Protective endogenous cyclic adenosine 5'-monophosphate signaling triggered by pemphigus autoantibodies.

Abstract

Pemphigus vulgaris (PV) is an autoimmune skin disease mediated by autoantibodies directed against the cadherin-type cell adhesion molecules desmoglein (Dsg) 3 and Dsg1 and is characterized by loss of keratinocyte cohesion and epidermal blistering. Several intracellular signaling pathways, such as p38MAPK activation and RhoA inhibition, have been demonstrated to be altered following autoantibody binding and to be causally involved in loss of keratinocyte cohesion. In this paper, we demonstrate that cAMP-mediated signaling completely prevented blister formation in a neonatal pemphigus mouse model. Furthermore, elevation of cellular cAMP levels by forskolin/rolipram or β receptor agonist isoproterenol blocked loss of intercellular adhesion, depletion of cellular Dsg3, and morphologic changes induced by Ab fractions of PV patients (PV-IgG) in cultured keratinocytes. Incubation with PV-IgG alone increased cAMP levels, indicating that cAMP elevation may be a cellular response pathway to strengthen intercellular adhesion. Our data furthermore demonstrate that this protective pathway may involve protein kinase A signaling because protein kinase A inhibition attenuated recovery from PV-IgG-induced cell dissociation. Finally, cAMP increase interfered with PV-IgG-induced signaling by preventing p38MAPK activation both in vitro and in vivo. Taken together, our data provide insights into the cellular response mechanisms following pemphigus autoantibody binding and point to a possible novel and more specific therapeutic approach in pemphigus.

• Authors: Volker Spindler, Franziska Vielmuth, Enno Schmidt, David S Rubenstein, Jens Waschke
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 185 Issue 11 Pg. 6831-8 (Dec 01 2010) ISSN: 1550-6606 [Electronic] United States
• PMID: 21037102 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Autoantibodies
• Immunoglobulin G
• Cyclic AMP

Topics

• Animals
• Animals, Newborn
• Autoantibodies (biosynthesis, physiology)
• Cell Line, Transformed
• Cyclic AMP (biosynthesis, physiology)
• Disease Models, Animal
• Epidermis (immunology, metabolism, pathology)
• Humans
• Immunoglobulin G (biosynthesis, physiology)
• Mice
• Mice, Inbred BALB C
• Pemphigus (immunology, metabolism, prevention & control)
• Signal Transduction (immunology)