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Background: Giant Cell Arteritis (GCA), the most common form of large vessel vasculitis, has traditionally been managed under the assumption that its cranial (C-GCA) and large vessel (LV-GCA) manifestations share a uniform pathophysiology. However, emerging evidence suggests that C-GCA and LV-GCA may differ substantially in terms of immune drivers, response to treatment, and clinical severity. C-GCA predominantly involves cranial arteries, often causing irreversible blindness, whereas LV-GCA targets the aorta and its major branches, carrying a two- to five-fold higher risk of life-threatening aortic aneurysm or dissection compared with the general population [1]. Although atherosclerosis (ASVD) remains the most frequent cause of aortic aneurysm overall, inflammatory mechanisms in LV-GCA appear to play a critical yet underexplored role. Elucidating how LV-GCA diverges from C-GCA and differentiates from degenerative ASVD is paramount for refining current treatment approaches and improving patient outcomes.
Objectives: The primary objective was to compare C-GCA and LV-GCA at a molecular and immunological level in order to characterise shared and distinct immune mechanisms across vascular compartments. The secondary objective was to characterise the specific immune and molecular features of LV-GCA compared to ASVD as an important additional comparator and confounder, thereby identifying inflammatory drivers of aortic aneurysm specific to LV-GCA.
Methods: Using spatial transcriptomic, we profiled the adventitia, media, and intima layers of aortic aneurysm specimens from patients with LV-GCA (n=7) and from those undergoing surgery for atherosclerotic aneurysm (n=4). Temporal artery biopsy samples from C-GCA (n=6) were integrated to allow direct comparison with LV-GCA. All groups had a similar mean age and male-to-female ratio, ensuring a balanced demographic distribution. Regions enriched for CD68+ macrophages, CD45+ immune infiltrates, and CD90+ fibroblasts were selected. Differentially expressed genes were identified via DEseq2 (p.adj < 0.05, |log2 fold| > 0.5), and immune cell proportions inferred by CIBERSORTx. Overrepresentation analyses used STRING_11. To localise specific B cell and plasma cell populations, immunohistochemistry (IHC) and immunofluorescence (IF) for CD20, CD138, and IgG were performed, with QuPath used for quantitative analysis.
Results: Distinct immunological profiles emerged when comparing C-GCA and LV-GCA. Whereas lymphocyte infiltrates in C-GCA mainly overlapped with the molecular signature of CD4+ memory and CD8+ T cells, alongside overexpression of T cell–related genes (CXCL9, CCL5, GZMA), LV-GCA showed a pronounced B cell–centric molecular profile and associated genes (MZB1, PAX5, CD79A). Notably, in both GCA subtypes, granuloma-associated macrophages molecularly overlapped and converged on an M0-like polarisation state, suggesting a shared mechanism of tissue damage. In parallel, comparing LV-GCA to ASVD aneurysms revealed further immunobiological divergence beyond the adventitia, where both conditions featured B cell–rich arterial tertiary lymphoid organs (ATLOs). In histologically intact LV-GCA media, genes associated with fibroblasts (COL6A1, MMP2), macrophage activation (FCGR3A, CD68, CD163), and antigen presentation (HLA-DPA1, HLA-DQA1, HLA-DQB1, C1QB, C1QC) were markedly upregulated compared with ASVD. Medial inflammatory granuloma lesions contained CD68+ macrophages, CD90+ fibroblasts, and mixed immune infiltrates. CD68+ macrophages displayed strong antigen-presenting (HLA-DRA, HLA-DRB1) and proteolytic (CTSB, CTSD, MMP9) activities. Meanwhile, CD90+ fibroblast-rich areas exhibited a strong upregulation of collagen genes (increased COL6A2, COL1A2, COL4A2) alongside reduced smooth muscle markers (MYH11, TAGLN), supporting their role in vascular remodelling. CD45+ regions were enriched for B cell memory and plasma cell signatures, with most upregulated genes linked to B cell proliferation and antibody production (MZB1, IGHG1–4). Correspondingly, IHC/IF confirmed abundant CD20+ B cells and CD138+ IgG+ plasma cells in the LV-GCA media – features absent in ASVD, where B cells were largely confined to the adventitia. By comparison, ASVD lesions were predominantly in the intima and plaque-specific (APOE, CCL18, FOS) with minimal B cell involvement.
Conclusion: These results suggest that C-GCA and LV-GCA are not immunobiologically identical, with LV-GCA displaying a distinct B cell–driven medial pathology. This contrasts with both the T cell–dominated cranial form and the intima-focused degenerative processes characteristic of atherosclerotic aneurysms. Although LV-GCA and C-GCA share pathogenic macrophage-driven processes in granulomatous areas, the prominent B cell–focused inflammation in LV-GCA points toward the need for more targeted therapeutic strategies. Recognising these divergent immunopathological pathways may enable clinicians to optimise treatment regimens, including B cell–directed interventions in LV-GCA, while leveraging common macrophage pathways to tackle overlapping disease mechanisms in both GCA subtypes.
REFERENCES: [1] Pugh D, Karabayas M, Basu N, et al. Large-vessel vasculitis. Nat Rev Dis Primers . 2022;7(1):93. Published 2022 Jan 6. doi:10.1038/s41572-021-00327-5.
Acknowledgements: This work was funded by Tenovus Scotland and Vasculitis UK.
Disclosure of Interests: Cecilia Ansalone: None declared, Maira Karabayas: None declared, John Cole: None declared, Evelyn Qian: None declared, Ishita Gupta: None declared, Danai Vossou: None declared, Samuel McAllister: None declared, Yoana Doncheva: None declared, Sylvia Wright: None declared, Nigel Jamieson: None declared, Carl S Goodyear Eli Lilly, Neil Basu Eli Lilly, AbbVie, Eli Lilly, Galapagos.
© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license (