Neutrophil-mediated carbamylation promotes articular damage in rheumatoid arthritis

Carbamylated histone antibodies potentiate osteoclast formation and associate with bone erosion in rheumatoid arthritis. Formation of autoantibodies to carbamylated proteins (anti-CarP) is considered detrimental in the prognosis of erosive rheumatoid arthritis (RA). The source of carbamylated antige...

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Published inScience advances Vol. 6; no. 44
Main Authors O’Neil, Liam J., Barrera-Vargas, Ana, Sandoval-Heglund, Donavon, Merayo-Chalico, Javier, Aguirre-Aguilar, Eduardo, Aponte, Angel M., Ruiz-Perdomo, Yanira, Gucek, Marjan, El-Gabalawy, Hani, Fox, David A., Katz, James D., Kaplan, Mariana J., Carmona-Rivera, Carmelo
Format Journal Article
LanguageEnglish
Published United States American Association for the Advancement of Science 01.10.2020
Subjects
Animals
Arthritis, Rheumatoid
Autoantibodies
Bone Resorption
Diseases and Disorders
Histones
Humans
Immunology
Mice
Neutrophils - pathology
Protein Carbamylation
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Summary:Carbamylated histone antibodies potentiate osteoclast formation and associate with bone erosion in rheumatoid arthritis. Formation of autoantibodies to carbamylated proteins (anti-CarP) is considered detrimental in the prognosis of erosive rheumatoid arthritis (RA). The source of carbamylated antigens and the mechanisms by which anti-CarP antibodies promote bone erosion in RA remain unknown. Here, we find that neutrophil extracellular traps (NETs) externalize carbamylated proteins and that RA subjects develop autoantibodies against carbamylated NET (cNET) antigens that, in turn, correlate with levels of anti-CarP. Transgenic mice expressing the human RA shared epitope (HLADRB1* 04:01) immunized with cNETs develop antibodies to citrullinated and carbamylated proteins. Furthermore, anti–carbamylated histone antibodies correlate with radiographic bone erosion in RA subjects. Moreover, anti–carbamylated histone–immunoglobulin G immune complexes promote osteoclast differentiation and potentiate osteoclast-mediated matrix resorption. These results demonstrate that carbamylated proteins present in NETs enhance pathogenic immune responses and bone destruction, which may explain the association between anti-CarP and erosive arthritis in RA.
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ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.abd2688