Background: The aim of the study was to investigate the landscape of B-cell-related gene expression profiling in rheumatoid arthritis (RA) synovium and explore the biological and clinical significance of these genes in RA.
Methods: Expression profiling of synovial biopsies from subjects with 152 RA patients, 22 osteoarthritis (OA) patients, and 28 healthy controls was downloaded from the Gene Expression Omnibus database. Single-sample gene set enrichment analysis (ssGSEA) was performed to evaluate the abundance of infiltrated immune cells, and the results were validated using immunohistochemical staining. GSEA was employed to decipher differences in B-cell-related biological pathways. B-cell-related differential expression genes (BRDEGs) were screened, and BRDEGs-based model was developed by machine learning algorithms and evaluated by an external validation set and clinical RA cohort, then biological functions were further analyzed.
Results: High levels of immune cell infiltration and B-cell-related pathway activation were revealed in RA synovium. BRDEGs were screened, and three key molecular markers consisting of FAS, GPR183, and TFRC were identified. The diagnosis model was established, and these gene markers have good discriminative ability for RA. Molecular pathological evaluation confirmed RA patients with high-risk scores presented higher levels of B-cell activation and RA characteristics. In addition, a competitive endogenous RNA network was established to elucidate the molecular mechanisms of the posttranscriptional network.
Conclusions: We described the B-cell-related molecular landscape of RA synovium and constructed a molecular diagnostic model in RA. The three genes FAS, GPR183, and TFRC may be potential targets for clinical diagnosis and immunoregulatory therapy of RA.
Amphiregulin (AREG) is a ligand of the epidermal growth factor receptor (EGFR) and has been shown to regulate the phagocytosis-induced cell death of monocytes in peripheral blood. AREG-dependent apoptotic signaling engages factors of the intrinsic and extrinsic apoptotic pathway, such as BCL-2, BCL-XL, and death ligand/receptor CD95/CD95L. Here, we tested the hypothesis that AREG influences costimulatory monocyte functions, which are crucial for T-cell responses. We found a stronger expression of AREG and EGFR in monocytes compared to lymphocytes. As a novel function of AREG, we observed reduced T-cell proliferation following polyclonal T-cell stimulation with OKT3. This reduction of proliferation occurred in the presence of monocytes as well as in their absence, monocyte signaling being replaced by crosslinking of OKT3. Increasing concentrations of AREG down-modulated the concentration of costimulatory B7 molecules (CD80/CD86) and HLA-DR on monocytes. In proliferation assays, CD28 expression on T cells was down-modulated on the application of OKT3 but unaltered by AREG. LcK activation, following OKT3-stimulation, was reduced in T cells that had been coincubated with AREG. The effects of AREG on T-cell phenotypes were also present when monocytes were depleted and OKT3 was crosslinked. The rearranged expression of immunological synapse proteins was accompanied by an alteration of T-cell polarization. Although the proportion of regulatory T cells was not shifted by AREG, IL-17-expressing T cells were significantly enhanced, with a bias toward TH1-polarization. Taken together, these results suggest that AREG acts as an immunoregulatory molecule at the interface between antigen-presenting cells and T cells.
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