Recognition of Amino Acid Motifs, Rather Than Specific Proteins, by Human Plasma Cell-Derived Monoclonal Antibodies to Posttranslationally Modified Proteins in Rheumatoid Arthritis

Arthritis & Rheumatology
Johanna SteenVivianne Malmström

Abstract

Antibodies against posttranslationally modified proteins are a hallmark of rheumatoid arthritis (RA), but the emergence and pathogenicity of these autoantibodies are still incompletely understood. The aim of this study was to analyze the antigen specificities and mutation patterns of monoclonal antibodies (mAb) derived from RA synovial plasma cells and address the question of antigen cross-reactivity. IgG-secreting cells were isolated from RA synovial fluid, and the variable regions of the immunoglobulins were sequenced (n = 182) and expressed in full-length mAb (n = 93) and also as germline-reverted versions. The patterns of reactivity with 53,019 citrullinated peptides and 49,211 carbamylated peptides and the potential of the mAb to promote osteoclastogenesis were investigated. Four unrelated anti-citrullinated protein autoantibodies (ACPAs), of which one was clonally expanded, were identified and found to be highly somatically mutated in the synovial fluid of a patient with RA. The ACPAs recognized >3,000 unique peptides modified by either citrullination or carbamylation. This highly multireactive autoantibody feature was replicated for Ig sequences derived from B cells from the peripheral blood of other RA patients. The pla...Continue Reading

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Citations

Apr 26, 2019·The Journal of Immunology : Official Journal of the American Association of Immunologists·Akilan KrishnamurthyAnca I Catrina
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Methods Mentioned

BETA
acetylation
flow cytometry
surface
immunoprecipitation
ELISAs
ELISA
electrophoresis
enzyme‐linked immunosorbent assay
surface plasmon resonance
peptide array

Software Mentioned

MUSCLE
GraphPad Prism
FigTree
Phylogeny
WebLogo

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