Integrative Genomic and Immune Repertoire Profiling Identifies Clonal Signatures Linked to Antithyroid Drug-Induced Agranulocytosis

Graves disease (GD) is the leading cause of hyperthyroidism and is often treated with antithyroid drugs (ATDs). Although ATD therapy is effective, it might cause a rare but serious adverse effect called ATD-induced agranulocytosis (TiA), which can lead to severe neutropenia and life-threatening infections. Previous studies have shown that certain human leukocyte antigen (HLA) alleles, including HLA-B*38:02 and HLA-DRB1*08:03 in Asian populations, have been associated with TiA susceptibility. However, the underlying mechanisms remain unclear, highlighting the need to investigate the TiA-related immune alterations to better understand its pathogenesis and mechanisms. In this study, we investigated the immune receptor repertoire in TiA patients. Global repertoire diversity, VJ gene usage, and V-J pairing remained preserved across phenotypes and disease phases. Notably, TiA patients exhibited several upregulated complementarity-determining regions 3 (CDR3) clonotypes compared to GD patients, suggesting their role in disease progression and pathogenesis. Single-cell immune repertoire analysis revealed that TiA-associated risk CDR3 sequences were predominantly expressed on CD8+ effector memory T cells (CD8 TEM) in patients with HLA-B*38:02, while CD4+ central memory T cells (TCM) showed increased expression of risk CDR3 sequences in patients with HLA-DRB1*08:03, suggesting distinct cellular mechanisms underlying HLA-associated TiA pathogenesis. In conclusion, this study sheds light on the adaptive immunoprofile associated with TiA development and provides insights into the adaptive immune profile of TiA and HLA-mediated disease susceptibility.