Antibodies against keratinocyte antigens other than desmogleins 1 and 3 can induce pemphigus vulgaris–like lesions
Vu Thuong Nguyen, … , Mark R. Pittelkow, Sergei A. Grando
Vu Thuong Nguyen, … , Mark R. Pittelkow, Sergei A. Grando
Published December 15, 2000
Citation Information: J Clin Invest. 2000;106(12):1467-1479. https://doi.org/10.1172/JCI10305.
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Article

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

Abstract

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 Dsg3null mice with a targeted mutation of the Dsg3 gene and the “balding” Dsg3bal/Dsg3bal 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 Dsg3null mice. Therefore, mucocutaneous lesions in PV patients could be caused by non-Dsg antibodies.

Authors

Vu Thuong Nguyen, Assane Ndoye, Leonard D. Shultz, Mark R. Pittelkow, Sergei A. Grando

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Figure 4

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Passive transfer of PV and PF IgGs to neonatal Dsg3null mouse produce tw...
Passive transfer of PV and PF IgGs to neonatal Dsg3null mouse produce two distinct phenotypes in the epidermis. The PF IgG that immunorecognized Dsg 1 and did not cross-react with Dsg 3 and the PV3 IgG that contained antibodies to both Dsg 1 and Dsg 3 were injected at a dose of 10 mg/g body weight into 10- to 12-hour-old neonates of the litter that resulted from breeding homozygous female and male Dsg3null mice. Wrinkling of the skin of a Dsg3null mouse was noticed approximately 20 hours after a single injection of PF IgG (a). Approximately 22 hours after injection, the pups were euthanized, and two skin specimens, one from the neck/head area and one from abdominal skin, were obtained, stained with H&E, and examined by light microscopy. In both anatomical regions, the epidermal split induced by PF IgGs is subcorneal, rather than suprabasilar (b and c). The subcorneal location of the split can be easily misinterpreted as being suprabasilar in locations where the basal cell layer is the only nucleated cell layer of the epidermis (arrows). The accurate conclusions, however, should be drawn based on the phenotype found in the skin regions where the epidermis is thick, such as in the most parts of the specimen from the head/neck area shown in the b. In this skin region, the suprabasilar split caused by PV3 IgG is seen in the deep epidermis (d). The Dsg 3–/– genotype of these mice was confirmed by PCR amplification of the sequences of genomic DNA extracted from the tail (1). Scale bar = 50 μm.