Lupus anti‐ribosomal P autoantibody proteomes express convergent biclonal signatures

Summary Lupus‐specific anti‐ribosomal P (anti‐Rib‐P) autoantibodies have been implicated in the pathogenesis of neurological complications in systemic lupus erythematosus (SLE). The aim of the present study was to determine variable (V)‐region signatures of secreted autoantibody proteomes specific for the Rib‐P heterocomplex and investigate the molecular basis of the reported cross‐reactivity with Sm autoantigen. Anti‐Rib‐P immunoglobulins (IgGs) were purified from six anti‐Rib‐P‐positive sera by elution from enzyme‐linked immunosorbent assay (ELISA) plates coated with either native Rib‐P proteins or an 11‐amino acid peptide (11‐C peptide) representing the conserved COOH‐terminal P epitope. Rib‐P‐ and 11‐C peptide‐specific IgGs were analysed for heavy (H) and light (L) chain clonality and V‐region expression using an electrophoretic and de‐novo and database‐driven mass spectrometric sequencing workflow. Purified anti‐Rib‐P and anti‐SmD IgGs were tested for cross‐reactivity on ELISA and their proteome data sets analysed for shared clonotypes. Anti ‐ Rib‐P autoantibody proteomes were IgG1 kappa‐restricted and comprised two public clonotypes defined by unique H/L chain pairings. The major clonotypic population was specific for the common COOH‐terminal epitope, while the second shared the same pairing signature as a recently reported anti‐SmD clonotype, accounting for two‐way immunoassay cross‐reactivity between these lupus autoantibodies. Sequence convergence of anti‐Rib‐P proteomes suggests common molecular pathways of autoantibody production and identifies stereotyped clonal populations that are thought to play a pathogenic role in neuropsychiatric lupus. Shared clonotypic structures for anti‐Rib‐P and anti‐Sm responses suggest a common B cell clonal origin for subsets of these lupus‐specific autoantibodies.