Seven chain adaptive immune receptor repertoire analysis in rheumatoid arthritis reveals novel features associated with disease and clinically relevant phenotypes
In rheumatoid arthritis (RA), the activation of T and B cell clones specific for self-antigens leads to the chronic inflammation of the synovium. Here, we perform an in-depth quantitative analysis of the seven chains that comprise the adaptive immune receptor repertoire (AIRR) in RA. In comparison to controls, we show that RA patients have multiple and strong differences in the BCR repertoire including reduced diversity as well as altered isotype, chain and segment frequencies. We demonstrate that therapeutic TNF inhibition partially restores this alteration but find a profound difference in the underlying biochemical reactivities between responders and non-responders. Combining the AIRR with HLA typing, we identify the specific TCR repertoire associated with disease risk variants. Integrating these features, we further develop a molecular classifier that shows the utility of the AIRR as a diagnostic tool. Simultaneous sequencing of the seven chains of the human AIRR reveals novel features associated with the disease and clinically relevant phenotypes, including response to therapy. These findings show the unique potential of AIRR to address precision medicine in immune-related diseases. Overall design: Three complementary study designs were conducted to characterize the immune repertoire of RA, including case-control, case-case and longitudinal analyses Please note that the gender information for each sample (included in mixed sample records) is provided in the corresponiding sample description field.