A-Type lamins, arising from the LMNA gene, are intermediate filaments proteins that belong to the lamina, a ubiquitous nuclear network. Naturally occurring mutations in these proteins have been shown to be responsible for several distinct diseases that display skeletal and/or cardiac muscle or peripheral nerve involvement. These include familial partial lipodystrophy of the Dunnigan type and the mandibuloacral dysplasia syndrome. The pathophysiology of this group of diseases, often referred to as laminopathies, remains elusive. We report a new condition in a 30-yr-old man exhibiting a previously undescribed heterozygous R133L LMNA mutation. His phenotype associated generalized acquired lipoatrophy with insulin-resistant diabetes, hypertriglyceridemia, hepatic steatosis, hypertrophic cardiomyopathy with valvular involvement, and disseminated whitish papules. Immunofluorescence microscopic analysis of the patient's cultured skin fibroblasts revealed nuclear disorganization and abnormal distribution of A-type lamins, similar to that observed in patients harboring other LMNA mutations. This observation broadens the clinical spectrum of laminopathies, pointing out the clinical variability of lipodystrophy and the unreported possibility of hypertrophic cardiomyopathy and skin involvement. It emphasizes the fact that the diagnosis of genetic alterations in A-type lamins requires careful and complete clinical and morphological investigations in patients regardless of the presenting signs.

Adult↗

PubMed2001

Mutations in CGI-58, the gene encoding a new protein of the esterase/lipase/thioesterase subfamily, in Chanarin-Dorfman syndrome.

Chanarin-Dorfman syndrome (CDS) is a rare autosomal recessive form of nonbullous congenital ichthyosiform erythroderma (NCIE) that is characterized by the presence of intracellular lipid droplets in most tissues. We previously localized a gene for a subset of NCIE to chromosome 3 (designated "the NCIE2 locus"), in six families. Lipid droplets were found in five of these six families, suggesting a diagnosis of CDS. Four additional families selected on the basis of a confirmed diagnosis of CDS also showed linkage to the NCIE2 locus. Linkage-disequilibrium analysis of these families, all from the Mediterranean basin, allowed us to refine the NCIE2 locus to an approximately 1.3-Mb region. Candidate genes from the interval were screened, and eight distinct mutations in the recently identified CGI-58 gene were found in 13 patients from these nine families. The spectrum of gene variants included insertion, deletion, splice-site, and point mutations. The CGI-58 protein belongs to a large family of proteins characterized by an alpha/beta hydrolase fold. CGI-58 contains three sequence motifs that correspond to a catalytic triad found in the esterase/lipase/thioesterase subfamily. Interestingly, CGI-58 differs from other members of the esterase/lipase/thioesterase subfamily in that its putative catalytic triad contains an asparagine in place of the usual serine residue.

1-Acylglycerol-3-Phosphate O-Acyltransferase↗

PubMed2000

A subepidermal bullous eruption associated with IgG autoantibodies to a 200 kd dermal antigen: the first case report from the United States.

We describe an 81-year-old white man in whom a subepidermal bullous eruption developed that clinically resembled bullous pemphigoid. The eruption promptly responded to oral tetracycline and niacinamide and topical clobetasol. Histologic examination of perilesional skin revealed neutrophilic infiltration with formation of papillary microabscesses and subepidermal cleavage. Direct immunofluorescence showed linear deposition of IgG and C3 along the basement membrane zone. By indirect immunofluorescence, circulating IgG autoantibodies bound exclusively to the dermal side of salt-split normal human skin. Immunoblot analysis demonstrated that the patient's autoantibodies reacted with a 200 kd dermal protein that was different from type VII collagen, the epidermolysis bullosa acquisita autoantigen. This patient represents the first confirmed case from the United States with a recently reported novel autoimmune subepidermal bullous disease associated with IgG autoantibodies to a 200 kd dermal antigen.

Aged↗

PubMed1999

Autoantibodies in lichen planus pemphigoides react with a novel epitope within the C-terminal NC16A domain of BP180.

