Unveiling the autoreactome: Proteome-wide immunological fingerprints reveal the promise of plasma cell depleting therapy

The prevalence and burden of autoimmune and autoantibody mediated disease
continues to rise, yet the etiologies of many of these diseases remain
unclear. Despite numerous new targeted immunomodulatory therapies,
comprehensive approaches to apply and evaluate the effects of these
treatments longitudinally are lacking. Here, we leverage advances in
PhIPseq methodology to explore the modulation, or lack thereof, for
autoreactive antibodies proteome-wide in both health and disease. We
demonstrate that each individual, regardless of disease state, possesses a
distinct set of autoreactivities constituting a unique immunological
fingerprint, or "autoreactome”, that is remarkably stable over years.
In addition to uncovering important new biology, the autoreactome can be
used to better evaluate the relative effectiveness of various therapies in
altering autoantibody repertoires. We find that therapies targeting B-Cell
Maturation Antigen (BCMA) profoundly alter an individual’s autoreactome,
while anti-CD19 and CD-20 therapies have minimal effects, strongly
suggesting a rationale for BCMA or other plasma cell targeted therapies in
autoantibody mediated diseases.