Abstract
Pemphigus vulgaris (PV) is an autoimmune epidermal blistering disease caused by autoantibodies directed against the desmosomal cadherin desmoglein-3 (Dsg3). Significant advances in our understanding of pemphigus pathomechanisms have been derived from the generation of pathogenic monoclonal Dsg3 antibodies. However, conflicting models for pemphigus pathogenicity have arisen from studies using either polyclonal PV patient IgG or monoclonal Dsg3 antibodies. In the present study, the pathogenic mechanisms of polyclonal PV IgG and monoclonal Dsg3 antibodies were directly compared. Polyclonal PV IgG cause extensive clustering and endocytosis of keratinocyte cell surface Dsg3, whereas pathogenic mouse monoclonal antibodies compromise cell-cell adhesion strength without causing these alterations in Dsg3 trafficking. Furthermore, tyrosine kinase or p38 MAPK inhibition prevents loss of keratinocyte adhesion in response to polyclonal PV IgG. In contrast, disruption of adhesion by pathogenic monoclonal antibodies is not prevented by these inhibitors either in vitro or in human skin explants. Our results reveal that the pathogenic activity of polyclonal PV IgG can be attributed to p38 MAPK-dependent clustering and endocytosis of Dsg3, whereas pathogenic monoclonal Dsg3 antibodies can function independently of this pathway. These findings have important implications for understanding pemphigus pathophysiology, and for the design of pemphigus model systems and therapeutic interventions.
Highlights
Desmosomes are adhesive intercellular junctions which are anchored to the keratin intermediate filament cytoskeleton [1,2,3,4,5]
Normal human epidermal keratinocytes were shifted from low calcium conditions to media containing 0.6 mM calcium chloride for 16–18 h and treated either with pemphigus vulgaris (PV) IgG or AK23, a monoclonal mouse IgG antibody directed against the putative adhesive interface near the amino-terminus of desmoglein 3 (Dsg3) [18]
In PV IgGtreated cultured keratinocytes, desmosomes were smaller in size, disorganized and exhibited reduced keratin association compared to control cells treated with normal human IgG (NH IgG) (Fig. 1P, Q, R, S)
Summary
Desmosomes are adhesive intercellular junctions which are anchored to the keratin intermediate filament cytoskeleton [1,2,3,4,5] These robust intercellular junctions are prominent in tissues that experience substantial mechanical stress, such as the skin and heart. Desmosomes are composed primarily of desmosomal cadherins, desmogleins and desmocollins, armadillo proteins such as plakoglobin and the plakophilins, and a plakin family member, desmoplakin. Together, these proteins couple calcium-dependent adhesive interactions mediated by the desmosomal cadherins to the intermediate filament cytoskeleton, thereby mechanically coupling adjacent cells [1,2,3]. It is wellestablished that PV and PF are caused by antibodies against desmogleins, the precise pathomechanism of pemphigus is not fully understood [11,13]
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