記述言語：英語   出版者・発行元：Ejnmmi Research  

Background: Radium-223 dichloride improves survival and delays symptomatic skeletal events in patients with bone-metastatic castration-resistant prostate cancer; however, therapeutic responses vary considerably among individuals, and predictive germline biomarkers remain undefined. We conducted a prospective multicenter genome-wide association study within the KYUCOG-1901 cohort to identify germline single-nucleotide polymorphisms associated with the clinical efficacy of radium-223. Results: Among 93 patients with bone-predominant castration-resistant prostate cancer treated with up to six cycles of radium-223, the intronic variant rs1568679 in MEIS2 reached genome-wide significance for association with ≥ 30% decline in prostate-specific antigen (P < 5.0 × 10⁻⁸). Patients carrying the rs1568679 CC genotype exhibited significantly greater prostate-specific antigen decline and significantly longer symptomatic skeletal event–free survival, radiographic progression-free survival, and overall survival compared with those with TT/TC genotypes. In multivariate analyses adjusting for established clinical prognostic factors, the rs1568679 CC genotype remained independently associated with favorable clinical outcomes. Although rs1568679 showed no significant expression quantitative trait loci effect on MEIS2 expression, pathway enrichment analysis of MEIS2-associated regulatory networks revealed strong enrichment of genes involved in DNA repair and genomic stability. Conclusions: The germline variant rs1568679 in MEIS2 may represent a potential biomarker associated with favorable response to radium-223 in metastatic castration-resistant prostate cancer. These findings suggest that MEIS2-related DNA repair regulation may influence susceptibility to α-particle–induced cytotoxicity and may facilitate biomarker-driven treatment strategies for optimizing Ra-223 therapy. Trial registration: University Hospital Medical Information Network (UMIN), UMIN000040358, registered 11 May 2020, https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000045641.

DOI： 10.1186/s13550-026-01463-3

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記述言語：英語   出版者・発行元：Development Growth and Differentiation  

Primordial germ cells (PGCs), the precursors of the germline, have unique cellular characteristics to undergo long-distance migration to the embryonic gonads and have the potential to differentiate into somatic cells. Among the animal models studying PGC development, the chicken PGCs are an ideal model, since it is a rare model in which long-term PGC cultivation is applicable. Although the cultural applicability of chicken PGC makes it attractive for revealing the PGC character and its developmental processes, some differences from in vivo PGCs are known, such as the remarkable upregulation of cell proliferation and a lesser ability to reach the gonads. Understanding these differences at the molecular level is crucial. To this end, we first performed SMART-seq-based single-cell RNA sequencing to compare transcriptomes between in vivo PGCs and cultured PGCs. Our results revealed that PGC cultivation causes a shift from a MYC-dependent to a MYCN-dependent gene regulatory network (GRN) in PGCs, suggesting that this reprogramming contributes to the acquisition of proliferation ability and stem cell characteristics in cultured PGCs. Additionally, our results suggest that the MYCN-dependent GRN increases the risk of somatic differentiation, particularly in neural fate, in cultured PGCs. In addition, our transcriptome analysis identified a new cell population that shows molecular characteristics of germline-biased undifferentiated cells. Thus, our study provides fundamental molecular information to understand both the effects of PGC cultivation and the developmental process of chicken PGCs.

DOI： 10.1111/dgd.70049

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Allergy and Clinical Immunology  

Background: IgG4-related disease (IgG4-RD), an example of a type I immune disease, is an immune-mediated fibrotic disorder characterized by dysregulated resolution of severe inflammation and wound healing. However, truly dominant or pathognomonic autoantibodies related to IgG4-RD are not identified. Objective: We sought to perform single-cell RNA sequencing and T-cell receptor and B-cell receptor sequencing to obtain a comprehensive, unbiased view of tissue-infiltrating T and B cells. Methods: We performed unbiased single-cell RNA-sequencing analysis for the transcriptome and T-cell receptor sequencing and B-cell receptor sequencing on sorted CD3+ T or CD19+ B cells from affected tissues of patients with IgG4-RD. We also conducted quantitative analyses of CD3+ T-cell and CD19+ B-cell subsets in 68 patients with IgG4-RD and 30 patients with Sjögren syndrome. Results: Almost all clonally expanded T cells in these lesions were either Granzyme K (GZMK)-expressing CD4+ cytotoxic T cells or GZMK+CD8+ T cells. These GZMK-expressing cytotoxic T cells also expressed amphiregulin and TGF-β but did not express immune checkpoints, and the tissue-infiltrating CD8+ T cells were phenotypically heterogeneous. MKI67+ B cells and IgD−CD27−CD11c−CXCR5− double-negative 3 B cells were clonally expanded and infiltrated affected tissue lesions. GZMK+CD4+ cytotoxic T cells colocalized with MKI67+ B cells in the extrafollicular area from affected tissue sites. Conclusions: The above-mentioned cells likely participate in T-B collaborative events, suggesting possible avenues for targeted therapies. Our findings were validated using orthogonal approaches, including multicolor immunofluorescence and the use of comparator disease groups, to support the central role of cytotoxic CD4+ and CD8+ T cells expressing GZMK, amphiregulin, and TGF-β in the pathogenesis of inflammatory fibrotic disorders.

