Homo sapiens isolate:Human IgG isolate Targeted Locus (Loci)

Characterization of autoantibody repertoires in antibody-mediated diseases is necessary to understand pathophysiology and therapeutic approaches. Previous studies have characterized antibodies genetically coded by autoimmune B-cells, but little is known about actual circulating autoantibodies. We characterized circulating autoantibody repertoires in pemphigus vulgaris (PV) and foliaceus (PF) patients, who have anti-desmoglein 3 and 1 autoantibodies, respectively. We used a mass spectrometry-based proteomic approach to characterize autoantibodies affinity purified on desmoglein. Compared to genetic analysis of anti-desmoglein B cells, which suggest an oligoclonal response, proteomic analysis indicates a much more polyclonal response in which a few clones disproportionately produce most of the autoantibodies. There was no convergence of the autoantibody response among patients, as determined by variable heavy chain gene usage or heavy chain CDR3 sequence. Longitudinal analysis of antibodies over up to 6.6 years indicated that, although many antibody clones persist, the clonal landscape (i.e. amount of each clonal ab) changes. Many genetically detectable anti-desmoglein B-cells do not contribute detectably to the antibody response at each time point. These studies indicate a dynamic autoantibody response; imply targeting of VH genes will not be a useful strategy for therapy; and explain why similar overall anti-desmoglein titers may give variable disease activity.