Lichen planus pemphigoides is an autoimmune subepidermal blistering disease. The finding of immunoglobulin G antibodies directed against the basement membrane zone differentiates it from bullous lichen planus. The aim of this study was to identify the target antigen of lichen planus pemphigoides autoantibodies. Sera from lichen planus pemphigoides patients (n = 4) stained the epidermal side of NaCl-split human skin in a pattern indistinguishable from that produced by bullous pemphigoid sera. In bullous pemphigoid, the autoimmune response is directed against BP180, a hemidesmosomal transmembrane collagenous glycoprotein. We previously demonstrated that bullous pemphigoid sera predominantly react with a set of four epitopes (MCW-0 through MCW-3) clustered within a 45 amino acid stretch of the major noncollagenous extracellular domain (NC16A) of BP180. By immunoblotting and enzyme-linked immunosorbent assay, lichen planus pemphigoides sera were also strongly reactive with recombinant bullous pemphigoid 180 NC16A. The lichen planus pemphigoides epitopes were further mapped using a series of overlapping recombinant segments of the NC16A domain. All lichen planus pemphigoides sera reacted with amino acids 46-59 of domain NC16A, a protein segment that was previously shown to be unreactive with bullous pemphigoid sera. Two lichen planus pemphigoides sera, in addition, reacted with the immunodominant antigenic region associated with bullous pemphigoid. In conclusion, there are now five bullous diseases that are associated with an autoimmune response to BP180: bullous pemphigoid; pemphigoid/herpes gestationis; cicatricial pemphigoid; linear immunoglobulin A disease; and lichen planus pemphigoides. In addition, we have identified a novel epitope within the BP180 NC16A domain, designated MCW-4, that appears to be uniquely recognized by sera from patients with lichen planus pemphigoides.

Adult↗

PubMed1999

Subepidermal autoimmune bullous skin diseases associated with B-cell lymphoproliferative disorders.

The development of several types of autoimmune disorders is well known in the course of B-cell lymphoproliferative diseases. In order to investigate whether these autoimmune diseases may target cutaneous antigens, especially those of the dermal-epidermal junction, we conducted a retrospective analysis of all cutaneous direct immunofluorescence studies performed in patients with B-cell neoplasia who presented with cutaneous lesions requiring a skin biopsy. Patients with linear deposits of immunoglobulin or C3 molecules at the dermal-epidermal junction were studied further, using immunoblotting and immunoelectron microscopy. Patients with no overt hematologic malignancies but with cutaneous lesions requiring direct immunofluorescence were studied as a control population. During the study period, the diagnosis of autoimmune blistering diseases of the dermal-epidermal junction was established in 9/102 (8.9% +/- 2%) patients with a B-cell lymphoid disorder, compared with 288/8,189 (3.5% +/- 0.04%) patients without underlying hemopathy (p < 0.01). Among the 9 patients, 7 were studied in detail. Immunologic studies demonstrated epidermolysis bullosa acquisita in 6 patients and cicatricial pemphigoid in 1. Autoimmune blistering diseases, especially epidermolysis bullosa acquisita, are part of the spectrum of autoimmune disorders associated with B-cell neoplasia.

Aged↗

PubMed1999

[Linear IgA dermatoses in children].

Explore the source record for details and available documents.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1998

Acquired junctional epidermolysis bullosa associated with IgG autoantibodies to the beta subunit of laminin-5.

We report the case of a 72-year-old man with clinical features resembling those of non-lethal junctional epidermolysis bullosa associated with IgG autoantibodies to the beta chain of laminin-5. The patient presented with a sudden onset of blistering and severe fragility of the skin and mucous membranes resulting in atrophic scars. Electron microscopy showed that the blistering arose in the lamina lucida. Indirect immunofluorescence indicated that the autoantibodies bound to the dermal side of 1 mol/L NaCl-split skin, and both direct and indirect immunoelectron microscopy demonstrated antibody binding to the lamina densa. Postembedding immunogold electron microscopy also revealed labelling in the lamina lucida beneath the hemidesmosomes. On immunoblotting, we found the autoantibodies to comigrate with the beta chain of laminin-5. Following the nomenclature of inherited junctional epidermolysis bullosa with mutations of the laminin-5 gene, we propose the name acquired junctional epidermolysis bullosa for this newly recognized disease.

