Antithyroid drug-induced agranulocytosis patients show distinct T-cell receptor repertoires compared to Graves' disease patients.

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.