Reed Rivera

Background: Anti-neutrophil cytoplasmic antibodies-associated vasculitis (AAV) is a rare small and medium-vessel autoimmune vasculitis driven by ANCA. ANCAs activate primed neutrophils, promoting degranulation, reactive oxygen species production, and neutrophil extracellular traps, resulting in endothelial cell injury and allowing feed-forward inflammation.^1,2 Clinically, AAV commonly affects the lungs, kidneys, and skin, and can result in life-threatening conditions such as pulmonary hemorrhage. Current treatment relies on immunosuppression, including high-dose glucocorticoids, which are limited by relapse and toxicity³. In addition, no single biomarker reliably diagnoses or tracks AAV, underscoring the need to better explore the mechanisms that initiate and sustain vascular inflammation. This need is increasingly relevant as immune checkpoint inhibitors become more widely used for cancer treatment and as these checkpoint blockades have been associated with triggering vasculitis⁴. These cases may serve as increasingly relevant treatment-related complications and help clarify AAV mechanisms. In parallel, ANCA-driven neutrophil activation, NET formation, and endothelial injury may also release self-DNA into inflamed tissue, making the DNA-sensing cGAS/STING signaling relevant as a potential amplifier of AAV pathogenesis and propagation⁵.

Objective: In this literature review, it was evaluated whether PD-L1-centered checkpoint dysfunction may act as an initiating factor in AAV, while self-DNA sensing through cGAS/STING may perpetuate vascular injury after cellular damage occurs.

Search Methods: PubMed was searched from 2017 to 2024 using the keywords: “ANCA-associated vasculitis,” “immune checkpoint,” “PD-L1,” “CMTM6,” “BTLA,” “neutrophil extracellular traps,” “cGAS,” “STING,” and “pulmonary vasculitis.”

Results: Mechanistic studies showed reduced PD-L1 surface expression on AAV monocytes and persistence of this defect after macrophage differentiation, and increased CD-4 positive T cell activation. This abnormality was linked to reduced CMTM6 expression, a protein that protects PD-L1 from lysosomal degradation. Lysosomal inhibition partially restored PD-L1 surface expression and reduced monocyte-driven T cell activation⁶. Reduced PD-L1 was also identified on neutrophils during active disease and remission correlated with higher vasculitis activity, extending the checkpoint dysfunction to a cell type central to ANCA-mediated injury⁷. In contrast, B- and T- Lymphocyte attenuator (BTLA) changes appeared selective, expression shifted mainly in double-negative T cells, but agonistic BTLA signaling still suppressed T-cell proliferation and Th17/IL-17 responses⁸. These findings argue against a global checkpoint collapse and support only specific checkpoints are relevant for AAV. In conjunction with this, DNA sensing pathway may amplify and sustain vascular inflammation. In pulmonary AAV models, fragmented extracellular DNA accumulated in bronchoalveolar lavage fluid, activated cGAS, increased cGAMP, and produced a type I interferon signature. Recruited monocyte-derived macrophages were major downstream effectors, driving IFN-beta production, pulmonary hemorrhage, and worsened disease severity⁹. A STING-associated vasculopathy model further showed that constitutive STING activation can cause lung and kidney inflammation, myeloid expansion, and T-cell cytopenia¹⁰.

Conclusion: AAV may involve selective weakening of inhibitory immune restraint primarily through PD-L1 abnormalities, which could permit early autoreactive myeloid-T-cell activation. cGAS/STING signaling may then convert injury-released self-DNA into sustained inflammation. Future work could determine whether checkpoint defects increase self-DNA release or cGAS/STING sensitivity, and whether combined pathway monitoring can improve biomarker development or targeted therapies.

Works Cited:

1. Kronbichler A, Lee KH, Denicolo S, et al. Immunopathogenesis of ANCA-associated vasculitis. Int J Mol Sci. 2020;21(19):7319. Published 2020 Oct 3. doi:10.3390/ijms21197319
2. Sharma P, Zonozi R, Geetha D. ANCA-Associated Vasculitis. Adv Kidney Dis Health. 2024;31(3):194-205. doi:10.1053/j.akdh.2024.04.005
3. Kermani TA, Warrington KJ, Dua AB. Treatment Guidelines in Vasculitis. Rheum DisClin North Am. 2022;48(3):705-724. doi:10.1016/j.rdc.2022.03.006
4. Hu JR, Florido R, Lipson EJ, et al. Cardiovascular toxicities associated with immune checkpoint inhibitors. Cardiovasc Res. 2019;115(5):854-868. doi:10.1093/cvr/cvz026
5. Pan J, Fei CJ, Hu Y, Wu XY, Nie L, Chen J. Current understanding of the cGAS-STING signaling pathway: Structure, regulatory mechanisms, and related diseases. Zool Res. 2023;44(1):183-218. doi:10.24272/j.issn.2095-8137.2022.464
6. Zeisbrich M, Chevalier N, Sehnert B, et al. CMTM6-Deficient Monocytes in ANCA-Associated Vasculitis Fail to Present the Immune Checkpoint PD-L1. Front Immunol. 2021;12:673912. Published 2021 May 24. doi:10.3389/fimmu.2021.673912
7. Singh J, Minz RW, Saikia B, et al. Diminished PD-L1 regulation along with dysregulated T lymphocyte subsets and chemokine in ANCA-associated vasculitis. Clin Exp Med. 2023;23(5):1801-1813. doi:10.1007/s10238-022-00908-y
8. Werner K, Dolff S, Dai Y, et al. The Co-inhibitor BTLA Is Functional in ANCA-Associated Vasculitis and Suppresses Th17 Cells. Front Immunol. 2019;10:2843. Published 2019 Dec 10. doi:10.3389/fimmu.2019.02843
9. Kessler N, Viehmann SF, Krollmann C, et al. Monocyte-derived macrophages aggravate pulmonary vasculitis via cGAS/STING/IFN-mediated nucleic acid sensing. J Exp Med. 2022;219(10):e20220759. doi:10.1084/jem.20220759
10. Warner JD, Irizarry-Caro RA, Bennion BG, et al. STING-associated vasculopathy develops independently of IRF3 in mice. J Exp Med. 2017;214(11):3279-3292. doi:10.1084/jem.20171351