A. Horváth

Identification of desmoglein 1 as autoantigen in a patient with intraepidermal neutrophilic IgA dermatosis type of IgA pemphigus

Abstract: In a 51‐year‐old female patient with intraepidermal neutrophilic IgA dermatosis (IEN) type of IgA pemphigus, circulating IgA, but not IgG, autoantibodies were detected to bind to the cell surface of the whole epidermis, being much stronger in the upper epidermis. In the patients skin a heavy intraepidermal IgA staining was observed throughout the whole epidermis, accompanied by a weak IgG and a more prominent C3 staining. IgA from the patients serum showed no reactivity either with epidermal proteins by immunoblot analysis, or with COS 7 cells transiently transfected with mammalian cell expression constructs containing full length human Dsc1, Dsc2 and Dsc3. Our patients IgA specifically reacted with conformational epitopes of human desmoglein (Dsg) 1 but not Dsg 3, when studied in a previously established, here for IgA antibody detection modified enzyme‐linked immunoabsorbent assay (ELISA) of baculovirus expression system. The immunoreactivity against keratinocyte cell surface was completely removed from the serum of the patient by pre‐incubation with recombinant Dsg1 baculoprotein. This finding indicates that the sera possess only IgA antibodies against the extracellular domain of Dsg1 baculoprotein, but no antibodies against components of keratinocyte cell surface other than Dsg1. This is the first case of IgA pemphigus where Dsg1 has been identified as the autoantigen.

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.

Neutralizing and complement-dependent enhancing antibodies in different stages of HIV infection

Reclustering and indirect immunofluorescence assays on MT-4 cells [carrying both CD4 and complement receptor type 2 (CR2)] were used to measure neutralizing and enhancing antibodies in sera obtained from HIV-1-infected individuals. Heat-inactivated sera were tested before and after mixing 1:1 with fresh seronegative human serum. Using heated samples, neutralizing antibodies were found in 20 out of 20 and 11 out of 19 serum samples of asymptomatic and symptomatic [AIDS, AIDS-related complex (ARC)] HIV-seropositive patients, respectively. In complement-restored samples, neutralizing activity was found in eight sera of asymptomatic patients and in none of the sera of AIDS and ARC patients; enhancing activity could be detected in four and 12 sera, respectively. A significant positive correlation was observed between the titres of neutralizing antibodies measured in the complement-restored samples and the absolute number of CD4+ lymphocytes. These findings indicate that the appearance of complement-dependent enhancing antibodies coincident with the loss of neutralizing antibodies may indicate a poor prognosis in HIV infection.

Exacerbation of paraneoplastic pemphigus by cyclophosphamide treatment: detection of novel autoantigens and bronchial autoantibodies

A 48‐year‐old woman with a follicular, grade III, B‐cell non‐Hodgkin lymphoma developed clinical, immunopathological and histological features of paraneoplastic pemphigus. The skin symptoms flared after repeated cyclophosphamide infusions, and were preceded and accompanied by a progressive dyspnoea. Although the skin and oral mucosal disease went into remission with high‐dose steroid and intravenous immunoglobulin therapy, the severe alveolitis led to death. Immunoblotting of human epidermal extracts showed that the patients serum IgG reacted with the 210‐kDa envoplakin, 190‐kDa periplakin, as well as the recombinant protein of BP180 NC16a domain. IgG and IgA enzyme‐linked immunosorbent assays for desmoglein 3 were positive, too. Indirect immunofluorescence studies on COS‐7 cells transiently transfected with desmocollin 1–3 cDNAs showed that the patients serum contained IgG and IgA antibodies to desmocollin 3 as well as IgG antibodies to desmocollin 2. Serum IgG and IgA strongly stained rat bronchial epithelium, corresponding to autoantibodies possibly involved in the pathomechanism of the severe lung disease. In this case, which was characterized by a mixed IgA/IgG antibody panel displaying known and unique antigenicity, the serious episodes of paraneoplastic pemphigus flared after cyclophosphamide treatment.

Correlation between T-Cell and Mast Cell Activity in Patients with Chronic Urticaria

Background: The presence of autoantibodies reacting with the high affinity IgE receptor (FcΕRIα) usually indicates a more severe form of chronic urticaria (CU). Previously, we showed an increased lymphocyte reactivity in CU patients; however, the relation between enhanced cellular immunity and the presence of anti-FcΕRIα-specific autoantibodies has not been investigated. Methods: Cellular and humoral immune reactivity of 50 CU patients and 28 healthy controls was studied.Serum sIL-2R, neopterin, and tryptase levels were measured to assess T-cell, monocyte/macrophage and mast cell activity, respectively. Helicobacter pylori (HP)-specific IgG antibody, and IgE levels were also tested. Anti-FcΕRIα-specific autoantibody was determined by Western blotting. In vivo histamine-releasing activity of patients’ sera was assessed by the autologous serum skin test (AST). Results: 17/50 CU patients, who both had IgG-type anti-FcΕRIα-antibodies by Western blotting and a positive AST response, were classified as autoimmune CU. All patients with CU had significantly higher serum sIL-2R and tryptase levels than healthy controls (p = 0.000257, p = 0.000166, respectively), indicating T-cell and mast cell activation. Patients with higher sIL-2R levels also had higher tryptase levels; the strongest correlation was shown in the autoimmune subgroup of patients (ρ = 0.688, p = 0.002). There was a tendency towards higher tryptase levels in the autoimmune subgroup, as compared to the nonautoimmune CU patients. While the serum IgE was significantly lower in autoimmune than in nonautoimmune CU (p = 0.000836), there was no significant difference in their sIL-2R, neopterin and HP-specific IgG antibody levels. CU patients with a positive AST response (38/50) had significantly higher tryptase levels (p = 0.0107) when compared to the negative skin test group. Conclusions: The significant correlation between sIL-2R and tryptase levels in patients with CU indicates that T cell activation is proportional to mast cell degranulation in these patients. The increased level of tryptase in autoimmune CU may suggest more severe disease.

