiweizen- und Antiretikulinverbindungen als auch mit dem erwähnten Antigliadin Antiserum konnte keine spezifische Immunfluorescenz in den untersuchten Häuten festgestellt werden. Hautbiopt-Schnitten von 3 DH-Patienten wurden mit einer Säurenlösung (pH 3,2) erprobt, um zu versuchen, die Antigen-Antikörperverbindungen, die möglicherweise anwesend sein könnten, voneinander zu trennen. Nach der oben erwähnten Erprobung zeigten die Versuchsteile eine ungeänderte IgA-Fluorescenz, und nach Wiederholung der soeben genannten Probe mit Antiweizen- und Antiretikulin-Antikörper zeigten sich abermals negative Resultate.Die Hauteluaten, von denen zwei IgA enthielten, zeigten keine Antikörper gegen Weizen oder Retikulin. Diese Resultate tragen nicht zu der Hypothese bei, daß die Antigene in den vermutlichen Immunverbindungen in der DH-Haut aus Gluten bestehen.

     

中国疱疹样皮炎特征分析：1958—2018年文献回顾

【摘要】 目的 总结我国疱疹样皮炎患者的疾病特征。方法 检索中国知网、万方和Pubmed数据库中公开发表的中国人疱疹样皮炎相关文献,根据纳入及排除标准对临床表现、普通病理、免疫病理特点进行筛选,分析符合诊断标准患者的疾病特征。结果 纳入55例疱疹样皮炎患者,发病年龄（44.9 ± 18.5）岁,男女比例约2.5∶1,平均诊断延迟4.1年。皮损主要表现为红斑基础上的紧张性水疱,分布在臀区、肘部、背部、膝部等部位。39例描述组织病理表现,37例可见表皮下疱,17例存在中性粒细胞浸润。33例描述皮损周围组织直接免疫荧光表现,31例可见IgA颗粒状沉积,23例沉积部位为真皮乳头。39例描述了治疗情况,其中25例使用氨苯砜或氨苯砜联合无谷胶饮食治疗,治疗效果明显,皮损多在1个月内消退。结论 中国疱疹样皮炎主要表现为红斑基础上的紧张性水疱,直接免疫荧光主要表现为IgA颗粒状沉积,病因可能具有遗传学特点,氨苯砜治疗效果良好。     

Circulating antibodies to gliadin subfractions in dermatitis herpetiformis and linear IgA dermatoses

Dermatitis herpetiformis (DH) and coeliac disease are associated and the rash of DH is gluten-dependent. The gliadin fraction responsible for the rash is unknown. In linear IgA dermatoses the role of gluten in the skin eruption remains controversial.
Anti-gliadin antibodies (AGA) were measured by an enzyme-linked immunosorbent assay in 10 normal controls; 35 patients with dermatitis herpetiformis (DH); 14 adults with linear IgA disease; and 13 patients with chronic bullous dermatosis of childhood. The presence of enteropathy was assessed by jejunal biopsy and intra-epithelial lymphocyte (IEL) counts.
DH with normal IEL counts on normal diet: IgG and IgA-AGA identical to controls. DH with raised IEL counts on gluten-free diet: slightly elevated IgG and IgA-AGA. DH with raised IEL counts on a normal diet: IgG and IgA were higher, with median IgG 1:2048 (control 1:512) median IgA 1:512 (control 1:128). DH patients with high IgG AGA had elevated titres to α, β, γ, and ω subfractions. The highest levels were for α and the lowest for ω.
For linear IgA disease IgG is normal but adults had raised IgA-AGA compared to controls ( P = 0.005).
In dermatitis herpetiformis the presence of anti-gliadin antibody was dependent on the degree of enteropathy, and, if present, was directed against all gliadin subfractions. The significance of the elevated IgA—AGA in the linear IgA disease is unknown.     

Lymphoma in patients with dermatitis herpetiformis and their first-degree relatives

BACKGROUND: The risk for lymphoma is increased in both dermatitis herpetiformis (DH) and in coeliac disease. The lymphoma most associated with coeliac disease is enteropathy-associated T-cell lymphoma. OBJECTIVES: To study the occurrence and type of lymphoma in a large series of patients with DH and their first-degree relatives. METHODS: The occurrence of lymphoma was studied in 1104 patients consecutively diagnosed with DH in two university hospitals during 1969-2001. A questionnaire was sent to 341 patients to examine the occurrence of lymphoma in their 1825 first-degree relatives. To analyse whether the DH patients with lymphoma had adhered to a gluten-free diet similarly to the patients without lymphoma, two age- and sex-matched patients with DH served as controls for each index case. Data on the gluten-free diet were collected from prospectively completed dietary forms and also from medical records. RESULTS: Eleven (1%) patients contracted lymphoma 2-31 years after the diagnosis of DH. Eight had B-cell-type lymphoma, two enteropathy-associated T-cell lymphoma and one remained unclassified due to missing material. Three (0.2%) of the first-degree relatives contracted lymphoma, all B-cell type. The 11 DH patients with lymphoma had adhered to a gluten-free diet significantly less strictly than the DH controls without lymphoma. CONCLUSIONS: The present study documents that patients with DH can have both B- and T-cell lymphoma. The DH patients with lymphoma had not adhered as strictly to the gluten-free diet as the control patients without lymphoma. The occurrence of lymphoma in the first-degree relatives was lower than in the patients with DH.     

