A novel mutation in the 1A domain of keratin 2e in ichthyosis bullosa of Siemens.
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Ichthyosis bullosa of Siemens (IBS) is a rare autosomal dominant skin disorder with clinical features similar to epidermolytic hyperkeratosis (EHK). Both diseases have been linked to the type II keratin cluster on chromosome 12q. Hyperkeratosis and blister formation are relatively mild in IBS compared with EHK, and the lysis of keratinocytes is restricted to the upper spinous and granular layers of the epidermis of IBS patients, whereas in EHK lysis occurs in the lower spinous layer. Recently, mutations in the helix initiation and termination motifs of keratin 2e (K2e) have been described in IBS patients. The majority of the mutations reported to date lie in the 2B region. In this report, we have examined a large kindred in which the disease was originally diagnosed as EHK and mapped to the type II keratin cluster on chromosome 12q. Molecular analysis revealed a novel amino acid substitution at the beginning of the conserved 1A region of the rod domain (I4N) of K2e, resulting from a T to A transversion in codon 188. (+info)
Autoantibodies in a subgroup of patients with linear IgA disease react with the NC16A domain of BP1801.
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Linear IgA disease is an autoimmune subepidermal blistering disease characterized by IgA deposits at the cutaneous basement membrane zone. IgA antibodies from linear IgA disease sera react with antigens of 97 kDa (LABD97) and 120 kDa (LAD-1), both of which appear to be fragments of the extracellular domain of bullous pemphigoid 180 (type XVII collagen). The aim of this study was to determine whether linear IgA disease sera react with the immunodominant region of BP180 (NC16A domain), which is a major target of IgG autoantibodies produced by patients with bullous pemphigoid. Indeed, 11 of 50 linear IgA disease sera were found to contain IgA autoantibodies that recognized a recombinant form of NC16A by immunoblotting. The same sera also reacted with NC16A by enzyme-linked immunosorbent assay. An epitope mapping analysis uncovered four linear IgA disease-associated epitopes located within the 45 amino acid N-terminal stretch of NC16A, all of which were previously identified as antigenic sites targeted by bullous pemphigoid autoantibodies. Eight of the linear IgA disease sera that were reactive with NC16A also recognized LAD-1 secreted by the SCC-25 cell line, and five sera recognized BP180 extracted from keratinocytes. Linear IgA disease sera depleted of reactivity to NC16A by immunoadsorption continued to react with both the LAD-1 antigen and BP180 by immunoblotting and with the basement membrane zone by indirect immunofluorescence microscopy. Our results demonstrate that IgA autoantibodies from a subset of linear IgA disease patients react with the same sites on BP180 that are targeted by IgG autoantibodies in bullous pemphigoid. (+info)
A novel asparagine-->aspartic acid mutation in the rod 1A domain in keratin 2e in a Japanese family with ichthyosis bullosa of Siemens.
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Ichthyosis bullosa of Siemens is a unique type of congenital ichthyosis characterized by mild hyperkeratosis over the flexural areas and blister formation after mechanical trauma and superficial denuded areas in the hyperkeratotic skin. Recently, mutations in the helix initiation or termination motifs of keratin 2e (KRT2E) have been described in ichthyosis bullosa of Siemens patients. The majority of the mutations reported to date lie in the 2B region. We report a novel amino acid substitution mutation (asparagine-->aspartic acid) in codon 192 at the conserved 1A helix initiation site of the rod domain of KRT2E in a Japanese family with ichthyosis bullosa of Siemens. Our data indicate aspartic acid substitution in codon 192 in the 1A helix initiation site is deleterious to keratin filament network integrity and leads to ichthyosis bullosa of Siemens phenotype. (+info)
The shed ectodomain of collagen XVII/BP180 is targeted by autoantibodies in different blistering skin diseases.
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Collagen XVII/BP180, an epidermal adhesion molecule, exists as a full-length transmembrane protein and as a soluble 120-kd ectodomain that is shed from the keratinocyte surface by furin-mediated proteolysis. Despite a number of studies on autoantibody targets in blistering skin diseases, it has remained unclear whether the physiologically shed ectodomain of collagen XVII plays a role as an autoantigen. Here we isolated the authentic, soluble form of human collagen XVII and showed that it is an autoantigen recognized by IgG and IgA autoantibodies in different blistering skin diseases and is, in some cases, the preferential target. The ectodomain was isolated from the epidermis, keratinocyte media, amniotic fluid, and pemphigoid blister fluid, and autoantibodies affinity-purified with this ectodomain bound to the proximal surface of the epidermis in normal skin but not in collagen XVII-deficient skin. The antibody reactivity was not dependent on the native conformation or the N-glycosylation of the soluble ectodomain, but was abolished by collagenase treatment. Sera of 81 patients with a clinically active blistering skin disease were reacted with full-length collagen XVII, the authentic soluble ectodomain, and recombinant fragments. In bullous and cicatricial pemphigoid, IgG reactive with full-length collagen XVII also recognized the soluble ectodomain. In linear IgA dermatosis and chronic bullous dermatosis of childhood, IgA targeted the soluble ectodomain more efficiently than the full-length protein. The use of recombinant fragments demonstrated that epitopes were present in several noncollagenous and collagenous subdomains of the molecule, and that a significant portion of the sera targeted Col15 domain, a hitherto unrecognized epitope region. (+info)
Antibodies to human papillomavirus type 5 are generated in epidermal repair processes.
