Invited review article
Beyond steric hindrance: The role of adhesion signaling pathways in the pathogenesis of pemphigus

https://doi.org/10.1016/j.jdermsci.2007.05.005Get rights and content

Summary

Epidermal cell adhesion depends on the intercellular interactions of transmembrane cadherin glycoproteins, which form the basis of adherens junctions and desmosomes. Pemphigus is a blistering disease of the skin and mucous membranes characterized by autoantibodies against the cell surface desmosomal cadherins, desmoglein (Dsg) 3 and Dsg1. An unanswered question in pemphigus pathophysiology is the mechanism of acantholysis, or loss of keratinocyte cell adhesion. One longstanding theory for pemphigus pathogenesis is the concept of steric hindrance, in which pathogenic pemphigus autoantibodies cause loss of intercellular adhesion by directly interfering with desmosomal cadherin trans-interactions. However, several recent studies have demonstrated that modulation of p38MAPK, Rho family GTPase, c-myc, protein kinase C, and phospholipase C signaling pathways prevents keratinocyte dissociation induced by pemphigus autoantibodies. As it is unlikely that desmosomal signaling would occur only in response to pemphigus autoantibodies, these studies suggest that numerous different signaling molecules may play a role in desmosomal homeostasis. Many of these same signaling pathways regulate classical cadherins in adherens junctions. Given the recent discovery of bidirectional crosstalk between adherens junctions and desmosomes, it would be valuable to understand how signaling pathways implicated in pemphigus pathogenesis may be involved in more general mechanisms of desmosome and adherens junction regulation. In this review, we will summarize the evidence supporting a role for steric hindrance and signaling mechanisms in the pathogenesis of pemphigus acantholysis and discuss potential analogues in the classical cadherin literature.

Section snippets

Pemphigus: the classic autoimmune disease of epidermal cell adhesion

Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are autoimmune blistering diseases characterized by antibodies to the desmosomal cadherins Dsg3 and Dsg1 (reviewed in [1]). In PF, autoantibodies to Dsg1 cause blisters in the superficial epidermis. In mucosal dominant PV, autoantibodies to Dsg3 cause blisters in the suprabasal layer of the mucous membranes but not skin. In mucocutaneous PV, autoantibodies against both Dsg3 and Dsg1 cause suprabasilar blisters in the skin and mucous

Putting it in context: intercellular adhesive junctions in the epidermis

A fundamental question in pemphigus pathophysiology is how autoantibody binding to Dsg cell surface antigens leads to acantholysis. To answer this question, it is important to first understand the role of Dsgs in normal epidermal cell adhesion and homeostasis.

Desmosomes and adherens junctions represent the primary intercellular adhesive junctions in the epidermis and demonstrate several structural similarities, in addition to shared proteins. Adherens junctions appear earlier in development

Framing the debate: evidence for steric hindrance as a primary pathogenic mechanism in pemphigus

Immunomapping of pemphigus antibodies has demonstrated that pathogenic antibodies bind the amino-terminal extracellular domain of Dsgs that is predicted to form the trans-adhesive interface between cells [20], [21], [22], based on the crystal structures of classical cadherin molecules [23], [24], [25]. Mice deficient for Dsg3 demonstrate acantholytic lesions in the oral mucosa and areas of skin trauma, mimicking the phenotype of mucosal PV [26]. Additionally, staphylococcal exfoliative toxins,

Signaling as a pathogenic mechanism in PV: action or reaction?

Recently, the steric hindrance model was questioned by the report that PF IgG caused dissociation of keratinocytes without blocking Dsg1 homophilic trans-interaction [41]. Although the total amount of PF IgG used in inhibition studies (35 μg/mL) may have been too low to detect inhibition of Dsg1 trans-interactions, these and other studies have suggested that steric hindrance is not a primary pathogenic mechanism in PV.

The studies using E-cadherin blocking antibodies discussed above indicate that

Conclusions

The studies discussed have identified activation of multiple signaling pathways after binding of pemphigus IgG to cells (summarized in Fig. 5). Extrapolating from the classical cadherin literature, these signaling events may occur as a coordinated response to the loss of cell adhesion after binding of pathogenic antibodies to Dsg antigens. Thus, the steric hindrance hypothesis may not be mutually exclusive with recent data demonstrating signaling events in keratinocytes following PV IgG

Acknowledgements

We thank Ken Ishii, John Stanley, and Andrew Kowalczyk for critical review of the manuscript. This work was supported by a Dermatology Foundation Career Development Award (ASP).

Preety M. Sharma obtained her BSc and MSc in Microbiology from the University of Mumbai, India. She received her PhD in Cell and Molecular Biology from the University of Arkansas under the mentorship of Dr. Ronald Okimoto and Dr. Walter Bottje in 2005. Her PhD research on the association of gene polymorphisms with feed efficiency in broiler chickens was nationally recognized by the Poultry Science Association research certificate of excellence. Subsequently, she joined the Department of

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    Preety M. Sharma obtained her BSc and MSc in Microbiology from the University of Mumbai, India. She received her PhD in Cell and Molecular Biology from the University of Arkansas under the mentorship of Dr. Ronald Okimoto and Dr. Walter Bottje in 2005. Her PhD research on the association of gene polymorphisms with feed efficiency in broiler chickens was nationally recognized by the Poultry Science Association research certificate of excellence. Subsequently, she joined the Department of Transplant Pathology at the University of Pittsburgh Medical Center as a postdoctoral associate, where she studied the phylogenetics and molecular biology of BK polyoma virus. Currently she is working on the phage display cloning of human pemphigus autoantibodies in the laboratory of Dr. Aimee Payne.

    Aimee Payne obtained her BS degree with honors in Biology from Stanford University in 1993. She received her MD and PhD degree in Molecular and Cellular Biology from Washington University School of Medicine in 2001. After her medical internship at Pennsylvania Hospital, she completed dermatology residency and her postdoctoral fellowship at the University of Pennsylvania, where her work on phage display cloning of human monoclonal pemphigus autoantibodies was recognized with the American Academy of Dermatology Young Investigator Award. In 2006, she joined the faculty of the Department of Dermatology at the University of Pennsylvania, where she studies mechanisms of pathophysiology in pemphigus. She has served on the Board of Directors of the Society for Investigative Dermatology from 2005 to 2007 and is a member of Faculty of 1000 Medicine. Her work has been supported by the American Skin Association, the Dermatology Foundation, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

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