Defining Mechanisms of Autoimmunity in Pemphigus Vulgaris

A prominent question in the field of autoimmunity is how these diseases arise. Currently, the etiologies of many autoimmune diseases remain unclear. The work described here provides insight into this question in the context of pemphigus vulgaris (PV), a prototypic autoimmune disease characterized by serum autoantibodies to desmoglein (Dsg) 3. We utilize a combination of both antibody phage display and heterohybridoma to probe the anti-Dsg3 antibody repertoires of patients with PV. We first address whether a cohort of four patients with active disease demonstrate any shared characteristics in their anti-Dsg3 antibody repertoires (Chapter 2), and if so, why. We find shared utilization of VH1-46 in at least anti-Dsg3 antibody across all four patients, and that these VH1-46 autoantibodies require few to zero somatic mutations to bind Dsg3, which may explain their presence in all four patients studied. Based on this, we propose a “shared VH gene usage” theory in the development of PV and investigate rotavirus as a potential viral trigger of this autoimmune disease, as VH1-46 has also been observed in the antibody response to the rotavirus intermediate capsid protein VP6 (Chapter 3). We determine that, while uncommon, it is possible for a VH1-46 antibody to cross-react to both Dsg3 and VP6, and this can occur through either V(D)J recombination or somatic hypermutation. In addition, a subset of these cross-reactive antibodies can both inhibit rotavirus replication and Dsg3 adhesion in vitro, indicating that these cross-reactive antibodies may have a role in the context of both rotavirus infection and PV. Our findings indicate that VH1-46 may persist in the anti-Dsg3 antibody repertoires of certain people due to the ability of some of these antibodies to cross-react to a foreign antigen and thus provide protection during infection. Ultimately, the data presented here provide a better understanding of the pathophysiology of this disease as well as potential etiologies of Dsg3 antibody reactivity