DOI： 10.1016/j.jaci.2023.11.916

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Allergy and Clinical Immunology  

Background: Germinal center (GC) responses controlled by T follicular helper (Tfh) and T follicular regulatory (Tfr) cells are crucial for the generation of high-affinity antibodies. Acquired immune responses to tissue-released antigens might be mainly induced in tertiary lymphoid organs (TLOs) with GCs in affected tissues. IgG4-related disease (IgG4-RD) demonstrates polarized isotype switching and TLOs in affected tissues. We performed single-cell transcriptomics of tissue-infiltrating T cells from these TLOs to obtain a comprehensive, unbiased view of tissue-infiltrating GC-Tfh cells. Objective: To identify GC-Tfh-cell subsets in TLOs in patients with IgG4-RD using single-cell transcriptomics. Methods: Single-cell RNA sequencing of sorted CD3+ T cells and multicolor immunofluorescence analysis were used to investigate CD4+CXCR5+Bcl6+ GC-Tfh cells in affected lesions from patients with IgG4-RD. Results: Infiltrating CD4+CXCR5+Bcl6+ Tfh cells were divided into 5 main clusters. We detected HLA+ granzyme K+ (GZMK+) Tfh cells with cytotoxicity-associated features in patients with IgG4-RD. We also observed abundant infiltrating Tfr cells with suppressor-associated features in patients with IgG4-RD. These GZMK+ Tfh cells and Tfr cells clustered together in affected tissues from patients with IgG4-RD. Conclusions: This single-cell data set revealed a novel subset of HLA+GZMK+ cytotoxic Tfh cells infiltrating affected organs in patients with IgG4-RD, suggesting that infiltrating Tfr cells might suppress cytotoxic Tfh cells.

DOI： 10.1016/j.jaci.2023.08.019

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Allergy and Clinical Immunology  

Background: How T follicular (Tfh) cells contribute to many different B-cell class-switching events during T-cell–dependent immune responses has been unclear. Diseases with polarized isotype switching offer a unique opportunity for the exploration of Tfh subsets. Secondary and tertiary lymphoid organs in patients with elevated tissue expression levels of IgE (Kimura disease, KD) and those of IgG4 (IgG4-related disease, IgG4-RD) can provide important insights regarding cytokine expression by Tfh cells. Objective: We sought to identify disease-specific Tfh cell subsets in secondary and tertiary lymphoid organs expressing IL-10 or IL-13 and thus identify different cellular drivers of class switching in 2 distinct types of fibrotic disorders: allergic fibrosis (driven by type 2 immune cells) and inflammatory fibrosis (driven by cytotoxic T lymphocytes). Methods: Single-cell RNA sequencing, in situ sequencing, and multicolor immunofluorescence analysis were used to investigate B cells, Tfh cells, and infiltrating type 2 cells in lesion tissues from patients with KD or IgG4-RD. Results: Infiltrating Tfh cells in tertiary lymphoid organs from IgG4-RD were divided into 6 main clusters. We encountered abundant infiltrating IL-10–expressing LAG3+ Tfh cells in patients with IgG4-RD. Furthermore, we found that infiltrating AICDA+CD19+ B cells expressing IL-4, IL-10, and IL-21 receptors correlated with IgG4 expression. In contrast, we found that infiltrating IL-13–expressing Tfh cells were abundant in affected tissues from patients with KD. Moreover, we observed few infiltrating IL-13–expressing Tfh cells in tissues from patients with IgG4-RD, despite high serum levels of IgE (but low IgE in the disease lesions). Cytotoxic T cells were abundant in IgG4-RD; in contrast, type 2 immune cells were abundant in KD. Conclusions: Our analysis revealed a novel subset of IL-10+LAG3+ Tfh cells infiltrating the affected organs of IgG4-RD patients. In contrast, IL-13+ Tfh cells and type 2 immune cells infiltrated those of KD patients.

DOI： 10.1016/j.jaci.2022.03.034

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