Circulating IgA anti-basement membrane zone antibodies in dermatitis herpetiformis.

Criculating anti-basement membrane zone antibodies of the IgA class were detected in the sera of 2 or 6 dermatitis herpetiformis (DH) patients who had linear in-vivo-bound IgA deposits and in 1 of 42 DH patients who had granular vivo-bound IgA deposits. In the former 2 patients the circulating antibodies were localized ultrastructurally to the identical site where the in vivo-bound antibodies were localized and were bound by antigens in either the lamina lucida or the subbasal lamina anchoring fibril area of the basement membrane zone of normal human skin.     

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.     

Dermatitis herpetiformis Duhring with linear deposits of IgA (linear IgA dermatosis)

Three patients with linear deposits of IgA along the epidermal basement membrane were studied. The clinical and histopathological picture as well as the response to dapsone were typical of dermatitis herpetiformis. Two of the three patients were HLA-B8/DR3-positive. By immunoelectron microscopy, the previously reported two types of linear IgA deposits were confirmed: in one patient, the IgA precipitates were localized below the basal lamina as in dermatitis herpetiformis, in the other two above the basal lamina in the lamina lucida as in bullous pemphigoid. The immunoelectron microscopic findings imply that in some patients with linear IgA dermatosis a pathomechanism different from that in classical dermatitis herpetiformis may be operative.     

Circulating antibodies to gliadin subfractions in dermatitis herpetiformis and linear IgA dermatosis of adults and children

Dermatitis herpetiformis (DH) and coeliac disease (CD) are linked but their association with linear IgA dermatosis (LAD) is unclear. Thirty-seven patients with DH and 27 with linear IgA dermatosis were investigated, of which 23/37 DH patients and 1/10 LAD patients had small intestinal enteropathy. Elevated IgG and IgA gliadin antibodies were found in the DH patients with enteropathy (CD). IgG gliadin antibodies in DH patients were directed against alpha, beta, gamma and omega gliadin subfractions. Elevated IgA gliadin antibodies in the adult LAD patients (n= 14) suggests that this condition may be associated with enteropathy or an IgA diathesis.     

IgA antiendomysial antibodies in dermatitis herpetiformis

Sera from 24 patients with dermatitis herpetiformis and 80 control subjects (patients with other bullous diseases, nonbullous dermatoses, and noncutaneous diseases) were studied to determine the usefulness of assay for IgA antiendomysial antibodies (IgA-EMA) in the diagnosis of dermatitis herpetiformis. The overall sensitivity of IgA-EMA for the diagnosis of dermatitis herpetiformis was 79% and the specificity was 96%. When the three patients with dermatitis herpetiformis who were faithfully following gluten-free diets were excluded, the sensitivity was 90% and the specificity was 96%. No patient in the bullous disease control group (including patients with linear IgA bullous dermatosis) had circulating IgA-EMA. One patient, who did not have direct immunofluorescence evidence for dermatitis herpetiformis but had IgA nephropathy, had a positive IgA-EMA result, an interesting association in light of the rare reports of dermatitis herpetiformis in patients with IgA nephropathy and IgA antigliadin antibodies associated with IgA nephropathy. Although direct immunofluorescence testing of skin biopsy specimens remains the most definitive diagnostic test for dermatitis herpetiformis, indirect immunofluorescence assay of serum for IgA-EMA is a minimally invasive study with a high sensitivity and specificity for dermatitis herpetiformis.     

Cutaneous IgA subclasses in dermatitis herpetiformis and linear IgA disease

The subclasses of the cutaneous IgA were studied in 8 patients with dermatitis herpetiformis and 4 with linear IgA disease. The cutaneous IgA in dermatitis herpetiformis consisted of both IgA1 and IgA2, although IgA1 predominated. This demonstrated that the IgA is polyclonal and may be both mucosal and blood derived. The IgA in linear IgA disease was exclusively IgA1, confirming previous work, and suggesting that mucosal IgA may not make a major contribution to the skin deposits.     

