Background Many autoimmune diseases are characterized by aberrant B cells which play a central role in pathogenesis. Each B cell expresses a B Cell Receptor (BCR), which determines its specificity in binding to different epitopes and downstream antibody generation. For autoimmune diseases such as Type 1 Diabetes, Rheumatoid Arthritis, Multiple Sclerosis, Crohn’s and Celiac disease our current understanding of the role of unique BCR repertoires is poorly understood.

Methods Recent advances in single-cell RNA sequencing has allowed the field to simultaneously profile both the BCR and whole transcriptome leading to the characterization of clonal diversity of B cell subtypes. Existing BCR profiling methods using microfluidic barcoding exhibit limited throughput (processing of only thousands to tens of thousands of cells) and are associated with higher costs. To overcome these limitations, we developed a method to simultaneously characterize the BCR repertoire and full transcriptomes of up to 1 million cells from up to 96 samples in one experiment using combinatorial barcoding. We then applied this method to profile 12 healthy and 12 diseased samples.

Results From the combined whole transcriptome and BCR data, we defined BCR isotypes, captured on average 82% of cells with paired chains, detected full length chains, distinguished expanded & unique clones resulting in over 900,000 clonotypes detected, and identified all major B cell subtypes.

Conclusions In this study, over a million isolated human B cells were profiled from 24 donors including individuals with Type-1 Diabetes, Multiple Sclerosis, Rheumatoid Arthritis, Crohn’s, and Celiac disease; paving the way for high-throughput and sensitive screening of BCR repertoires to further the understanding of B cell biology and disease. The dataset is publicly available for researchers to further investigate and parse out deeper insights into immunology.