Antibodies to dsDNA in connective tissue diseases measured by ultramicro enzyme-linked immunosorbent assay (ELISA) adapted to the chamber analytical technique (CAT)

Summary Human sera (171 samples of patients with connective tissue diseases (CTD) were screened for anti-dsDNA antibodies by ultramicro ELISA adapted to the chamber analytical technique (CAT). The assay offers sensitivity superior to the Crithidia luciliae immunofluorescence technique (CLIFT). Positive results are not restricted to systemic lupus erythematosus (SLE). Nine sera of other CTD patients exhibited antibodies to dsDNA as well. This might be a symptom of a relatively slight immunodisturbance with presence of low-avidity antibodies.     

Expression of eotaxin, interleukin 13 and tumour necrosis factor-alpha in dermatitis herpetiformis

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.     

Immunoglobulin, complement and epidermal transglutaminase deposition in the cutaneous vessels in dermatitis herpetiformis

BACKGROUND: Recently, epidermal transglutaminase (TG) has been identified within the papillary IgA granules in dermatitis herpetiformis (DH). Although IgA type autoantibodies to tissue and epidermal TGs are characteristic serological markers for DH, these antibodies do not bind to normal papillary skin structures. AIMS: To test the possibility of IgA immune complex precipitation within the vessel walls as a first step in the pathogenesis of skin symptoms, we analysed immunoglobulin, complement, and epidermal TG deposition along the vascular system of DH skin. METHODS: Punch biopsy specimen were taken from 116 DH patients' skin, and evaluated for the presence of vascular immune precipitates by direct immunofluorescence. Skin samples from 16 DH patients were also studied for tissue and epidermal TGs. RESULTS: In 74 (64%) of the 116 DH skin studied, significant vascular staining accompanied the DH-specific granular IgA fluorescence (IgA and C3 in 39 patients; IgA alone in 18; IgA, C3 and IgM together in five; IgM alone in 12). In most cases (92%), the precipitates were detected in the small vessels of the papillary dermis; however, a subpapillary vascular fluorescence was also observed in a few patients (8%). Skin IgA colocalized with epidermal TG in the vessel walls and within the scattered papillary peri- and intervascular DH bodies. Tissue TG did not colocalize either with the immunoglobulins or with the complement precipitates of the dermis. Furthermore, we could not detect keratinocyte TG in the DH bodies nor in the vessel walls. CONCLUSIONS: These findings support possible immune complex precipitation in the vessel walls of DH skin and further confirm the significance of epidermal but not tissue TG in the pathomechanism of skin symptoms.     

Neutrophil CD11b,L-selectin and Fc IgA receptors in patients with dermatitis herpetiformis

BACKGROUND: The skin lesions found in patients with dermatitis herpetiformis (DH) are characterized by the presence of neutrophils at the dermal papillary tips in areas where the diagnostic cutaneous IgA deposits are found. Although the presence of the skin lesions of DH is known to be associated with gluten-sensitive enteropathy, the mechanisms that control the development of skin lesions are not known. OBJECTIVES: To determine if circulating neutrophils from patients with DH have evidence of priming as shown by increased expression of CD11b, decreased expression of L-selectin and increased function of neutrophil Fc IgA receptor. METHODS: Neutrophils from 12 normal subjects and 10 DH patients with active, ongoing disease and 14 DH patients with quiescent disease activity were examined by fluorescence-activated cell sorter for expression of cell surface CD11b, L-selectin expression, Fc IgA expression (CD89) and for the function of the Fc IgA receptor by determining the binding capacity of neutrophils for monoclonal human IgA. RESULTS: Neutrophils from patients with active, ongoing DH had increased expression of CD11b when compared with patients with inactive DH or normal subjects [mean net geometric mean channel fluorescence (GMCF): active DH, 403.3; inactive DH, 237.8; normal subjects, 290.5; P < 0.05]. L-selectin expression in both groups of DH patients was significantly lower than that seen in normal subjects (mean net GMCF: active DH, 363.2; inactive DH, 375.2; normal subjects, 432.7; P < 0.05). No difference in CD89 expression was seen in any of the groups; however, the function of Fc IgA receptor was increased in patients with active DH when compared with patients with inactive DH and normal subjects. CONCLUSIONS: Neutrophils from patients with active, ongoing DH show an increased expression of CD11b, decreased expression of L-selectin and increased ability to bind IgA, consistent with a pattern of priming of the neutrophils. This priming may occur in the gut as a result of the ongoing mucosal immune response that is present in patients with DH on a gluten-containing diet and may predispose neutrophils to localize in the skin of patients with DH.