Aged↗

PubMed1998

Lichen planus pemphigoides is a heterogeneous disease: a report of five cases studied by immunoelectron microscopy.

Lichen planus pemphigoides (LPP) is a rare and controversial disease. It is characterized by bullae arising on lichen planus papules and on uninvolved skin, subepidermal bullae in histology, and linear deposits of IgG and C3 along the basal membrane zone on immunofluorescence of peribullous skin. Our goal was to identify the localization of the target antigen in cases of LPP. Five patients diagnosed with LPP on clinical, histological and immunofluorescence criteria were explored by immunoelectron microscopy and immunoblot. Our results show that the target antigen in LPP is not unique. The localization of the immune deposits was consistent with a diagnosis of bullous pemphigoid in two cases, of cicatricial pemphigoid in two cases and of epidermolysis bullosa acquisita in one case. Our study supports the view that LPP is a heterogeneous condition in which lichen planus may induce different subepidermal acquired bullous dermatoses.

Adolescent↗

PubMed1997

Epidermolysis bullosa acquisita diagnosed by direct immunoelectron microscopy of the conjunctiva.

OBJECTIVE: To describe for the first time the direct immunoelectron microscopic pattern of immune deposits on the conjunctival basement membrane in epidermolysis bullosa acquisita (EBA). DESIGN: Case reports. PARTICIPANTS: Two patients. INTERVENTION: Epidermolysis bullosa acquisita associated with cicatrizing conjunctivitis. MAIN OUTCOME MEASURES: Direct immunofluorescence and direct immunoelectron microscopy without freezing on conjunctival and skin biopsy specimens, indirect immunofluorescence, Western immunoblot analysis. RESULTS: Results of direct immunoelectron microscopic examination of the conjunctiva showed the presence of immune deposits in the anchoring fibril zone, just beneath the lamina densa, in both patients. This finding was the same as the direct immunoelectron microscopic pattern shown in the skin of these patients, which is known to be very specific for EBA. Direct immunofluorescence was positive in the conjunctiva of only one patient. Indirect immunofluorescence and Western immunoblot analysis failed to detect circulating autoantibodies. CONCLUSIONS: Direct immunoelectron microscopy on the conjunctiva is a useful diagnostic tool to differentiate EBA from other related autoimmune mucocutaneous blistering diseases.

Adult↗

PubMed1997

Blind loop syndrome: an unusual cause of panniculitis.

We describe a 52-year-old woman with panniculitis and blind loop syndrome. She had undergone a gastrectomy for peptic ulcer 4 years before. Tender erythematous nodules on her palms and soles were associated with diarrhea and weight loss. A biopsy specimen revealed septal and lobular panniculitis. A glucose hydrogen breath test was consistent with bacterial overgrowth. These results were consistent with panniculitis associated with a blind loop syndrome. Only four cases of this association have been reported previously.

Animals↗

PubMed1997

IgA-epidermolysis bullosa acquisita in a child resulting in blindness.

Epidermolysis bullosa acquisita (EBA) is an acquired subepidermal bullous disease characterized by IgG autoantibodies directed against type VII collagen, the major component of anchoring fibrils. The classical phenotype of EBA is a non-inflammatory, mechanobullous disease resembling the dystrophic forms of inherited epidermolysis bullosa. Mucous membrane involvement is frequent but usually mild. We report a 1-year-old girl suffering from IgA-EBA, who presented with an initial eruption of disseminated urticarial lesions and tense blisters of the skin but subsequently developed severe oral and ocular lesions reminiscent of cicatricial pemphigoid. Direct immunofluorescence of the skin and buccal mucosa revealed linear IgA and C3 at the basement membrane zone (BMZ). IgA anti-BMZ autoantibodies stained the dermal side of salt-split skin by indirect immunofluorescence and recognized a dermal protein of 290 kDa co-migrating with type VII collagen by immunoblotting. Direct and indirect immunoelectron microscopy revealed IgA deposits overlying the anchoring fibrils. The ocular involvement led to total blindness in spite of intense treatment. This case of childhood IgA-EBA is particularly striking because of the cicatricial pemphigoid phenotype with severe ocular involvement which resulted in blindness. It reinforces the necessity to use modern immunological methods to classify autoimmune bullous diseases in order to allow early and appropriate treatment.

