PMID- 30407753 OWN - NLM STAT- MEDLINE DCOM- 20191227 LR - 20200401 IS - 2326-5205 (Electronic) IS - 2326-5191 (Print) IS - 2326-5191 (Linking) VI - 71 IP - 4 DP - 2019 Apr TI - Beyond Autoantibodies: Biologic Roles of Human Autoreactive B Cells in Rheumatoid Arthritis Revealed by RNA-Sequencing. PG - 529-541 LID - 10.1002/art.40772 [doi] AB - OBJECTIVE: To obtain the comprehensive transcriptome profile of human citrulline-specific B cells from patients with rheumatoid arthritis (RA). METHODS: 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. RESULTS: Citrulline-specific B cells, in comparison to citrulline-negative B cells, from patients with RA differentially expressed the interleukin-15 receptor alpha (IL-15Ralpha) 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-15Ralpha 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. CONCLUSION: 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. CI - (c) 2018, American College of Rheumatology. FAU - Mahendra, Ankit AU - Mahendra A AD - University of Houston, Houston, Texas. FAU - Yang, Xingyu AU - Yang X AD - Georgia Institute of Technology, Atlanta. FAU - Abnouf, Shaza AU - Abnouf S AD - University of Houston, Houston, Texas. FAU - Adolacion, Jay R T AU - Adolacion JRT AD - University of Houston, Houston, Texas. FAU - Park, Daechan AU - Park D AD - Ajou University, Suwon, Republic of Korea. FAU - Soomro, Sanam AU - Soomro S AD - University of Houston, Houston, Texas. FAU - Roszik, Jason AU - Roszik J AD - University of Texas MD Anderson Cancer Center, Houston. FAU - Coarfa, Cristian AU - Coarfa C AD - Baylor College of Medicine, Houston, Texas. FAU - Romain, Gabrielle AU - Romain G AD - University of Houston, Houston, Texas. FAU - Wanzeck, Keith AU - Wanzeck K AD - University of Alabama at Birmingham. FAU - Bridges, S Louis Jr AU - Bridges SL Jr AUID- ORCID: 0000-0003-3785-1389 AD - University of Alabama at Birmingham. FAU - Aggarwal, Amita AU - Aggarwal A AD - Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India. FAU - Qiu, Peng AU - Qiu P AD - Georgia Institute of Technology, Atlanta. FAU - Agarwal, Sandeep K AU - Agarwal SK AD - Baylor College of Medicine, Houston, Texas. FAU - Mohan, Chandra AU - Mohan C AD - University of Houston, Houston, Texas. FAU - Varadarajan, Navin AU - Varadarajan N AUID- ORCID: 0000-0001-7524-8228 AD - University of Houston, Houston, Texas. LA - eng SI - GENBANK/GSE99006 GR - RP130570/Cancer Prevention and Research Institute of Texas/International GR - CA160591/United States Department of Defense/International GR - R01 CA174385/CA/NCI NIH HHS/United States GR - RP180466/Cancer Prevention and Research Institute of Texas/International GR - E-1774/Welch Foundation/International GR - 1705464/National Science Foundation/International GR - 509800/Melanoma Research Alliance/International PT - Evaluation Study PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20190223 PL - United States TA - Arthritis Rheumatol JT - Arthritis & rheumatology (Hoboken, N.J.) JID - 101623795 RN - 0 (Autoantibodies) RN - 0 (Cytokines) RN - 0 (IL15RA protein, human) RN - 0 (Receptors, Interleukin-15) RN - EC 2.7.10.1 (EGFR protein, human) RN - EC 2.7.10.1 (ErbB Receptors) SB - IM CIN - Nat Rev Rheumatol. 2019 Mar;15(3):132-133. PMID: 30679818 MH - Arthritis, Rheumatoid/blood/*genetics/*immunology MH - Autoantibodies/*genetics/immunology MH - B-Lymphocytes/*immunology MH - Cytokines/blood/immunology MH - ErbB Receptors/blood/immunology MH - Humans MH - Leukocytes, Mononuclear/immunology MH - Receptors, Interleukin-15/blood/immunology MH - Sequence Analysis, RNA MH - Signal Transduction/immunology MH - Transcriptome/*immunology PMC - PMC6741783 MID - NIHMS995939 EDAT- 2018/11/09 06:00 MHDA- 2019/12/28 06:00 PMCR- 2020/04/01 CRDT- 2018/11/09 06:00 PHST- 2018/05/10 00:00 [received] PHST- 2018/11/01 00:00 [accepted] PHST- 2018/11/09 06:00 [pubmed] PHST- 2019/12/28 06:00 [medline] PHST- 2018/11/09 06:00 [entrez] PHST- 2020/04/01 00:00 [pmc-release] AID - 10.1002/art.40772 [doi] PST - ppublish SO - Arthritis Rheumatol. 2019 Apr;71(4):529-541. doi: 10.1002/art.40772. Epub 2019 Feb 23.