Uncovering a Shared Epitope-Activated Protein Citrullination Pathway
Rheumatoid arthritis (RA) is closely associated with shared epitope (SE)-coding alleles and circulating anticitrullinated protein Abs (ACPA), but neither the respective pathogenic roles of SE and ACPA in RA nor the mechanisms underlying their coassociation are known. It was recently shown that the S...
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Published in | The Journal of immunology (1950) Vol. 205; no. 3; pp. 579 - 586 |
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Main Authors | , , |
Format | Journal Article |
Language | English |
Published |
United States
AAI
01.08.2020
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Subjects | |
Online Access | Get full text |
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Summary: | Rheumatoid arthritis (RA) is closely associated with shared epitope (SE)-coding
alleles and circulating anticitrullinated protein Abs (ACPA), but neither the respective pathogenic roles of SE and ACPA in RA nor the mechanisms underlying their coassociation are known. It was recently shown that the SE functions as a signal transduction ligand that activates a cell surface calreticulin-mediated, proarthritogenic, bone erosive pathway in an experimental model of RA. In this study, we demonstrate that stimulation of murine macrophages with LPS or DTT facilitated cell surface translocation of calreticulin, which in turn enabled increased SE-activated calcium signaling and activation of peptidylarginine deiminase with the resultant increased cellular abundance of citrullinated proteins. The i.p. administration of LPS to transgenic mice carrying a human SE-coding
allele lead to increased serum levels of TNF-α and anticitrullinated cyclic peptide Abs, along with terminal phalanx bone destruction. These data uncover a previously unknown signal transduction pathway by which the SE facilitates protein citrullination, ACPA production, and bone destruction. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 V.v.D. and W.H.A. designed and conducted the experiments and wrote the manuscript. J.H. conceptualized and oversaw the project and edited the manuscript. V.v.D. and W.H.A. are equal contributors. |
ISSN: | 0022-1767 1550-6606 |
DOI: | 10.4049/jimmunol.1901108 |