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 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. 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.
OBJECTIVE: To obtain the comprehensive transcriptome profile of humancitrulline-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 RApatients 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 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 RApatients, the expression of IL-15Rα protein was enriched in citrulline-specific B cells from the patients' peripheral blood, and surprisingly, all B cells from RApatients 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.
Authors: Deepak A Rao; Michael F Gurish; Jennifer L Marshall; Kamil Slowikowski; Chamith Y Fonseka; Yanyan Liu; Laura T Donlin; Lauren A Henderson; Kevin Wei; Fumitaka Mizoguchi; Nikola C Teslovich; Michael E Weinblatt; Elena M Massarotti; Jonathan S Coblyn; Simon M Helfgott; Yvonne C Lee; Derrick J Todd; Vivian P Bykerk; Susan M Goodman; Alessandra B Pernis; Lionel B Ivashkiv; Elizabeth W Karlson; Peter A Nigrovic; Andrew Filer; Christopher D Buckley; James A Lederer; Soumya Raychaudhuri; Michael B Brenner Journal: Nature Date: 2017-02-01 Impact factor: 49.962
Authors: Christina D Swanson; Elliot H Akama-Garren; Emily A Stein; Jacob D Petralia; Pedro J Ruiz; Abdolhossein Edalati; Tamsin M Lindstrom; William H Robinson Journal: J Immunol Date: 2012-03-05 Impact factor: 5.422
Authors: S Takemura; A Braun; C Crowson; P J Kurtin; R H Cofield; W M O'Fallon; J J Goronzy; C M Weyand Journal: J Immunol Date: 2001-07-15 Impact factor: 5.422