Frontiers in immunology · 2026
Distinct remission immune architectures under rituximab and azathioprine in AQP4-IgG-positive neuromyelitis optica spectrum disorder.
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Shin Wangyong, Yoon Bohwan, Kim Hyo Jae, Seo Dayoung, Jang Inhye, Ryu Jihong, Choi Lynkyung, Kim Jinhee, Kim Hyunjin, Lim Young-Min, Jin Hyung-Seung, Lee Eun-Jae
Аннотация
INTRODUCTION: Maintenance immunotherapy is effective in AQP4-IgG-positive neuromyelitis optica spectrum disorder (NMOSD), but how mechanistically distinct maintenance therapies organize the remission immune landscape and its relationship to neurological disability remains poorly defined.
METHODS: We performed integrated multiparameter flow cytometry and plasma cytokine profiling in serial remission samples (up to three per patient) from 28 patients receiving rituximab (RTX, n = 14) or azathioprine (AZA, n = 14). Between-treatment comparisons, within-treatment coupling analyses, and disability-associated immune analyses were conducted using age-adjusted patient-clustered regression models with prespecified false discovery rate control.
RESULTS: RTX showed clear target engagement, characterized by profound B-cell depletion, gradual post-infusion reconstitution, and sustained reduction of natural killer T (NKT)-like cells. Beyond lineage depletion, RTX was associated with regulatory remodeling, including a memory-skewed regulatory T (Treg) phenotype and a lower effector-to-regulatory balance. In B-detectable RTX samples, the reconstituting B-cell compartment was transitional/naive-skewed with marked suppression of memory B cells. Although remission-phase cytokines were broadly low, interferon gamma-induced protein 10/CXC motif chemokine ligand 10 (IP-10/CXCL10) remained selectively elevated under RTX. Importantly, remission immune architecture differed by therapy: AZA showed a T cell immunoreceptor with Ig and ITIM domains (TIGIT)-linked regulatory disability axis, whereas RTX showed disability coupling to soluble inflammatory mediators, particularly interleukin-6 (IL-6) and IP-10.
CONCLUSION: Mechanistically distinct maintenance therapies impose divergent remission immune architectures in NMOSD. These findings support a treatment-aware framework for biomarker interpretation and suggest that remission monitoring should consider therapy-specific immune networks rather than isolated immune markers.
METHODS: We performed integrated multiparameter flow cytometry and plasma cytokine profiling in serial remission samples (up to three per patient) from 28 patients receiving rituximab (RTX, n = 14) or azathioprine (AZA, n = 14). Between-treatment comparisons, within-treatment coupling analyses, and disability-associated immune analyses were conducted using age-adjusted patient-clustered regression models with prespecified false discovery rate control.
RESULTS: RTX showed clear target engagement, characterized by profound B-cell depletion, gradual post-infusion reconstitution, and sustained reduction of natural killer T (NKT)-like cells. Beyond lineage depletion, RTX was associated with regulatory remodeling, including a memory-skewed regulatory T (Treg) phenotype and a lower effector-to-regulatory balance. In B-detectable RTX samples, the reconstituting B-cell compartment was transitional/naive-skewed with marked suppression of memory B cells. Although remission-phase cytokines were broadly low, interferon gamma-induced protein 10/CXC motif chemokine ligand 10 (IP-10/CXCL10) remained selectively elevated under RTX. Importantly, remission immune architecture differed by therapy: AZA showed a T cell immunoreceptor with Ig and ITIM domains (TIGIT)-linked regulatory disability axis, whereas RTX showed disability coupling to soluble inflammatory mediators, particularly interleukin-6 (IL-6) and IP-10.
CONCLUSION: Mechanistically distinct maintenance therapies impose divergent remission immune architectures in NMOSD. These findings support a treatment-aware framework for biomarker interpretation and suggest that remission monitoring should consider therapy-specific immune networks rather than isolated immune markers.