Dystrophic epidermolysis bullosa complicated by cutaneous squamous cell carcinoma and pulmonary and renal amyloidosis

Summary A 25‐year‐old woman with Hallopeau−Siemens recessive dystrophic epidermolysis bullosa had generalized blistering, scarring and milia since birth. In the course of the disease, acral pseudosyndactyly developed, and the patient suffered from corneal erosions, oesophageal strictures, malabsorption, recurrent severe pneumonias and nephrotic syndrome. In addition, she had severe anaemia, sideropaenia, hypocalcaemia, heavy proteinuria and hypoalbuminaemia. A rapidly growing skin squamous cell carcinoma developed on the neck that spread to axillary and cervical lymph nodes. Recurrent hypocalcaemic tetanic convulsions and dyspnoea and a pneumonia refractory to antibiotics led to the premature demise of the patient. Autopsy revealed extensive amyloidosis of the renal, hepatic and splenic tissues. AA type amyloid deposits were detected in the renal glomeruli and in the lung, explaining the patients unusually severe pulmonary infections. In essence, the patient had severe recessive dystrophic epidermolysis bullosa, complicated by squamous cell carcinoma, recurrent pneumonias and nephrotic syndrome due to secondary amyloidosis of the kidney and lung. The possibility of secondary pulmonary amyloidosis should be considered in severe dystrophic epidermolysis bullosa patients with recurrent pulmonary infections.

Multicentre study of fragrance allergy in Hungary. Immediate and late type reactions.

The authors followed the frequency of fragrance contact sensitization in Hungary in a multicentre study in the years 1998 and 1999. A total of 3604 patients were tested with fragrance mix (FM), and positive reactions were observed in 294 (8.2%). In 160 FM hypersensitive patients, the study was continued with patch testing of the mix constituents (cinnamic alcohol, cinnamic aldehyde, eugenol, amyl cinnamic aldehyde, hydroxycitronellal, geraniol, isoeugenol, oak moss absolute). Of the patients tested, 70.6% produced positive reactions to the constituents. FM contact sensitization was mainly observed in female patients (74.4%). The incidence of contact urticaria in FM hypersensitive patients was 6.1%. Simultaneous patch test trials of other environmental contact allergens, in both early and late evaluations, mainly confirmed hypersensitivity reactions to balsams. Female dominance of hypersensitivity reactions observed during testing the individual components of the mix was striking (82.4%). In positive skin reactions, cinnamic alcohol, isoeugenol and oak moss provoked skin symptoms most frequently. We also tested the 104 patients who produced negative reactions to FM with the constituent individual allergens, with 11.9% positive incidence. The clinical symptoms of the patients were above all manifest in the form of contact eczema, located on the hands, face, eyelids and axillae. With this study, the authors, members of the Hungarian Contact Dermatitis Research Group, call attention to one of the most frequent allergens in the environment.

Identification of two novel nonsense mutations in the transglutaminase 1 gene in a Hungarian patient with congenital ichthyosiform erythroderma

Abstract: Congenital ichthyosiform erythroderma (CIE) belongs together with lamellar ichthyosis (LI) to the group of autosomal recessive congenital ichthyoses (ARCI). Mutations in the transglutaminase (TGase) 1 gene (TGM1) have been identified in several families with LI and in some families with CIE. We report a case of CIE with two new nonsense mutations: a C7780G transversion in exon 11 resulting in a premature stop codon at aminoacid residue Y503X and a C8533G transversion in exon 13 leading to a nonsense mutation at S669X. These mutations were also identified in a heterozygous pattern in the unaffected parents. These two termination‐codons result in the translation of a truncated protein at the C‐terminal end domain of the TGM 1 molecule. B.C1 monoclonal antibody failed to detect TGase 1 in the patients skin sample, and TGase activity measured by monodansyl cadaverine‐incorporation showed the reduced TGase activity at the distribution of TGase 1 in the epidermis.

Wegener's granulomatosis presenting as pyoderma gangrenosum

A 59‐year‐old male patient developed a necrotizing ulceration on the right shin. Both clinical and histopathologic examinations suggested pyoderma gangrenosum. After temporary improvement of skin symptoms under peroral glucocorticoid treatment, a hemorrhagic‐purulent discharge started from the nose, he began to have fever, malaise, cough, and a chest X‐ray revealed inflammation in the lung. Cerebral CT and MRI disclosed midline bone loss within the nasal septum and granulomatosus tissue masses protruding into the right orbit. The c‐ANCA test was positive, serum IgA was elevated, and he had microhaematuria and proteinuria. In this severe case of Wegeners granulomatosis prolonged methylprednisone and cyclophosphamide treatment was initiated. Both the skin symptoms and the granulomatosus infiltrations resolved.

High frequency of the 425A→G splice‐site mutation and novel mutations of the COL7A1 gene in central Europe: significance for future mutation detection strategies in dystrophic epidermolysis bullosa

Background  Mutations in the type VII collagen gene (COL7A1) are responsible for dominant and recessive forms of dystrophic epidermolysis bullosa (DEB). These mutations are usually specific for individual families; only a few cases of recurring mutations have been identified.