Arthritis & rheumatology (Hoboken, N.J.) · 2026
Single-Cell RNA Sequencing Informs Precision Targeting of Monogenic Lupus Associated With IKZF1 Haploinsufficiency.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Zheng Qi, Tan Yejun, Wang Zhaoling, Qian Yanjie, Ma Qian, Shen Danping, Lu Meiping
Аннотация
OBJECTIVE: This study aimed to investigate the mechanisms of immune dysregulation in a pediatric patient with monogenic lupus driven by IKZF1 haploinsufficiency.
METHODS: Peripheral immune cells from a patient with IKZF1 haploinsufficiency, patients with lupus with no currently known genetic mutations, and healthy controls were analyzed using single-cell RNA sequencing. Bioinformatic analyses, including pseudotime trajectory and network reconstruction, were performed. Activation of the type I interferon (IFN) pathway was evaluated by measuring serum cytokine levels, IFN signatures, and the phosphorylation status of JAK and STAT.
RESULTS: The patient with IKZF1 haploinsufficiency exhibited notable B cell and T cell dysregulation, with nearly total absence of Breg cells and an increased percentage of naive CD4+ T cells. Pseudotime analysis in this patient suggested simplified B cell differentiation trajectories with arrested maturation and naive-like cell resurgence. Weighted gene coexpression network analysis identified a lupus-linked gene module (IKZF1, DUSP1, JUN, FOS), with inferred networks suggesting compensatory stress circuits (DUSP1, DDX17). Overactivation of the IFN/JAK/STAT signaling pathway was observed in the patient with IKZF1 haploinsufficiency. Given persistent thrombocytopenia, baricitinib combined with mycophenolate mofetil was administered based on these findings. Her platelet count returned to normal in a month after combination therapy with baricitinib.
CONCLUSION: IKZF1 haploinsufficiency disrupted lymphocyte homeostasis, especially of Breg cells and naive CD4+ T cells, highlighting these as key IKZF1 functional targets. A phenotype- and single cell-based approach may offer a pathway toward more precise diagnosis and personalized treatment strategies for monogenic lupus.
METHODS: Peripheral immune cells from a patient with IKZF1 haploinsufficiency, patients with lupus with no currently known genetic mutations, and healthy controls were analyzed using single-cell RNA sequencing. Bioinformatic analyses, including pseudotime trajectory and network reconstruction, were performed. Activation of the type I interferon (IFN) pathway was evaluated by measuring serum cytokine levels, IFN signatures, and the phosphorylation status of JAK and STAT.
RESULTS: The patient with IKZF1 haploinsufficiency exhibited notable B cell and T cell dysregulation, with nearly total absence of Breg cells and an increased percentage of naive CD4+ T cells. Pseudotime analysis in this patient suggested simplified B cell differentiation trajectories with arrested maturation and naive-like cell resurgence. Weighted gene coexpression network analysis identified a lupus-linked gene module (IKZF1, DUSP1, JUN, FOS), with inferred networks suggesting compensatory stress circuits (DUSP1, DDX17). Overactivation of the IFN/JAK/STAT signaling pathway was observed in the patient with IKZF1 haploinsufficiency. Given persistent thrombocytopenia, baricitinib combined with mycophenolate mofetil was administered based on these findings. Her platelet count returned to normal in a month after combination therapy with baricitinib.
CONCLUSION: IKZF1 haploinsufficiency disrupted lymphocyte homeostasis, especially of Breg cells and naive CD4+ T cells, highlighting these as key IKZF1 functional targets. A phenotype- and single cell-based approach may offer a pathway toward more precise diagnosis and personalized treatment strategies for monogenic lupus.