Investigating the role of marginal zone B cells in the pathogenesis of pemphigus vulgaris

Pemphigus vulgaris (PV) is a life-threatening blistering disease mediated by anti-desmoglein antibodies. Pathogenic antibodies in PV are predominantly of the IgG4 subtype and are produced by short lived antibody secreting cells (ASCs). The reasons for this are unclear and B cell responses that are important for their induction are incompletely understood. Marginal zone B (MZB) cells are a distinct mature B cell subset that give rise to short lived ASCs and class switch to IgG4 in disease states. Our preliminary data demonstrates a high frequency of desmoglein autoreactivity amongst MZB cells. This project will investigate their role in the pathogenesis of PV as follows:

1. RNA sequencing of desmoglein specific cells in blood and skin to identify their transcriptomic properties and clonal relationships, specifically between MZB and IgG4 ASCs.

2. To compare pre- and post rituximab blood and skin samples to identify the phenotype of short lived pathogenic ASCs that are depleted after treatment.

3. To extrapolate these findings to other IgG4 mediated autoimmune diseases to assess whether there is shared disease biology. This project will therefore use PV as a disease model to identify the cellular responses that generate pathogenic ASCs, important factors that influence their longevity and potential therapeutic targets against them.