Antibodies against keratinocyte antigens other than desmogleins 1 and 3 can induce pemphigus vulgaris-like lesions

• Published in: The Journal of clinical investigation 2000-12, Vol.106 (12), p.1467-1479
• Main Authors: Nguyen, V T, Ndoye, A, Shultz, L D, Pittelkow, M R, Grando, S A
• Format: Article
• Language: English
• Subjects: Acantholysis - immunology; Animals; Animals, Newborn; Autoantibodies - blood; Autoantibodies - immunology; Baculoviridae - genetics; Blister - immunology; Blister - pathology; Cadherins - genetics; Cadherins - immunology; Desmoglein 1; Desmoglein 3; Gene Deletion; Histocytochemistry; Humans; Immunization, Passive; Immunoglobulin G - blood; Immunoglobulin G - immunology; Keratinocytes - immunology; Mice; Mice, Knockout; Pemphigus - blood; Pemphigus - genetics; Pemphigus - immunology; Pemphigus - pathology; Phenotype; Recombinant Fusion Proteins - immunology; Skin - immunology; Skin - pathology
• ISSN: 0021-9738
• DOI: 10.1172/JCI10305

Pemphigus is an autoimmune disease of skin adhesion associated with autoantibodies against a number of keratinocyte antigens, such as the adhesion molecules desmoglein (Dsg) 1 and 3 and acetylcholine receptors. The notion that anti-Dsg antibodies alone are responsible for blisters in patients with pemphigus vulgaris (PV) stems from the ability of rDsg1 and rDsg3 to absorb antibodies that cause PV-like skin blisters in neonatal mice. Here, we demonstrate that PV IgGs eluted from rDsg1-Ig-His and rDsg3-Ig-His show similar antigenic profiles, including the 38-, 43-, 115-, and 190-kDa keratinocyte proteins and a non-Dsg 3 130-kDa polypeptide present in keratinocytes from Dsg 3 knockout mouse. We injected into Dsg 3-lacking mice the PV IgGs that did not cross-react with the 160-kDa Dsg 1 or its 45-kDa immunoreactive fragment and that showed no reactivity with recombinant Dsg 1. We used both the Dsg3(null) mice with a targeted mutation of the Dsg3 gene and the "balding" Dsg3(bal)/Dsg3(bal) mice that carry a spontaneous null mutation in Dsg3. These PV IgGs caused gross skin blisters with PV-like suprabasal acantholysis and stained perilesional epidermis in a fishnet-like pattern, indicating that the PV phenotype can be induced without anti-Dsg 3 antibody. The anti-Dsg 1 antibody also was not required, as its presence in PV IgG does not alter the PV-like phenotype in skin organ cultures and because pemphigus foliaceus IgGs produce a distinct phenotype in Dsg3(null) mice. Therefore, mucocutaneous lesions in PV patients could be caused by non-Dsg antibodies.