Circulating reticulin autoantibodies of IgA class in dermatitis herpetiformis

Circulating reticulin autoantibodies of IgA class and anti-nuclear antigen antibodies were found in a high frequency in dermatitis herpetiformis patients as compared with age- and sex-matched controls.     

Pemphigus foliaceus with anti-intercellular and anti-basement membrane zone antibodies. Blocking immunofluorescence and Western immunoblotting studies

In a patient with clinical, histologic, and routine direct immunofluorescence (IF) findings compatible with pemphigus foliaceus (PF), anti-intercellular and anti-basement membrane zone (BMZ) antibodies were found on indirect IF. Blocking IF studies using the biotin-avidin method revealed that intercellular staining of this patient's serum was significantly decreased by sera of PF patients, however, reaction of this patient's serum was not blocked by sera of PV and BP patients. Western immunoblot analysis using the SDS extracts of normal human epidermis demonstrated that this patient's serum reacted with 370-, 220-, 170-, 130- and 21-kD proteins. Another PF serum reacted with 170- and 21-kD proteins. BP sera reacted with 220-, 68-, 46 and 21-kD proteins. Considering the results of the previous reports and this study, 220- and 170-kD protein bands are specific for BP and PF, respectively, and this is the first case of PF with both anti-intercellular and anti-BMZ circulating antibodies including immunoblotting analysis.     

Treatment of dermatitis herpetiformis and linear IgA bullous dermatosis

Dermatitis herpetiformis (DH) and linear IgA bullous dermatosis (LABD) are IgA-mediated autoimmune bullous diseases. They share an identical histopathology, but are differentiated on the basis of the pattern of IgA deposition on direct immunofluorescence. While DH responds to a gluten-free diet, LABD rarely responds to gluten restriction. In the management of DH, adhering to a gluten-free diet promotes healing of small intestine villus atrophy, resolution of cutaneous disease, and lowers the risk of lymphoma. Dapsone is palliative but not curative in the treatment of DH and LABD. Patients taking systemic dapsone or sulfa-based medication for the treatment of DH or LABD should have a reasonable knowledge of the inherent side effects.     

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.     

IgA class antibodies in dermatitis herpetiformis: reaction with tissue antigens

The mechanism for deposition of IgA in dermatitis herpetiformis (DH) remains unclear. To test the hypothesis that a circulating IgA class antibody in DH patients binds to constituents of normal human skin, we employed the highly sensitive methods of immunoblotting and indirect immunofluorescence. Sera from 64 DH patients, 67 randomly selected normal control subjects, 29 histocompatibility locus antigen (HLA) B8/DR3/DQw2 controls, and 12 psoriatic patients were tested for IgA binding to various substrates, including dermal and epidermal extracts, fibroblast and keratinocyte supernatants, monkey esophagus sections, and whole and saline-split normal human skin sections. Significant differences observed among the groups in the frequency of detectable IgA antibodies reacting with various substrates were as follows: 1) IgA antibodies in 30% of both DH and HLA B8/DR3/DQw2 sera bound to a 60-Kd protein in dermal extracts (p less than 0.25 versus non-HLA matched controls); 2) IgA antiendomysial antibodies were present in 38% of DH patients (predominantly those not on gluten-free diets), whereas both normal control groups had frequencies of 5-10% (p less than 0.025); 3) there was more nonspecific IgA antibody-binding to dermal, epidermal, and bovine proteins in DH and HLA control sera than in normal sera; and 4) IgA antibodies directed against the basement membrane were present with an increased frequency of 25% in both DH and HLA B8/DR3/DQw2 sera (p less than 0.1 versus non-HLA matched controls). Therefore, these results do not support the hypothesis that there is an unique antigen within normal human skin to which IgA antibodies from DH sera bind.     

