Cancer Cell | 在多发性骨髓瘤中，IRF4需要ARID1A来建立浆细胞特性 (美国国立研究院癌症研究中心)

DOI: 10.1016/j.ccell.2024.05.026

Tom T. et al.

Nat Immunol. 2024

    Immune-mediated inflammatory diseases (IMIDs), including Crohn's disease (CD), ulcerative colitis (UC), and rheumatoid arthritis (RA), lead to chronic inflammation due to impaired immune tolerance, which in turn leads to organ damage. Anti-tumor necrosis factor (anti-TNF) drugs have significantly improved the treatment of these diseases, but about 40% of patients do not respond to treatment or fail to achieve sustained remission. They constructed longitudinal single-cell RNA sequencing (scRNA-seq) profiles of adalimumab in CD and UC. The atlas contains approximately 1 million single-cell transcriptomes from 216 intestinal biopsy samples from 41 subjects, divided into 109 cell states, providing a detailed cellular census of perturbations caused by anti-TNF therapy. Using external IBD datasets, the authors developed a molecular method to quantify inflammation in the study cohort, which is comparable between CD and UC, provides a standardized method for assessing inflammation levels, and is of great value for comparing different samples and understanding disease severity. The study also explored the cellular correlation of endoscopic and histopathological indicators. The abundance of cell states correlated more strongly with histological inflammatory features than with clinical or endoscopic outcome measures. In inflammatory CD, there is a specific expansion of Th1 cells and epithelial remodeling is also unique, whereas in UC, there are differences in cell populations, such as an increase in IgG+ plasma cells and Th17 cells. These differences in cellular composition between CD and UC help us understand the different pathophysiological mechanisms behind each disease. Inflammatory hubs are localized to different spatial niches of CD and UC. Through consistent non-negative matrix factorization (cNMF), they identified gene expression programs (GEPs) within the cell type. Interferon response hubs were observed in both CD and UC, and the GEPs shared between CD and UC were spatially localized, providing insights into the spatial distribution of inflammation-related processes within the gut. Epithelial and myeloid features predict anti-TNF therapy outcomes. At baseline, differences in epithelial cell frequency and myeloid cell status correlated with remission and non-remission after adalimumab treatment. In CD, remission was associated with higher epithelial cell frequencies and specific myeloid cell status, whereas in UC, colonic goblet cells were more abundant in the remission group at baseline. These findings suggest that specific cellular signatures prior to treatment can predict response to anti-TNF therapy. Specific cellular features also underpin the failure to respond to anti-TNF therapy. After treatment, in unresolved cases, epithelial increase was inadequate and immune cell changes were minimal, except for myeloid expansion in UC. The abundance of cell states showed different patterns after treatment, and the differential analysis of cell-cell interactions showed an increase in interactions in unmitigated cases, suggesting worsening of the disease at the cellular level. Finally, the shared immune-mediated inflammatory disease (IMID) pathway is associated with the lymphocyte type of RA. Similarities in TNF pathway gene expression and lymphocyte infiltration procedures associated with interferon signaling were found in IBD and RA. This suggests that there may be a common pathological mechanism in these diseases, and that targeting interferon signaling may be a potential therapeutic strategy for IBD and RA.