Beyond Autoantibodies: Biologic Roles of Human Autoreactive B Cells in Rheumatoid Arthritis Revealed by RNA-Sequencing.
Journal
Arthritis & rheumatology (Hoboken, N.J.)
ISSN: 2326-5205
Titre abrégé: Arthritis Rheumatol
Pays: United States
ID NLM: 101623795
Informations de publication
Date de publication:
04 2019
04 2019
Historique:
received:
10
05
2018
accepted:
01
11
2018
pubmed:
9
11
2018
medline:
28
12
2019
entrez:
9
11
2018
Statut:
ppublish
Résumé
To obtain the comprehensive transcriptome profile of human citrulline-specific B cells from patients with rheumatoid arthritis (RA). Citrulline- and hemagglutinin-specific B cells were sorted by flow cytometry using peptide-streptavidin conjugates from the peripheral blood of RA patients and healthy individuals. The transcriptome profile of the sorted cells was obtained by RNA-sequencing, and expression of key protein molecules was evaluated by aptamer-based SOMAscan assay and flow cytometry. The ability of these proteins to effect differentiation of osteoclasts and proliferation and migration of synoviocytes was examined by in vitro functional assays. Citrulline-specific B cells, in comparison to citrulline-negative B cells, from patients with RA differentially expressed the interleukin-15 receptor α (IL-15Rα) gene as well as genes related to protein citrullination and cyclic AMP signaling. In analyses of an independent cohort of cyclic citrullinated peptide-seropositive RA patients, the expression of IL-15Rα protein was enriched in citrulline-specific B cells from the patients' peripheral blood, and surprisingly, all B cells from RA patients were capable of producing the epidermal growth factor ligand amphiregulin (AREG). Production of AREG directly led to increased migration and proliferation of fibroblast-like synoviocytes, and, in combination with anti-citrullinated protein antibodies, led to the increased differentiation of osteoclasts. To the best of our knowledge, this is the first study to document the whole transcriptome profile of autoreactive B cells in any autoimmune disease. These data identify several genes and pathways that may be targeted by repurposing several US Food and Drug Administration-approved drugs, and could serve as the foundation for the comparative assessment of B cell profiles in other autoimmune diseases.
Identifiants
pubmed: 30407753
doi: 10.1002/art.40772
pmc: PMC6741783
mid: NIHMS995939
doi:
Substances chimiques
Autoantibodies
0
Cytokines
0
IL15RA protein, human
0
Receptors, Interleukin-15
0
EGFR protein, human
EC 2.7.10.1
ErbB Receptors
EC 2.7.10.1
Banques de données
GENBANK
['GSE99006']
Types de publication
Evaluation Study
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
529-541Subventions
Organisme : Cancer Prevention and Research Institute of Texas
ID : RP130570
Pays : International
Organisme : United States Department of Defense
ID : CA160591
Pays : International
Organisme : NCI NIH HHS
ID : R01 CA174385
Pays : United States
Organisme : Cancer Prevention and Research Institute of Texas
ID : RP180466
Pays : International
Organisme : Welch Foundation
ID : E-1774
Pays : International
Organisme : National Science Foundation
ID : 1705464
Pays : International
Organisme : Melanoma Research Alliance
ID : 509800
Pays : International
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2018, American College of Rheumatology.
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