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Review
. 2012 Mar;132(3 Pt 2):776-84.
doi: 10.1038/jid.2011.390. Epub 2011 Dec 22.

Desmoglein as a target in skin disease and beyond

Masayuki Amagai  1 , John R Stanley
Affiliations
Review

Desmoglein as a target in skin disease and beyond

Masayuki Amagai et al. J Invest Dermatol. 2012 Mar.

Abstract

Much of the original research on desmosomes and their biochemical components was through analysis of skin and mucous membranes. The identification of desmogleins 1 and 3, desmosomal adhesion glycoproteins, as targets in pemphigus, a fatal autoimmune blistering disease of the skin and mucous membranes, provided the first link between desmosomes, desmogleins, and human diseases. The clinical and histological similarities of staphylococcal scalded skin syndrome or bullous impetigo and pemphigus foliaceus led us to identify desmoglein 1 as the proteolytic target of staphylococcal exfoliative toxins. Genetic analysis of striate palmoplantar keratoderma and hypotrichosis identified their responsible genes as desmogleins 1 and 4, respectively. More recently, these fundamental findings in cutaneous biology were extended beyond the skin. Desmoglein 2, which is expressed earliest among the four isoforms of desmoglein in development and found in all desmosome-bearing epithelial cells, was found to be mutated in arrythmogenic right ventricular cardiomyopathy and has also been identified as a receptor for a subset of adenoviruses that cause respiratory and urinary tract infections. The story of desmoglein research illuminates how dermatological research, originally focused on one skin disease, pemphigus, has contributed to understanding the biology and pathophysiology of many seemingly unrelated tissues and diseases.

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Figures

Figure 1
Figure 1
One of the major pieces of evidence that desmoglein 1 is the pemphigus foliaceus antigen. 2-dimensional gel electrophoresis of extracts of epidermis followed by immunoblotting with pemphigus foliaceus serum and an anti-desmoglein 1 antibody shows that both identify spots with the same migration, convincing proof that both bind the same protein. (From, Koulu, L., Kusumi, A., Steinberg, M.S., Klaus Kovtun, V., and Stanley, J.R. 1984. Human autoantibodies against a desmosomal core protein in pemphigus foliaceus. J. Exp. Med. 160:1509–1518).
Figure 2
Figure 2
Original data from the cloning of pemphigus vulgaris antigen. A) Purified λgt11 expression phage that contain cDNA for pemphigus vulgaris antigen. A single clone multiplies in bacteria, and all its offspring were blotted to nitrocellulose. All resultant clones stain positively with pemphigus vulgaris sera. The cDNA was sequenced to show that the protein produced was desmoglein 3. B) John Stanley (left) and Masayuki Amagai on the day in 1991 when the pemphigus vulgaris antigen clone was identified. (Amagai, M., Klaus-Kovtun, V., and Stanley, J.R. 1991. Autoantibodies against a novel epithelial cadherin in pemphigus vulgaris, a disease of cell adhesion. Cell 67:869–877.)
Figure 3
Figure 3
A monoclonal, monovalent anti-desmoglein 1 antibody cloned from a pemphigus foliaceus patient causes typical histology of pemphigus foliaceus when injected into normal human skin organ culture.
Figure 4
Figure 4
Coomassie blue gel showing cleavage of the 84-kD extracellular domain of desmoglein 1 to a 50 kD and 34 kD fragment, increasing with time of incubation with exfoliative toxin A. (Hanakawa, Y., Schechter, N.M., Lin, C., Nishifuji, K., Amagai, M., and Stanley, J.R. 2004. Enzymatic and molecular characteristics of the efficiency and specificity of exfoliative toxin cleavage of desmoglein 1. J. Biol. Chem. 279:5268–5277.)
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The future: therapy of pemphigus based on the understanding of its pathophysiology and immunology
Anti-idiotypic therapy
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Rituximab
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Signaling
    1. Berkowitz P, Hu P, Warren S, Liu Z, Diaz LA, Rubenstein DS. p38MAPK inhibition prevents disease in pemphigus vulgaris mice. Proc Natl Acad Sci U S A. 2006;103:12855–12860. - PMC - PubMed
    1. Nguyen VT, Arredondo J, Chernyavsky AI, Kitajima Y, Pittelkow M, Grando SA. Pemphigus vulgaris IgG and methylprednisolone exhibit reciprocal effects on keratinocytes. J Biol Chem. 2004;279:2135–2146. (Corticosteroids may by therapeutic in pemphigus by increasing synthesis of desmogleins) - PubMed

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