Coexistence of linear IgA dermatitis herpetiformis and systemic lupus erythematosus

A vesiculobullous eruption of dermatitis herpetiformis and systemic lupus erythematosus developing simultaneously in a 26 year old woman is described. The lesions were characterized by pruritic urticarial vesicles, eosinophilic and neutrophilic abscesses, and the presence of the linear type of IgA deposition at the basement membrane zone. These lesions respond to dapsone, although high dosages of prednisone and cyclophosphamide were not effective.     

Circulating autoantibodies to tissue transglutaminase differentiate patients with dermatitis herpetiformis from those with linear IgA disease

BACKGROUND: Dermatitis herpetiformis (DH) is highly associated with celiac disease. Recently, tissue transglutaminase (tTG) was identified as the autoantigen of IgA antibodies in celiac disease. The prevalence of antibodies to tTG in DH patients is not known. OBJECTIVE: The purpose of this study was to determine whether DH patients show circulating IgA autoantibodies to tTG, to compare their serum levels with those from patients with other subepidermal autoimmune bullous diseases, and to correlate levels of antibodies to tTG with the extent of small bowel disease. METHODS: Sera were obtained from consecutive patients with DH (n = 11), linear IgA disease (n = 15), bullous pemphigoid (n = 10), and epidermolysis bullosa acquisita (n = 6) and were studied by indirect immunofluorescence on monkey esophagus and NaCl-split human skin. IgA reactivity to tTG was measured by enzyme-linked immunosorbent assay. The extent of mucosal involvement in jejunal biopsy specimens was assessed according to the grading of Marsh. RESULTS: All untreated DH patients showed circulating IgA autoantibodies to tTG. One DH patient already undergoing therapy, the 15 patients with linear IgA disease, and all other controls revealed no autoantibodies to tTG. In addition, serum levels of IgA anti-tTG antibodies reflected the degree of histopathologic changes in jejunal mucosa from biopsy specimens in DH patients. CONCLUSION: Our results show that circulating IgA autoantibodies to tTG are detectable in DH but not in linear IgA disease or other subepidermal autoimmune bullous diseases. The levels of IgA anti-tTG antibodies reflect the extent of histopathologic changes of the jejunal mucosa in DH.     

Sulphamethoxypyridazine for dermatitis herpetiformis, linear IgA disease and cicatricial pemphigoid

One-hundred and sixty-eight cases of dermatitis herpetiformis were reviewed to compare the clinical response to and incidence of side-effects from dapsone and sulphamethoxypyridazine. Thirty-seven received sulphamethoxypyridazine (0.25-1.5 g/day) as a single agent therapy at some stage during their care and 161 had dapsone only (50-450 mg/day). Thirty of these patients received both drugs, but at different times. Both were highly effective in controlling the skin disease in 97% of patients on dapsone and 89% on sulphamethoxypyridazine. While 36 (22%) of dapsone-treated subjects had intolerable side effects warranting a change in therapy, this occurred in only five (13.5%) of those treated with sulphamethoxypyridazine. Sulphamethoxypyridazine was also effective as a single agent in three patients with linear IgA disease who had suffered adverse effects from dapsone, and in 10 out of 15 patients with oral and cutaneous lesions of cicatricial pemphigoid.     

Discrete palmar and plantar symptoms in children with dermatitis herpetiformis Duhring

Unusual, discrete palmar and plantar symptoms observed in thirty of forty-seven children with dermatitis herpetiformis are described. The diagnosis was verified in every case by the demonstration of granular IgA deposits in the skin. Forty-five of the children showed villous atrophy in jejunal biopsy specimens. In four cases extensive, exudative, bullous palmar symptoms, similar mild plantar changes, and healing with desquamation were observed. At least once during treatment we found very discrete, reddish-brown spots or small blisters on the flexor surface of the fingers and on the palms in thirty patients. Similar lesions occurred on the soles and plantar surface of the toes in only three patients. In asymptomatic patients and those treated with either a gluten-free diet or sulfone/sulfapyridine, the phenomenon was not manifest.