The whole blood transcriptomes of ANCA-associated vasculitis and giant cell arteritis show striking overlap in upregulated immune pathways, with only 19 differentially expressed genes between the two clinically distinct vasculitis subtypes, suggesting that 'the rather homogeneous transcriptome of circulating immune cells does not sufficiently explain the clinically distinct phenotypes of AAV and GCA.'
Key Findings
Results
AAV patients had 104 differentially expressed genes compared to healthy controls, while GCA patients had 504 differentially expressed genes compared to healthy controls.
Whole blood was collected from 12 untreated newly diagnosed or relapsing patients with AAV, 10 untreated newly diagnosed patients with GCA, and 11 age- and sex-matched healthy controls.
Transcriptomes were analysed by RNA sequencing.
GCA showed a substantially larger number of DEGs relative to healthy controls than AAV (504 vs. 104).
Both patient groups were untreated at the time of sample collection.
Results
Only 19 genes were differentially expressed between AAV and GCA, despite their clinically distinct phenotypes.
The small number of DEGs between the two vasculitis subtypes was described as 'striking' by the authors.
This finding contrasts with the larger numbers of DEGs observed when each disease group was compared to healthy controls.
The minimal transcriptomic difference between AAV and GCA was observed in whole blood samples.
Results
Gene Set Enrichment Analysis revealed a striking overlap in upregulated signaling pathways between AAV and GCA compared to healthy controls, with seven out of ten top pathways shared.
Shared upregulated pathways included 'IL6 JAK Stat3 signalling', 'TNF signalling', and 'complement activation'.
Seven out of ten top signaling pathways were shared between AAV and GCA when each was compared to healthy controls.
Overrepresentation Analysis of DEGs distinguishing both vasculitis subtypes from healthy controls identified pathways exclusively involved in innate immunity.
Results
GCA patients showed increased levels of CD42a on platelets compared to AAV patients, consistent with increased expression of platelet-associated genes in GCA.
CD42a is a platelet receptor component assessed by flow cytometry.
Increased platelet-associated gene expression was detected in GCA compared to AAV at the transcriptomic level.
Flow cytometry was used to validate the transcriptomic findings at the protein level for CD42a.
This platelet-related difference represents one of the distinguishing features between the two vasculitis subtypes.
Results
Overrepresentation Analysis of differentially expressed genes in both vasculitis subtypes versus healthy controls identified pathways exclusively involved in innate immunity.
ORA was conducted using Gene Ontology and Gene Set Enrichment Analysis (GSEA).
The finding applied to both AAV and GCA when compared separately to healthy controls.
This suggests innate immune activation is a shared feature of both vasculitis subtypes at the whole blood transcriptome level.
Discussion
The study concludes that the whole blood transcriptome does not sufficiently explain the clinically distinct phenotypes of AAV and GCA.
AAV is a small vessel vasculitis while GCA is a large vessel vasculitis, representing two clinically distinct forms.
Both conditions carry a high risk of relapse.
The authors suggest that tissue-resident immune cells or local inflammatory processes in affected vessel walls may better account for clinical differences.
The 'rather homogeneous transcriptome of circulating immune cells' was cited as insufficient to explain phenotypic differences.
What This Means
This research studied two different types of blood vessel inflammation (vasculitis): ANCA-associated vasculitis (AAV), which affects small blood vessels, and giant cell arteritis (GCA), which affects large blood vessels. Despite being very different diseases clinically — affecting different vessel sizes, causing different symptoms, and requiring somewhat different treatments — the researchers found that the genes being actively used in the blood cells of patients with these two diseases look remarkably similar. When comparing AAV patients to healthy people, 104 genes were different; when comparing GCA patients to healthy people, 504 genes were different; but between the two disease groups themselves, only 19 genes differed. Both diseases showed activation of the same immune pathways in the blood, including inflammation signals involving IL-6, TNF, and the complement system.
One notable difference the researchers did find was that GCA patients had higher activity of platelet-related genes and higher levels of a platelet surface protein called CD42a compared to AAV patients. Platelets are small blood components involved in clotting and inflammation, and this difference may reflect the distinct vascular complications seen in GCA. The shared immune pathways activated in both diseases — particularly those involving innate immunity (the body's first-line defense system) — suggest that circulating blood cells respond similarly regardless of which vessels are inflamed.
This research suggests that looking at gene activity in blood alone may not be enough to understand why these two diseases look so different in patients. The key differences between AAV and GCA may lie not in the circulating blood cells but in the immune cells directly within the affected blood vessel walls, which were not captured in this study. This has implications for how researchers study these diseases and develop targeted treatments — future work may need to focus on tissue samples from the inflamed vessels themselves rather than blood samples.
Amsler J, Kreuzer M, Petelytska L, Krättli S, Iaremenko O, Brunner M, et al.. (2026). Same, Same, but Different-Whole Blood Transcriptomes of ANCA-Associated Vasculitis and Giant Cell Arteritis.. International journal of molecular sciences. https://doi.org/10.3390/ijms27198513