Dataset Information

Beyond Autoantibodies: Biologic Roles of Human Autoreactive B Cells in Rheumatoid Arthritis Revealed by RNA-Sequencing.

ABSTRACT:

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.

SUBMITTER: Mahendra A

PROVIDER: S-EPMC6741783 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Beyond Autoantibodies: Biologic Roles of Human Autoreactive B Cells in Rheumatoid Arthritis Revealed by RNA-Sequencing.

Mahendra Ankit A Yang Xingyu X Abnouf Shaza S Adolacion Jay R T JRT Park Daechan D Soomro Sanam S Roszik Jason J Coarfa Cristian C Romain Gabrielle G Wanzeck Keith K Bridges S Louis SL Aggarwal Amita A Qiu Peng P Agarwal Sandeep K SK Mohan Chandra C Varadarajan Navin N

Arthritis & rheumatology (Hoboken, N.J.) 20190223 4

<h4>Objective</h4>To obtain the comprehensive transcriptome profile of human citrulline-specific B cells from patients with rheumatoid arthritis (RA).<h4>Methods</h4>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 SOMA ...[more]

PMID: 30407753

Similar Datasets

Project description:Objective: use comprehensive molecular profiling to understand the molecular mechanisms that affect clinical response to anti-TNF therapy in rheumatoid arthritis (RA) and to identify predictive markers to differentiate good responders and non-responders. Methods: two independent cohorts of 40 and 36 biologic-naïve RA patients were selected from the Corrona (Comparative Effectiveness Registry to study Therapies for Arthritis and Inflammatory coNditions) CERTAIN registry and categorized by EULAR response criteria. Whole-blood RNA and plasma samples from baseline and after 3 months of anti-TNF treatment were profiled using RNA-seq, shotgun proteomics and glycopeptide analysis. A cell type-specific transcriptional data analysis was applied to RNA-seq data to evaluate the impact of the most common immune cell sub-populations. Results: a treatment-related molecular signature was identified that showed a high level of correlation (ρ=0.62; permutation p<0.01) between cohorts. Treatment led to a reduction of neutrophils, independent of the status of response. Gene expression differences between good responders and non-responders at baseline did not manifest statistically significant concordance genome-wide between the two cohorts. However, a cell type-specific analysis indicated increased representation of innate cell type signatures in good responders and, conversely, increased expression of adaptive cell type signatures in non-responders at baseline in both cohorts. This result was confirmed by applying the cell-type specific analysis to other publicly available RA datasets. Evaluation of the neutrophil to lymphocyte ratio (NLR) at baseline in the remaining patients (n=1962) from the CERTAIN database using a logistic regression model further confirmed the observation (odds ratio of good/moderate response = 1.20 [95% CI = 1.03 – 1.41; p = 0.02]). Conclusion: differences in innate/adaptive immune cell type composition at baseline may be a major contributor to response to anti-TNF treatment within the first 3 months of therapy.

Dataset Information

Beyond Autoantibodies: Biologic Roles of Human Autoreactive B Cells in Rheumatoid Arthritis Revealed by RNA-Sequencing.

Objective

Methods

Results

Conclusion

Publications

Beyond Autoantibodies: Biologic Roles of Human Autoreactive B Cells in Rheumatoid Arthritis Revealed by RNA-Sequencing.

Similar Datasets

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