Biased Usage of V/D/J Genes and Clonal Diversity in IgG Repertoires Correlates with Disease Activity and Clinical Features in Systemic Autoimmune Diseases.

Abstract

Objective: To examine whether features of the B cell receptor (BCR) IgG repertoire correlate with disease activity and clinical phenotypes in systemic autoimmune diseases (SAIDs).

Methods: High-throughput sequencing was performed on IgG heavy chain repertoires from 138 patients with SAIDs, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), scleroderma (SSc), and idiopathic inflammatory myopathy (IIM), as well as 36 healthy controls (HC). We analyzed V/D/J gene usage, clonal distribution and diversity, CDR3 length distribution and amino acid usage, and the correlation between specific BCR features and clinical features.

Results: SAIDs showed skewed usage of V/D/J genes and V-D-J combinations, with altered CDR3 length distributions and amino acid usage in SLE, RA, SSc, and IIM. Notably, SLE and RA exhibited a pronounced expansion of mid-ranked clones and significantly higher clonal diversity compared to HC. Specific genes, including IGHD2-15, IGHV1-24, IGHV1-69-2, IGHV1-8, and IGHV4 family members, along with increased clonal diversity, were closely associated with disease activity and clinical phenotypes in SLE and RA.

Conclusions: IgG repertoire features reflect disease-related immune perturbations and may serve as potential biomarkers for disease progression, diagnostics and targeted therapies in SAIDs.