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We reported previously that patients with psoriasis harbored at a very high frequency DNA sequences of the oncogenic human papillomavirus type 5 (HPV5) associated with epidermodysplasia verruciformis. Moreover anti-HPV5 antibodies were detected in 25% of the cases. Our aim was to find out whether keratinocyte hyperproliferation and/or autoimmunity could be responsible for HPV5 expression in psoriasis. We found that epidermal repair in patients with extensive second degree burns (n = 19) is frequently associated with the generation of anti-HPV5 antibodies. In patients with autoimmune bullous diseases (n = 118), a condition in which keratinocyte proliferation is involved in repair mechanisms, the prevalence of anti-HPV5 antibodies (15%-25%) was similar to that reported in psoriasis and significantly higher than that (5%) observed in individuals with no known history of human papillomavirus infection (n = 119). A high detection rate (57.9%) of HPV5 DNA was observed in patients with bullous diseases. Anti-HPV5 antibodies were found in patients with autoimmune connective tissue disorders with cutaneous involvement (n = 40) as frequently as in patients with bullous diseases. HPV5 DNA was detected in one of the 10 patients studied. In contrast, the prevalence of anti-HPV5 antibodies in patients with autoimmune neurological disorders (n = 47) and in patients with common warts (n = 28) or invasive carcinomas of the skin (n = 40) was as low as in the general population. It is worth stressing that a similar prevalence of antibodies against HPV1 was found in all groups studied. Our data strongly suggest that extensive keratinocyte proliferation is a major factor for the generation of anti-HPV5 antibodies and that autoimmunity may contribute to this phenomenon. It remains to be determined whether HPV5 and other human papillomavirus genotypes associated with epidermodysplasia verruciformis contribute to the hyperproliferation of keratinocytes occurring in epidermal repair and in psoriasis. (+info)
Autoantibodies against the processed ectodomain of collagen XVII (BPAG2, BP180) define a canine homologue of linear IgA disease of humans.
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Linear IgA disease (LAD) is an acquired autoimmune subepidermal blistering dermatosis that affects human children and adults. In contrast to bullous pemphigoid, in which autoantibodies recognize transmembrane type XVII collagen (BP180, BPAG2), LAD is associated with skin-fixed and circulating IgA autoantibodies that target LAD-1, the processed extracellular form of type XVII collagen. An immunologic homologue of LAD in humans was identified in two dogs according to the following criteria: 1) erosive, ulcerative, and crusted lesions seen on the face, in the oral cavity, and on the extremities, 2) dermoepidermal clefting present in the basement membrane lamina lucida without inflammation or with mild neutrophilic infiltration, 3) basement membrane-fixed IgG and/or IgA antibodies, and 4) circulating IgA and IgG autoantibodies that target the 120-kd soluble protein LAD-1. The present study establishes unequivocally the existence of a naturally occurring canine model of LAD of humans. (+info)
Erythema exsudativum multiforme induced by granulocyte colony-stimulating factor in an allogeneic peripheral blood stem cell donor.
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We describe a healthy peripheral blood stem cell (PBSC) donor who developed a cutaneous reaction, erythema exsudativum multiforme, during the administration of granulocyte colony-stimulating factor (G-CSF) for mobilization. The cutaneous lesions were located on his hips, apart from the site of G-CSF injection. Treatment with topical corticosteroid was commenced, and the lesions resolved completely within a week. Adverse cutaneous reactions induced by G-CSF have been reported infrequently in healthy donors. Further documentation of cases and their full evaluation will be of great importance for both physicians and PBSC donor. (+info)
Detection of human herpesvirus 8 DNA in pemphigus and chronic blistering skin diseases.
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Increased incidences of Kaposi's sarcoma and lymphoid malignancies have been observed in patients with pemphigus, and the human herpesvirus 8 (HHV-8) is very strongly associated with these tumors. Because the virus may be one of the triggering factors of pemphigus, we undertook this study to screen for the presence of HHV-8 in chronic blistering skin diseases including pemphigus. A total of 45 paraffin-embedded specimens were studied using nested polymerase chain reaction (PCR) with primers to amplify a 160-base pair HHV-8 fragment. HHV-8 DNA could be detected in 7 of 9 patients with pemphigus vulagris, and 1 of 2 with pemphigus foliaceus. All specimens of other blistering skin diseases were negative for HHV-8. On sequencing PCR products, the sequences were almost identical with the prototypic sequence for HHV-8, and a few base- pair substitutions at 1086C-T and 1139A-C were detected. The results of our study suggests that HHV-8 might have trophism for pemphigus lesions. Further studies including comparison of HHV-8 DNA load in both lesional and normal skin in the same patient, serological and animal studies would be helpful to study the relationship between HHV-8 and pemphigus. (+info)