Pemphigus autoantibodies generated through somatic mutations target the desmoglein-3 cis-interface

Area of Science:

• Immunology
• Dermatology
• Autoimmune Diseases

Background:

• Pemphigus vulgaris (PV) is an autoimmune blistering disease.
• It is caused by autoantibodies targeting desmoglein (DSG) proteins DSG3 and DSG1.
• This leads to loss of keratinocyte cell adhesion.

Purpose of the Study:

• To investigate the characteristics of pathogenic autoantibodies in PV.
• To identify the specific targets of these autoantibodies on DSG3.
• To understand the role of somatic mutations in PV autoreactivity.

Main Methods:

• Isolation of IgG antibodies specific for DSG3 from PV patients.
• In vitro disruption of keratinocyte monolayers.
• Passive transfer model in neonatal mice.
• Epitope mapping to DSG3 extracellular subdomains (EC1 and EC2).
• Site-specific serological assays.
• Analysis of immunoglobulin gene usage and somatic mutations.

Main Results:

• Three isolated antibodies disrupted keratinocyte monolayers; two were pathogenic in mice.
• Pathogenic antibodies targeted the EC1 and EC2 subdomains of DSG3, involved in cis-adhesive interactions.
• The cis-adhesive interface on EC1 is the primary target for PV autoantibodies.
• Isolated autoantibodies exhibited high somatic mutations in complementarity-determining regions.
• Loss of DSG3 binding occurred upon reversion of somatic mutations to germline sequences.

Conclusions:

• The cis-adhesive interface of DSG3 is the immunodominant target for pathogenic PV autoantibodies.
• Autoreactivity in PV is dependent on somatic mutations, potentially arising from an immune response to an unrelated antigen.