PhIP-Seq characterization of autoantibodies from patients with multiple sclerosis, type 1 diabetes and rheumatoid arthritis

Autoimmune disease arises when the immune system loses tolerance to the body’s own proteins in genetically susceptible individuals. Identifying which self-proteins are being targeted has traditionally required candidate-by-candidate testing, which limits the scale and breadth of discovery. The authors had previously built a phage-displayed synthetic human peptidome — a library that displays short peptide fragments spanning the human proteome on the surface of bacteriophage particles — and validated it on a small set of patients with neurological autoimmunity.

This study scales that approach. Using phage immunoprecipitation sequencing (PhIP-Seq), the team screened 298 independent antibody repertoires drawn from healthy donors and from patients across three autoimmune diseases: multiple sclerosis (MS), type 1 diabetes (T1D), and rheumatoid arthritis (RA). For each individual, the assay returns a list of peptide-antibody interactions — an autoantibody fingerprint that includes both reactivities common in the general population and reactivities associated with specific disease states.

Three cohort-level findings emerged. T1D patients displayed a prematurely polyautoreactive phenotype — that is, broader autoreactivity than their matched controls. The MS cohort, examined in both cerebrospinal fluid and serum from 63 patients, surfaced both novel antibody-peptide interactions and reactivities consistent with prior literature. The RA cohort, examined in synovial fluid and serum from 64 patients, revealed novel disease-associated specificities that did not depend on the patient’s conventional seropositivity status. Together the work demonstrates that proteome-wide autoantibody profiling is feasible at population scale and is informative about both shared and disease-specific autoreactivity.