Circulating IgG from a large subset of bullous pemphigoid (BP) patients reacted on immunoblot with a 120-kDa protein in conditioned keratinocyte culture medium and in keratinocyte cell extracts. A protein with a similar molecular weight was recognized by circulating IgA from a subset of patients with linear IgA dermatosis (LAD). Both affinity-purified 120-kDa-specific BP IgG and 120-kDa-specific LAD IgA bound to the roof of salt-split skin. Both proteins recognized are collagenous glycoproteins. Deglycosylation with N-glycosidase F resulted in an identical reduction in molecular weight for both the BP-IgG-recognized protein and the LAD-IgA-recognized protein. Both proteins were equally susceptible to digestion with type VII collagenase. Furthermore, both proteins were absent from conditioned culture medium of keratinocytes from patients with BP180-deficient general atrophic benign epidermolysis bullosa (GABEB). Immunodepletion studies showed that the 120-kDa LAD antigen could be removed from conditioned culture medium by anti-120-kDa BP IgG. Thus these results indicate that these proteins are either highly related or, most probably, identical. A strong antigenic relationship between the 120-kDa protein and the 180-kDa bullous pemphigoid antigen (BP180) was detected by cross-reaction of affinity-purified anti-120-kDa BP patient antibodies to BP180 and cross-reaction of monoclonal anti-180-kDa antibodies to the 120-kDa protein. Notwithstanding this cross-reactivity, the 120-kDa protein also exhibits unique epitopes demonstrated by the nonreactivity of individual anti-120-kDa BP and LAD patient serum with the 180-kDa antigen.
Integrin alpha6beta4 is a hemidesmosomal transmembrane molecule involved in maintaining basal cell-matrix adhesion through interaction of the large intracytoplasmic tail of the beta4 subunit with the keratin intermediate filament network, at least in part through its binding with plectin and BP180/type XVII collagen. Here we report a patient with predominant features of epidermolysis bullosa simplex due to a mutation in the integrin beta4 gene. The patient, a 49-y-old female, had mild blistering of hands and feet from birth on, dystrophy of the nails with onychogryposis, and enamel hypoplasia. She had no alopecia and no history of pyloric atresia. Electron microscopy and antigen mapping of a skin blister revealed that the level of separation was intraepidermal, low in the basal keratinocytes through the attachment plaque of the hemidesmosome. Immuno-fluorescence microscopy revealed absent binding of monoclonal antibody 450-11 A against the third fibronectin III repeat on the intracellular domain of integrin beta4, whereas binding was reduced with monoclonal antibodies recognizing epitopes on amino-terminal and carboxy-terminal ends of the polypeptide. At the molecular level the phenotype was caused by a novel 2 bp deletion 4733delCT in ITGB4, resulting in in-frame skipping of exon 36 and a deduced 50 amino acid deletion (1450-1499) within the third fibronectin type III repeat in the cytoplasmic domain of the integrin beta4 polypeptide. Immunoblot analysis demonstrated a 5 kDa shorter beta4 polypeptide. The 4733delCT mutation was heterozygously present in the DNA. The patient is also expected to be heterozygous for a null allele, as no full-size protein was detected in vitro and the epitope 450-11 A was absent in vivo. These data show that deletion of the third fibronectin type III repeat in the cytoplasmic domain of integrin beta4, which is thought to interact with BP180/type XVII collagen, is clinically pathogenic and results in a mild phenotype with predominant features of epidermolysis bullosa simplex.
This study shows that in a considerable number of supposedly IgG-mediated pemphigus patients IgA to Dsg1 and Dsg3 is also present. In most cases the antigen specificity of the IgA follows the antigen specificity of the IgG, although in a small number of cases IgA is present against the Dsg not recognized by IgG.
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