IRF4 Activity Is Required in Established Plasma Cells to Regulate Gene Transcription and Mitochondrial Homeostasis

et al. 2021

Med Oncol

Ibrutinib has clear efficacy for activated B-cell-like diffuse large B cell lymphoma (ABC-DLBCL) in previous clinical researches. However, the resistance of Ibrutinib has limited its therapeutic benefit and the potential mechanism remains unclear. This study was aimed to identify potential candidate genes and miRNA targets to overcome Ibrutinib resistance in ABC-DLBCL. First, two expression profiles were downloaded from the GEO database, which used to identify the DEGs related to Ibrutinib resistance in ABC-DLBCL cell lines by GEO2R analysis separately. And the common DEGs were obtained though Venn diagram. Then Gene ontology (GO) and pathway enrichment analysis were conducted by DAVID database. From STRING database, BCL6, IL10, IL2RB, IRF4, CD80, PRDM1and GZMB were determined to be the hub genes by protein–protein interaction (PPI) network. Through miRNA-mRNA targeting network, we found that BCL6, IRF4, CD80, and PRDM1 were common target genes of miR-30 family. The cBioPortal database showed that BCL6 had the highest level of genetic alterations among DLBCL. In addition, another expression profile from GEO database showed that BCL6 was significantly high expression in no responsive patients after Ibrutinib treatment, and the receiver operating characteristic (ROC) curve which was used to evaluate the relationship between BCL6 expression and its effect was 0.67. MTT assay showed that treatment with FX1 (a BCL6 inhibitor) can enhance the sensitivity of Ibrutinib in C481S BTK HBL-1 cells. The results suggested that BCL6 and miR-30 family maybe associate with Ibrutinib resistance in ABC-DLBCL.

Section: Discussionmentioning

confidence: 99%

Identification BCL6 and miR-30 family associating with Ibrutinib resistance in activated B-cell-like diffuse large B-cell lymphoma

Huang

et al. 2021

Med Oncol

“…In addition, we found that 8 genes (DOCK2, IRF4, Rac2, Lgals3, H2-Oa, Pdcd1lg2, Sash3, and Mzb1) related to B cell function or differentiation [42][43][44][45][46][47][48][49] were also downregulated after schistosome infection (Table 2), which might potentially contribute to the inhibition of IgE response. Genes related to lung development (FOXF1, ANO9, TRIM6, MMP27, Epor, Gata1, and Serpina) [50][51][52] and cell integrity (Villin and CRB1) [53,54] were found to be upregulated too, which indirectly supported the observed therapeutic effect of schistosome infection (Table 2).…”

Section: Lung-stage Schistosome Infection Moulded the Microenvironmenmentioning

confidence: 94%

Allergen specific Treg upregulated by lung-stage schistosome infection alleviates allergic airway inflammation via inhibiting IgE secretion

Luo

et al. 2020

Preprint

Schistosome infection showed protective effects against allergic airway inflammation (AAI). However,controversial findings exist especially regarding the timing of helminth infection and the underlying mechanisms. Moreover, most previous studies focused on understanding the preventive effect of schistosome infection on asthma (infection before allergen sensitization), while its therapeutic effects (infection after allergen sensitization) were rarely investigated. In this study, we investigated the therapeutic effects of schistosome infection on AAI using a mouse model of OVA induced asthma. To explore how the timing of schistosome infection influences its therapeutic effect, the mice were percutaneously infected with cercaria of Schistosoma japonicum at either 1 day before OVA induced asthma attack (infection at lung-stage during AAI) or 14 days before OVA induced asthma attack (infection at post lung-stage during AAI). We found that lung-stage schistosome infection significantly ameliorated OVA-induced AAI, whereas post lung-stage infection showed no therapeutic effect. Mechanistically, the lung-stage schistosome infection significantly upregulated the frequency of Treg, especially OVA specific Treg, in lung tissue, which negatively correlated with the level of OVA specific IgE. Depletion of Treg in vivo counteracted the therapeutic effect. Furthermore, transcriptomic analysis of lung tissue showed that lung-stage schistosome infection during AAI shaped the microenvironment to favor Treg induction. In conclusion, our data showed that lung-stage schistosome infection could relieve OVA induced asthma in a mouse model. The therapeutic effect was mediated by the upregulated OVA specific Treg which suppressed IgE production and Th2 cytokine secretion. Our results may facilitate the discovery of a new therapy for AAI.

“…We postulated that lung-stage schistosome infection generated a microenvironment facilitating Treg development in lung ( Figure 8C). In addition, we found that 8 genes (DOCK2, IRF4, Rac2, Lgals3, H2-Oa, Pdcd1lg2, Sash3, and Mzb1) related to B cell function or differentiation (49)(50)(51)(52)(53)(54)(55)(56) were also downregulated after schistosome infection (Table 2), which might potentially contribute to the inhibition of IgE response. Genes related to lung development (FOXF1, ANO9, TRIM6, MMP27, Epor, Gata1, and Serpina) (57)(58)(59) and cell integrity (Villin and CRB1) (60,61) were found to be upregulated too, which indirectly supported the observed therapeutic effect of schistosome infection (Table 2).…”

Section: Lung-stage Schistosome Infection Moulded the Microenvironmenmentioning

confidence: 94%

Allergen Specific Treg Upregulated by Lung-stage Schistosome Infection Alleviates Allergic Airway Inflammation via Inhibiting IgE Secretion

Luo

et al. 2020

Preprint

Background. Schistosome infection showed protective effects against allergic airway inflammation (AAI). However, controversial findings exist regarding the timing of helminth infection and the underlying mechanisms. Moreover, the therapeutic effects of schistosome infection on asthma were rarely investigated. Methods. The mice were percutaneously infected with cercaria of Schistosoma japonicum at either 1 day (infection at lung-stage during AAI) or 14 days before OVA induced asthma attack (infection at post lung-stage during AAI). Lung pathology, inflammatory cytokines, IgE and frequency of Treg were measured to evaluate the therapeutic effect. The modulation of allergen specific Treg were elucidated by adoptive transfer and Treg deletion in vivo. Finally, RNAseq was employed to explore the key molecules and pathways that might contribute to Treg upregulation. Results. We found that lung-stage schistosome infection significantly ameliorated OVA-induced AAI, whereas post lung-stage infection showed no therapeutic effect. Mechanistically, the lung-stage schistosome infection significantly upregulated the frequency of Treg, especially OVA specific Treg, in lung tissue, which negatively correlated with the level of OVA specific IgE. Depletion of Treg in vivo counteracted the therapeutic effect. Furthermore, transcriptomic analysis of lung tissue showed that lung-stage schistosome infection during AAI shaped the microenvironment to favor Treg induction. Conclusions. Our results proved that lung-stage schistosome infection could relieve OVA induced AAI in mouse model by the upregulated OVA specific Treg, which may facilitate the discovery of a new therapy for asthma.