Desmoglein 3-specific B cell receptor

The Desmoglein 3 (DSG3)-specific B cell receptor (BCR) is a membrane-bound immunoglobulin expressed on the surface of B cells that specifically recognizes and binds to desmoglein 3, a cadherin-type cell adhesion molecule primarily found in epithelial tissues. DSG3 is best known as the primary autoantigen in pemphigus vulgaris (PV), an autoimmune blistering disease characterized by pathogenic autoantibodies targeting DSG3, leading to loss of keratinocyte cohesion and mucocutaneous blistering. In pemphigus vulgaris, autoreactive B cells expressing DSG3-specific BCRs are responsible for producing pathogenic anti-DSG3 IgG antibodies. The presence of these autoreactive B cells is central to disease pathogenesis; their activation leads to class switching from IgM to IgG, which is necessary for induction of the PV phenotype. Studies using knock-in mouse models with Dsg3-specific BCRs have shown that class switching from IgM to IgG enables these antibodies to access desmosomal cores and cause tissue pathology typical of PV. Selective depletion/modulation strategies—such as CAAR-T therapy—are under development aiming at precision elimination or control over these rare but highly consequential immune clones.

CAAR-T: Cytotoxic T cell killing of anti-DSG3-BCR-expressing autoreactive B lymphocytes FcRn Antagonism: Reduced circulating levels of pathogenic antibodies by blocking neonatal Fc receptor-mediated recycling