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Ligation of CD180 inhibits IFN-? signaling in a Lyn-PI3K-BTK-dependent manner in B cells.

ABSTRACT: A hallmark of systemic lupus erythematosus (SLE) is the consistent production of various auto-antibodies by auto-reactive B cells. Interferon-? (IFN-?) signaling is highly activated in SLE B cells and plays a vital role in the antibody response by B cells. Previous studies have shown that CD180-negative B cells, which are dramatically increased in SLE patients, are responsible for the production of auto-antibodies. However, the association between CD180 and IFN-? signaling remains unknown. In the present study, we explored the effect of CD180 on regulating the activation of IFN-? signaling in B cells. We found that the number of CD180-negative B cells was increased in MRL/Mp-Fas(lpr/lpr) lupus-prone mice compared with wild-type mice. Phenotypic analysis showed that CD180-negative B cells comprised CD138⁺ plasmablast/plasma cells and GL-7⁺ germinal center (GC) B cells. Notably, ligation of CD180 significantly inhibited the IFN-?-induced phosphorylation of signal transducer and activator of transcription 2 (STAT-2) and expression of IFN-stimulated genes (ISGs) in a Lyn-PI3K-BTK-dependent manner in vitro. Moreover, ligation of CD180 could also inhibit IFN-?-induced ISG expression in B cells in vivo. Furthermore, the Toll-like receptor 7 and Toll-like receptor 9 signaling pathways could significantly downregulate CD180 expression and modulate the inhibitory effect of CD180 signaling on the activation of IFN-? signaling. Collectively, our results highlight the close association between the increased proportion of CD180-negative B cells and the activation of IFN-? signaling in SLE. Our data provide molecular insight into the mechanism of IFN-? signaling activation in SLE B cells and a potential therapeutic approach for SLE treatment.

SUBMITTER: You M

PROVIDER: S-EPMC5301152 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Ligation of CD180 inhibits IFN-α signaling in a Lyn-PI3K-BTK-dependent manner in B cells.

You Ming M Dong Guanjun G Li Fanlin F Ma Feiya F Ren Jing J Xu Yujun Y Yue Huimin H Tang Ruijing R Ren Deshan D Hou Yayi Y

Cellular & molecular immunology 20150817 2

A hallmark of systemic lupus erythematosus (SLE) is the consistent production of various auto-antibodies by auto-reactive B cells. Interferon-α (IFN-α) signaling is highly activated in SLE B cells and plays a vital role in the antibody response by B cells. Previous studies have shown that CD180-negative B cells, which are dramatically increased in SLE patients, are responsible for the production of auto-antibodies. However, the association between CD180 and IFN-α signaling remains unknown. In th ...[more]

PMID: 26277892

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Project description:We have studied the tumor genomic evolution in a patient with metastatic breast cancer bearing an activating PIK3CA mutation. The patient was treated with the PI3Kα inhibitor BYL719 and achieved a lasting clinical response on BYL719, but eventually progressed to treatment and died shortly thereafter. A rapid autopsy was performed and a total of 14 metastatic lesions were collected for further analysis. In order to identify possible genetic determinants of acquired resistance to PI3Kα inhibition, we took a three-step approach. First, we examined both the primary tumor (before BYL719 treatment) and the new lung metastasis by whole genome sequencing (DNA from the spleen was used as a normal control). Then, we analyzed the primary tumor, lung metastasis, and the peri-aortic lesion that remained stable (responding) at the time of progression to BYL719 therapy by whole exome sequencing. Finally, to confirm and expand our findings, we sequenced the primary tumor and all the metastatic lesions to >500-fold coverage using a custom targeted deep-sequencing assay, MSK-IMPACT. Using this 3-step approach, we have demonstrated that patient’s lesion underwent parallel genetic evolution at multiple metastatic sites with different PTEN genomic alterations leading to a convergent PTEN- null phenotype resistant to PI3Kα inhibition. In order to expand our observations, we analyzed paired samples (pre-treatment and at progression) from six additional patients enrolled in the BYL719 trial. Acquired bi-allelic loss of PTEN was found in one additional patient treated with BYL719 whereas in two patients PIK3CA mutations present in the primary tumor were no longer detected at the time of progression. To functionally characterize our findings, inducible PTEN knockdown in sensitive cells resulted in resistance to BYL719, while simultaneous PI3K-p110β blockade reverted this resistance phenotype, both in cell lines and in PTEN-null xenografts derived from our patient. We conclude that parallel genetic evolution of separate sites with different PTEN genomic alterations leads to a convergent PTEN-null phenotype resistant to PI3Kα inhibition.

Dataset Information

Ligation of CD180 inhibits IFN-? signaling in a Lyn-PI3K-BTK-dependent manner in B cells.

Publications

Ligation of CD180 inhibits IFN-α signaling in a Lyn-PI3K-BTK-dependent manner in B cells.

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