Activated B cells steer fibroblasts towards a proinflammatory phenotype in giant cell arteritis

OBJECTIVES: Giant cell arteritis (GCA) is characterized by chronic large-vessel inflammation and remodelling. Within affected arteries, especially in aorta, organized B cell clusters are mainly localized in adventitia, where fibroblasts represent the dominant stromal population. This study aims to investigate fibroblast heterogeneity within these clusters and B cell-fibroblast interactions in vitro as possible contributors to disease chronicity in GCA. METHODS: Fibroblast phenotypes in CD20+B cell clusters in GCA and atherosclerotic aortic tissues were characterized using immunohistochemistry for fibroblast markers (CD90, PDPN, FAP, CD248, α-SMA) and cytokine expression (IL-6, GM-CSF, BAFF). In vitro, peripheral blood B cells from treatment-naïve GCA patients and healthy donors were stimulated and cocultured with human aortic adventitial fibroblasts (HAoAFs) using either direct cell coculture or transwell systems. To identify relevant molecular pathways for B cell-fibroblast interaction, HAoAFs were pre-treated with infliximab, tocilizumab, baricitinib or upadacitinib, followed by exposure to activated B cell conditioned medium (aBCCM). Protein secretion was assessed by ELISA, Luminex and Olink, mRNA expression was determined by qPCR. RESULTS: CD90+PDPN+immunofibroblasts mainly localized centrally, whereas CD90+FAP+ and CD90+CD248+fibroblasts mostly located at the border of the clusters. Fibroblasts in/around clusters co-expressed IL-6, GM-CSF, and BAFF. In vitro, HAoAFs cocultured with activated B cells or supernatants thereof upregulated IL-6, GM-CSF, PDPN, and FAP mRNA, and actively secreted IL-6, GM-CSF and BAFF, while type I collagen expression was suppressed. JAK-STAT inhibition abrogated these pro-inflammatory effects, whereas TNF-α and IL-6 receptor blockade did not. CONCLUSION: Activated B cells drive fibroblasts toward a pro-inflammatory phenotype, potentially sustaining chronic inflammation and disease progression in GCA. JAK-STAT signalling appears central to this effect, highlighting its therapeutic potency at the vascular level in GCA.