Epiligrin, the major human keratinocyte integrin ligand, is a target in both an acquired autoimmune and an inherited subepidermal blistering skin disease.

Abstract

Epiligrin, the major component of human keratinocyte extracellular matrix, serves as the preferred integrin ligand for a3ft in plasma membranes and focal adhesions, and colocalizes with a684 in hemidesmosomes. In human skin, epiligrin is found in the lamina lucida subregion of epidermal basement membrane, where it is thought to be associated with anchoring filaments. We have identified three patients with an acquired mucosal predominant subepidermal blistering disease who have IgG anti-basement membrane autoantibodies that bind the lamina lucida/lamina densa interface of epidermal basement membrane, stain cultured human keratinocyte extracellular matrix, and immunoprecipitate disulfide linked polypeptides of 170, 145, 125, and 95 kD in human keratinocyte culture media in a pattern identical to that of PlEl, a murine monoclonal antiepiligrin antibody. Comparative immunoprecipitation studies of patient sera, PlEl, and GB3 monoclonal antibody show that epiligrin is identical to the antigen (i.e., BM600 or GB3 antigen) previously reported to be absent from the skin of patients with lethal junctional epidermolysis bullosa, an inherited subepidermal blistering disease. Moreover, skin from a fetus with this disease shows no evidence of reactivity to patient antiepiligrin autoantibodies or PlEl. These studies show that antiepiligrin autoantibodies are a specific marker for a novel autoimmune blistering disease and that the epidermal basement membrane antigen absent in patients with lethal junctional epidermolysis bullosa is epiligrin. (J. Clin. Invest. 1992.

Murine Laminin α3A and α3B Isoform Chains Are Generated by Usage of Two Promoters and Alternative Splicing

“…Laminin-5 is also the target for autoantibodies in cicatricial pemphigoid, an acquired autoimmune disease characterized by mucosal subepidermal blistering. The epitopes have been localized on the carboxyl-terminal globular domain of the laminin ␣3 chain (25). This is consistent with the observation that treatment with monoclonal antibody BM165, which is directed against the G domain of the laminin ␣3 chain, prevents adhesion of keratinocytes in vitro and in vivo (13) and with the experimental evidences for a role of the G domain of laminin-5 in nucleation and structural integrity of hemidesmosomes (26).…”

A Cell Signal Pathway Involving Laminin-5, α3β1 Integrin, and Mitogen-activated Protein Kinase Can Regulate Epithelial Cell Proliferation

“…The latter results in the dysadhesion of keratinocytes, thereby bringing about blistering in the epidermis in the region of keratinocyte-extracellular matrix interaction. In cicatricial pemphigoid, autoantibodies against LN5 appear to be pathogenic, and antibody binding to the basement membrane zone induces epithelial blistering (Domloge-Hultsch et al, 1992).…”

“…The latter results in the dysadhesion of keratinocytes, thereby bringing about blistering in the epidermis in the region of keratinocyte-extracellular matrix interaction. In cicatricial pemphigoid, autoantibodies against LN5 appear to be pathogenic, and antibody binding to the basement membrane zone induces epithelial blistering (Domloge-Hultsch et al, 1992).Yet even though LN5 is clearly involved in adhesion, its expression at the leading edges of migrating tumor populations suggests that this heterotrimer may play roles in cell motility and cell proliferation (Pyke et al, 1994(Pyke et al, , 1995. There is already published evidence that LN5 can enhance epithelial cell motility under certain circumstances (Zhang and Kramer, 1996;Giannelli et al, 1997;Goldfinger et al, 1998).…”

IgG anti-laminin-332 autoantibodies are present in a subset of patients with mucous membrane, but not bullous, pemphigoid

“…Affinity purified fluorescein isothiocyanate-conjugated goat F(ab′) 2 anti-human IgG (Biosource International, Camarillo, CA), horse radish peroxidase-conjugated goat F(ab′) 2 anti-mouse IgG (Biosource), alkaline phosphatase-conjugated goat F(ab′) 2 anti-human IgG (Biosource), alkaline phosphatase-conjugated goat F(ab′) 2 anti-rabbit IgG (Biosource), and ascites fluids containing mouse monoclonal anti-human IgG 1 (clone HP6001), anti-human IgG 2 (clone HP6014), anti-human IgG 3 (clone HP6050), anti-human IgG 4 (clone HP6025) (all from Sigma, St Louis, MO) were used in this study.…”