Autoantibodies↗

PubMed1997

A highly sensitive enzyme-linked immunosorbent assay for the detection of circulating anti-BP180 autoantibodies in patients with bullous pemphigoid.

The BP180 antigen, a component of the epidermal anchoring complex, has been identified as one of the major antigenic targets of autoantibodies associated with the blistering skin disease, bullous pemphigoid. Our research group has recently demonstrated that reactivity of bullous pemphigoid autoantibodies to the BP180 ectodomain is almost entirely restricted to a set of four antigenic sites clustered within the membrane-proximal noncollagenous stretch (NC16A). Using a passive transfer mouse model, antibodies to the corresponding noncollagenous region of murine BP180 were shown to trigger an inflammatory subepidermal blistering disease that closely mimics bullous pemphigoid. We now report the development of an enzyme-linked immunoabsorbent assay system that is extremely sensitive in detecting disease-specific autoantibodies in the sera of bullous pemphigoid patients. The target antigen in this assay is a recombinant form of the BP180 NC16A domain that contains all four of the well-defined bullous pemphigoid-associated antigenic sites. Of 50 randomly selected bullous pemphigoid sera tested, 47 (94%) were positive in this assay, whereas no specific reactivity was detected in any of the 107 controls. Interestingly, all three of the bullous pemphigoid sera that were negative in this assay had been obtained from patients who were already undergoing treatment. The NC16A enzyme-linked immunosorbent assay is more sensitive than any of the standard techniques for detecting circulating bullous pemphigoid autoantibodies, including other enzyme-linked immunosorbent assays, immunoblotting, and indirect immunofluorescence. Finally, the NC16A enzyme-linked immunosorbent assay provides immunologic information that cannot be obtained from direct immunofluorescence studies of skin biopsies, and that may well be relevant in the diagnosis and treatment of bullous pemphigoid.

Autoantibodies↗

PubMed1997

Drug-induced linear IgA disease: target antigens are heterogeneous.

No information is available concerning the target antigen(s) in drug-induced linear IgA disease. The purpose of this study was to define better drug-induced linear IgA disease by studying its immunopathological, immunoultrastructural and immunochemical characteristics in three patients. In the first patient, IgA deposits were seen in the lamina lucida. In the second and the third patients, IgA deposits were seen on each side of the lamina densa. Immunoblotting of the first patient's serum showed that IgA reacted with a protein of 230 kDa similar to the bullous pemphigoid-associated antigen 1 (BPAG 1). The second patient's serum did not react with specific bands. In the third patient IgA antibodies reacted with a protein of 97 kDa on epidermal extracts. Our findings suggest that, as in idiopathic forms, the target antigen is not unique in drug-induced linear IgA disease. In some patients, drug-induced linear IgA disease may represent an IgA class response to the BPAG 1.

Adult↗

PubMed1997

Epidermolysis bullosa acquisita in childhood.

BACKGROUND: Epidermolysis bullosa acquisita (EBA) is an autoimmune bullous disease characterized by the presence of antitype VII collagen antibodies, leading to the formation of bullae in the dermoepidermal junction. This disease is rare in childhood. OBSERVATIONS: We report 3 new cases of EBA in children. The 3 patients were similar; all 3 children were black, with a clinical phenotype resembling linear IgA bullous disease in children and typical histologic and immunologic features of EBA. In the 3 patients, diagnosis was proven using immune electron microscopy and Western blot analysis, where antitype VII collagen antibodies were demonstrated. Patients 1 and 2 were successfully treated with a combination of prednisone and dapsone. In patient 3, the lesions healed without specific therapy. We found 11 other pediatric cases of EBA in the literature and studied those cases in addition to the cases presented herein to describe the characteristics of EBA in childhood. CONCLUSIONS: Epidermolysis bullosa acquisita is a rare disease in childhood. Mucosal involvement is frequent and severe. Because the clinical features are misleading, the use of immune electron microscopy and Western blot analysis is essential to making a diagnosis. Treatment with a combination of prednisone and dapsone is often effective. The prognosis in children is better than it is in adult patients.

Adolescent↗