Changes in the autoimmune blistering response: a clinical and immunopathological shift from pemphigus foliaceus to bullous pemphigoid.

We describe a 64-year-old Brazilian man who developed bullous pemphigoid (BP) 12 years after pemphigus foliaceus (PF) was diagnosed. On his first presentation in 1992, histological examination revealed intraepidermal blistering and acantholysis at the granular layer, direct immunofluorescence (DIF) demonstrated intercellular deposits of C3 in the epidermis, and indirect immunofluorescence showed the presence of IgG antibodies against the intercellular spaces. In 2004, laboratory findings revealed a subepidermal blister with neutrophils and eosinophils (by histology), DIF demonstrated deposition of IgG and C3 along the basement membrane zone, salt-split skin showed IgG deposition in the epidermal side of the blister, and immunoblotting showed reactivity against BP180. The occurrence of two autoimmune blistering conditions in the same patient is a rare event, and may suggest an intermolecular epitope-spreading phenomenon.

Immunodominant autoepitopes of type VII collagen are short, paired peptide sequences within the fibronectin type III homology region of the noncollagenous (NC1) domain.

Autoantibodies to type VII collagen are associated with the blistering diseases epidermolysis bullosa acquisita and bullous systemic lupus erythematosus. We showed previously that these autoantibodies recognize epitopes within the noncollagenous (NC1) region of type VII collagen. That region is composed of fibronectin type III homology units that may contribute to intermolecular cross-linking and basement membrane adhesion functions of type VII collagen. In this study, we defined the specific amino acid sequences recognized by these autoantibodies. By fusion protein analysis, sera from patients with epidermolysis bullosa acquisita and bullous lupus were found to react with two regions within the fourth (E-1) and eighth (E-2) fibronectin homology repeats, each consisting of approximately 100 amino acids. Affinity purification studies showed E-1 and E-2 to be independent and non-cross-reactive epitope regions. These regions were probed further by enzyme-linked immunosorbent assay analysis of overlapping octapeptide sets derived from the amino acid sequences of E-1 and E-2. The results showed two reactive, closely associated octapeptide sequences within each region, both lying in amphipathic portions of fibronectin type III homology repeats. These studies identify short peptide sequences within the NC1 domain of type VII collagen that are targeted independently by autoantibodies. These sequences may play a direct role in determining the properties of type VII collagen that influence adhesion between this molecule and other basement membrane proteins, and their alteration by antibody binding may be the immunopathogenic event underlying epidermolysis bullosa acquisita and bullous lupus.

Autoantibodies to type VII collagen recognize epitopes in a fibronectin-like region of the noncollagenous (NC1) domain.

Autoantibodies to type VII collagen are characteristic of the blistering diseases epidermolysis bullosa acquisita and bullous systemic lupus erythematosus (SLE). Blisters in those diseases are due to defective adhesion of the lamina densa subregion of the epithelial basement membrane to the underlying dermis. Previous studies indicating that type VII collagen contributes to lamina densa-dermal adhesion by cross-linking lamina densa and dermal matrix proteins suggests that autoantibodies may contribute to blisters by interfering with type VII collagen function. That hypothesis is supported by previous studies showing autoantibodies from a small number of epidermolysis bullosa acquisita patients recognize proteolytic fragments containing the 145-kD noncollagenous domain of type VII collagen. In this study, we examined reactivity of autoantibodies from a large number of epidermolysis bullosa acquisita and bullous SLE patients with fusion proteins representing most of the noncollagenous domain of type VII collagen and that those regions are homologous to type III repeats of fibronectin. These results suggest autoantibodies binding to fibronectin homology regions within the 145-kD noncollagenous domain may interfere with the adhesion function of type VII collagen and contribute to lamina densa-dermal dysadhesion in epidermolysis bullous acquisita and bullous SLE.

Noncollagenous (NC1) domain of collagen VII resembles multidomain adhesion proteins involved in tissue-specific organization of extracellular matrix.

Type VII collagen (C7) is a stratified squamous epithelial basement membrane protein composed of three identical alpha chains, each consisting of a 145-kDa amino-terminal noncollagenous (NC1) domain and a 145-kDa carboxyl-terminal collagenous domain. Morphologic and biochemical studies have shown that tissue-specific aggregates of C7 dimers called anchoring fibrils may contribute to epithelial basement membrane organization and adherence by interacting with extracellular matrix (ECM) proteins such as type IV collagen. In this study, we cloned a cDNA encoding most of the NC1 domain of C7. The deduced amino acid sequence revealed motifs characteristic of multidomain ECM proteins that contribute to the tissue-specific organization of ECM including a region of 7 1/2 sequential fibronectin type III (Fn III) homology repeats, a potential collagen-binding region homologous to the A domain of von Willebrand factor (vWf) and an RGD sequence. A purified C7 fusion protein containing these motifs specifically bound to type IV collagen in a functional assay. These results suggest that regions within the NC1 domain of C7 mediate interactions with lamina densa and dermal ECM proteins including type IV collagen. Structural mutations and autoepitopes in these regions may represent mechanisms for the development of defective basement membrane organization and adherence in genetic and autoimmune forms of epidermolysis bullosa.