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Proteomic Profiling of the Large-Vessel Vasculitis Spectrum Identifying Shared Signatures of Innate Immune Activation and Stromal Remodeling.

Robert T Maughan·Erin Macdonald-Dunlop·Lubna Haroon-Rashid·Louise Sorensen·Natalie Chaddock·Shauna Masters·Andrew Porter·Marta Peverelli·Charis Pericleous·Andrew Hutchings·James Robinson·Taryn Youngstein·Raashid A Luqmani·Justin C Mason·Ann W Morgan·James E Peters
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Abstract

OBJECTIVE: Takayasu arteritis (TAK) and giant cell arteritis (GCA), the most common forms of large-vessel vasculitis (LVV), can result in serious morbidity. Understanding the molecular basis of LVV should aid in developing better biomarkers and treatments. METHODS: Plasma proteomic profiling of 184 proteins was performed in two cohorts. Cohort 1 included patients with established TAK (n = 96) and large-vessel GCA (LV-GCA) (n = 35) in addition to healthy control participants (HCs) (n = 35). Cohort 2 comprised patients presenting acutely with possible cranial GCA (C-GCA) in whom the diagnosis was subsequently confirmed (C-GCA, n = 150) or excluded (Not C-GCA, n = 89). Proteomic findings were compared to published transcriptomic data from LVV-affected arteries. RESULTS: In cohort 1, comparison to HCs revealed 52 differentially abundant proteins (DAPs) in TAK and 72 DAPs in LV-GCA. Within-case analyses identified 16 and 18 disease activity-associated proteins in TAK and LV-GCA, respectively. In cohort 2, comparing C-GCA versus not C-GCA revealed 31 DAPs. Analysis within C-GCA cases suggested the presence of distinct endotypes, with more pronounced proteomic changes in the biopsy-proven subgroup. Cross-comparison of TAK, LV-GCA, and biopsy-proven C-GCA revealed highly similar plasma proteomic profiles, with 26 shared DAPs including interleukin 6 (IL-6), monocyte/macrophage-related proteins (CCL7, CSF1), tissue remodeling proteins (TIMP1, TNC), and novel associations (TNFSF14, IL-7R). Plasma proteomic findings reflected LVV arterial phenotype; for 42% of DAPs, the corresponding gene was differentially expressed in tissue. CONCLUSION: These findings suggest shared pathobiology across the LVV spectrum involving innate immunity, lymphocyte homeostasis, and tissue remodeling. Network-based analyses highlighted immune-stromal cross-talk and identified novel therapeutic targets (eg, TNFSF14).

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HumansGiant Cell ArteritisProteomicsFemaleMaleMiddle AgedTakayasu ArteritisAgedImmunity, InnateCohort StudiesAdultBiomarkersTissue Inhibitor of Metalloproteinase-1Interleukin-6Case-Control StudiesJournal ArticleResearch Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov't

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Robert T Maughan, Erin Macdonald-Dunlop, Lubna Haroon-Rashid, Louise Sorensen, Natalie Chaddock, Shauna Masters, Andrew Porter, Marta Peverelli, Charis Pericleous, Andrew Hutchings, James Robinson, Taryn Youngstein, Raashid A Luqmani, Justin C Mason, Ann W Morgan, James E Peters. 2025-02-27. Proteomic Profiling of the Large-Vessel Vasculitis Spectrum Identifying Shared Signatures of Innate Immune Activation and Stromal Remodeling.. https://doi.org/10.1002/art.43110

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