Shared B cell receptor repertoire signatures across autoimmune diseases from integrated public datasets 2309774

Abstract

Abstract Introduction Autoimmune disorders arise from aberrant adaptive immune responses against self tissues and affect millions worldwide. B cells play a central role in many autoimmune diseases, as autoantibody production can directly drive disease pathogenesis. Each B cell expresses a unique B cell receptor (BCR), whose secreted form is an antibody. B cell tolerance is established during B cell development by eliminating or silencing cells with self-reactive BCRs before they reach maturity. However, this process is impaired in several autoimmune diseases. Thus, high-throughput profiling of the BCR repertoire can potentially reveal disease-associated alterations in BCR composition. Although many studies have sequenced BCR repertoires in autoimmune conditions, integrative analyses across diseases remain limited due to heterogeneous protocols and inconsistent metadata. Here, we conducted a large-scale meta-analysis of public BCR sequencing datasets to identify shared repertoire signatures of autoimmunity across multiple diseases. Methods We utilized nf-core/airrflow, an automated data analysis workflow we previously developed to homogeneously process BCR sequencing data using the Immcantation framework. Relevant clinical metadata were curated and harmonized from the original studies. The standardized analysis workflow enables extension of this meta-analysis to additional public datasets as they become available. Results We integrated BCR repertoires from 736 individuals with myasthenia gravis, systemic lupus erythematosus, type 1 diabetes, rheumatoid arthritis, and healthy controls from 13 publicly available studies. Across diseases, we evaluated repertoire features previously implicated in autoimmunity, including BCR heavy chain CDR3 length, CDR3 physicochemical properties, and IGHV gene usage. Conclusion This study demonstrates the feasibility and value of harmonised re-analysis of public BCR repertoire datasets, resulting in a unified resource for the study of BCR repertoires across autoimmune diseases. Funding Source This work is funded by the R01 supplement 3R01AI114780-09S1 to KCO, SHK and GG, and R01AI114780 to KCO. Topic Categories Basic Autoimmunity (BA)