This item is under embargo for a period of 12 months from the date of publication, in accordance with the publisher's policy.The La/SSB autoantigen is a major target of long-term humoral autoimmunity
in primary Sjögren’s Syndrome (SS) and systemic lupus erythematosus.
A majority of patients with linked anti-Ro60/Ro52/La responses target
an NH2-terminal epitope designated LaA that is expressed on Ro/La
ribonucleoprotein complexes and the surface membrane of apoptotic cells.
In this study, we used high-resolution Orbitrap mass spectrometry to
determine the clonality, isotype and V-region sequences of LaA-specific
autoantibodies in seven patients with primary SS. Anti-LaA immunoglobulin
(Ig)Gs purified from polyclonal sera by epitope-specific affinity chromatography
were analysed by combined database and de-novo mass
spectrometric sequencing. Autoantibody responses comprised two heavily
mutated IgG1 kappa-restricted monoclonal species that were shared (public)
across unrelated patients; one clonotype was specified by an IGHV3-30
heavy chain paired with IGKV3-15 light chain and the second by an IGHV3-
43/IGKV3-20 pairing. Shared amino acid replacement mutations were also
seen within heavy and light chain complementarity-determining regions,
consistent with a common breach of B cell tolerance followed by antigendriven
clonal selection. The discovery of public clonotypic autoantibodies
directed against an immunodominant epitope on La, taken together with
recent findings for the linked Ro52 and Ro60 autoantigens, supports a model
of systemic autoimmunity in which humoral responses against protein–RNA
complexes are mediated by public sets of autoreactive B cell clonotypes.This work was supported by an Australian National Health
and Medical Research Council grant 1041900 to T. P.
Gordon and T. K. Chataway
