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Beyond autoantibodies: Biological roles of human autoreactive B cells in rheumatoid arthritis revealed by whole transcriptome profiling

Ankit Mahendra, Xingyu Yang, Shaza Abnouf, Daechan Park, Sanam Soomro, Jay RT Adolacion, Jason Roszik, Cristian Coarfa, Gabrielle Romain, Keith Wanzeck, S. Louis Bridges Jr., Amita Aggarwal, Peng Qiu, Sandeep Krishna Agarwal, Chandra Mohan, Navin Varadarajan
doi: https://doi.org/10.1101/144121
Ankit Mahendra
1Department of Chemical & Biomolecular Engineering, University of Houston, Houston, TX
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Xingyu Yang
2Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia
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Shaza Abnouf
1Department of Chemical & Biomolecular Engineering, University of Houston, Houston, TX
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Daechan Park
3Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
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Sanam Soomro
4Department of Biomedical Engineering, University of Houston, Houston, TX
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Jay RT Adolacion
1Department of Chemical & Biomolecular Engineering, University of Houston, Houston, TX
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Jason Roszik
5Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX
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Cristian Coarfa
6Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, TX
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Gabrielle Romain
1Department of Chemical & Biomolecular Engineering, University of Houston, Houston, TX
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Keith Wanzeck
7Division of Clinical Immunology & Rheumatology, University of Alabama at Birmingham, Birmingham, AL
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S. Louis Bridges Jr.
7Division of Clinical Immunology & Rheumatology, University of Alabama at Birmingham, Birmingham, AL
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Amita Aggarwal
8Department of Clinical Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
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Peng Qiu
2Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia
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Sandeep Krishna Agarwal
9Section of Immunology, Allergy and Immunology, Department of Medicine, Baylor College of Medicine, Houston, TX
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Chandra Mohan
4Department of Biomedical Engineering, University of Houston, Houston, TX
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Navin Varadarajan
1Department of Chemical & Biomolecular Engineering, University of Houston, Houston, TX
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Abstract

Although the contribution of B-cell derived autoreactive antibodies to rheumatoid arthritis (RA) has been studied extensively, the autoantibody-independent roles of B cells in the progression of the disease is not well-defined. Here we present the first comprehensive transcriptome profile of human autoreactive B cells in an autoimmune disease by performing RNA-sequencing of citrulline-specific B cells from RA patients. In order to facilitate a comprehensive understanding of the profile of these citrulline-specific (RA-CCPPOS) B cells, we performed comparative analyses to both citrulline-negative (RA-CCPNEG) B cells from the same donors, and identified 431 differentially expressed genes (DEGs); and hemagglutinin-specific (HA) B cells from healthy individuals and identified 1658 DEGs. Three-way comparisons of these B cell populations demonstrated that RA-CCPPOS B cells, in comparison to the RA-CCPNEG B cells, demonstrate a potential role in protein citrullination and inflammation; RA-CCPPOS B cells in comparison to HA-specific B cells demonstrate RA-specific signatures like the expression of pro-inflammatory cytokines, chemokines, costimulatory molecules and B-cell activation cascades; and all B cells from RA patients demonstrated a significant impact of the multitude of TNF signaling pathways. Furthermore, transcription factor profiling suggested that cyclic AMP (cAMP) related pathways and downstream signaling molecules are selectively enriched in RA-CCPPOS cells in comparison to the other two B cell subsets. We advanced the understanding of the citrulline reactive B cells in RA pathophysiology by documenting and validating two novel observations in independent cohorts of patients: (1) the expression of IL15Rα is restricted to citrulline-specific cells within RA patients and the concentration of soluble IL15Rα is elevated in the sera of RA patients, (2) B cells from RA patients are capable of producing epidermal growth factor ligand, amphiregulin (AREG) which in turn has a direct impact on the mechanistic effectors of RA, osteoclasts and fibroblastlike synoviocytes (FLS). Overall, our comprehensive dataset identifies several existing FDA-approved drugs that can potentially be repurposed for RA and can serve as a foundation for studying the multi-faceted roles of B cells in other autoimmune diseases.

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Posted June 01, 2017.
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Beyond autoantibodies: Biological roles of human autoreactive B cells in rheumatoid arthritis revealed by whole transcriptome profiling
Ankit Mahendra, Xingyu Yang, Shaza Abnouf, Daechan Park, Sanam Soomro, Jay RT Adolacion, Jason Roszik, Cristian Coarfa, Gabrielle Romain, Keith Wanzeck, S. Louis Bridges Jr., Amita Aggarwal, Peng Qiu, Sandeep Krishna Agarwal, Chandra Mohan, Navin Varadarajan
bioRxiv 144121; doi: https://doi.org/10.1101/144121
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Beyond autoantibodies: Biological roles of human autoreactive B cells in rheumatoid arthritis revealed by whole transcriptome profiling
Ankit Mahendra, Xingyu Yang, Shaza Abnouf, Daechan Park, Sanam Soomro, Jay RT Adolacion, Jason Roszik, Cristian Coarfa, Gabrielle Romain, Keith Wanzeck, S. Louis Bridges Jr., Amita Aggarwal, Peng Qiu, Sandeep Krishna Agarwal, Chandra Mohan, Navin Varadarajan
bioRxiv 144121; doi: https://doi.org/10.1101/144121

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