Immunology letters · 2025
Characteristics and specific differential gene analysis of the TCR immune repertoire in secondary adult HLH lymphocytes.
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Chen Yongsheng, Xiao Wenrui, Yuan Shiyi, Wang Cong, Shi Meizhen, Yu Dan, Zhang Ying, Lou Shifeng
Аннотация
BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a severe, life-threatening, and hyperinflammatory disorder characterized by excessive immune activation and systemic immune dysregulation. Despite advancements in diagnosis, the underlying alterations in the immune repertoire in HLH remain poorly understood. This study aimed to characterize remodeling in the T cell receptor (TCR) immune repertoire in patients with HLH, focusing on V(D)J gene usage, complementarity-determining region 3 (CDR3) diversity, and clonotypic distribution, to better understand the immunological basis of the disease.
METHODS: Thirty individuals were enrolled, including 16 untreated patients with HLH(U group), 4 patients with HLH undergoing post-induction therapy (T group), and 10 healthy controls (Hc group). Peripheral blood TCRβ sequencing was performed to analyze V(D)J gene usage, CDR3 length distribution, and repertoire diversity. The relative diversity index (RDI) and hierarchical clustering of V-J pairing frequencies were applied to evaluate immune repertoire alterations. Statistical analyses included one-way ANOVA and Wilcoxon rank-sum tests to assess group differences, with a significance threshold of P < 0.05.
RESULTS: Compared to healthy individuals, patients with HLH exhibited significant alterations in TCR diversity, including increased CDR3 length variability and shifts in V(D)J gene usage (P < 0.05). In particular, TRBV5-1 and TRBJ2-7 expression was observed in patients with HLH. The V-J pairing analysis demonstrated that HLH samples clustered distinctly from healthy controls, suggesting immune dysregulation. RDI analysis revealed a significantly higher diversity in the M-HLH group than in the non-M-HLH group (P < 0.05), indicating higher clonal expansion in the malignant subgroup. Following induction therapy, TCR diversity showed partial recovery (P < 0.05);however, the immune repertoire remained distinct from that of healthy individuals (P < 0.05).
CONCLUSIONS: HLH is associated with profound immune repertoire remodeling, particularly in V-J gene pairing and CDR3 diversity. The RDI values and significant differences in gene pairing suggest antigen-driven clonal expansion in patients with HLH. Immune repertoire profiling may act as an effective biomarker for HLH classification and disease monitoring. Further studies with larger cohorts and longitudinal data are required to validate these findings and explore their clinical application in HLH.
METHODS: Thirty individuals were enrolled, including 16 untreated patients with HLH(U group), 4 patients with HLH undergoing post-induction therapy (T group), and 10 healthy controls (Hc group). Peripheral blood TCRβ sequencing was performed to analyze V(D)J gene usage, CDR3 length distribution, and repertoire diversity. The relative diversity index (RDI) and hierarchical clustering of V-J pairing frequencies were applied to evaluate immune repertoire alterations. Statistical analyses included one-way ANOVA and Wilcoxon rank-sum tests to assess group differences, with a significance threshold of P < 0.05.
RESULTS: Compared to healthy individuals, patients with HLH exhibited significant alterations in TCR diversity, including increased CDR3 length variability and shifts in V(D)J gene usage (P < 0.05). In particular, TRBV5-1 and TRBJ2-7 expression was observed in patients with HLH. The V-J pairing analysis demonstrated that HLH samples clustered distinctly from healthy controls, suggesting immune dysregulation. RDI analysis revealed a significantly higher diversity in the M-HLH group than in the non-M-HLH group (P < 0.05), indicating higher clonal expansion in the malignant subgroup. Following induction therapy, TCR diversity showed partial recovery (P < 0.05);however, the immune repertoire remained distinct from that of healthy individuals (P < 0.05).
CONCLUSIONS: HLH is associated with profound immune repertoire remodeling, particularly in V-J gene pairing and CDR3 diversity. The RDI values and significant differences in gene pairing suggest antigen-driven clonal expansion in patients with HLH. Immune repertoire profiling may act as an effective biomarker for HLH classification and disease monitoring. Further studies with larger cohorts and longitudinal data are required to validate these findings and explore their clinical application in HLH.