Is Chronic Venous Insufficiency a Structural Disease or a T Cell-Driven Immune Disease? What Cytokine Network Analysis Suggests

Key papers Vodovotz L et al. Ann Transl Med. 2021;9(22):1643 (PMID: 34988152) · Fraile-Martinez O et al. Biomedicines. 2025;13(1):150 (PMID: 39857734)

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More than a vein problem?

Chronic venous insufficiency (CVI) is among the most common vascular conditions in adults. For a long time medicine has understood it through a mechanical paradigm: valve failure → venous hypertension → structural change in the vein wall.

Immunological work over the past several years is changing that picture. CVI may be not only a structural disease but one in which a T cell-driven immune and inflammatory response forms the core of the pathophysiology.

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1. The central paper: Pittsburgh, Annals of Translational Medicine, 2021

A vascular surgery team at the University of Pittsburgh (Vodovotz, Zamora, Sachdev and colleagues) measured 25 immune mediators in blood and in vein wall tissue from patients with CVI and from healthy controls, and interpreted the results with computational cytokine network modelling. Rather than asking only which cytokines were higher or lower, they mapped how strongly each mediator was correlated with the others, and drew those correlations as networks.

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2. Finding 1: a coordinated network in health, a fragmented one in CVI

In healthy controls, cytokine concentrations were low, but the mediators were strongly interconnected in a complex network — the signature of a finely regulated, homeostatic immune system.

In CVI patients the result was paradoxical. Plasma concentrations of 20 of the cytokines differed from controls (P < 0.05), and most were lower, not higher — yet the correlations between mediators had largely collapsed and the network was far less complex. The authors characterised this as a stagnant post-inflammatory state.

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3. Finding 2: three hubs survive — IL-17A, IL-12p70, IFN-γ

Within the fragmented network, only three mediators remained more highly interconnected in venous insufficiency: IL-17A (the Th17 signature), IL-12p70 (which drives Th1 differentiation) and IFN-γ (the Th1 signature). Together they form the classic signature of Th1 and pathogenic Th17 responses, and suggest that these may be active drivers of CVI rather than bystanders.

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4. Finding 3: evidence of pathogenic Th17 — IL-17A correlates with GM-CSF

Pathogenic Th17 cells secrete IL-17A together with GM-CSF, without IL-10, and produce potent inflammation and tissue damage. In this study, IL-17A and GM-CSF were highly correlated in the blood of CVI patients but not in controls — direct evidence that Th17 cells in CVI are activated toward a pathogenic phenotype.

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5. Finding 4: the vein wall as a source of immune activation — IL-15

Vein segments harvested at surgery were analysed by Luminex, comparing refluxing varicose veins with competent saphenous veins. The most prominent difference was significantly higher IL-15 expression in the refluxing veins. IL-15 promotes the survival, proliferation and activation of NK cells and CD8+ T cells. This supports a new idea: that the vein wall itself acts as an immunoregulatory tissue, recruiting and activating immune cells locally.

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6. Independent confirmation: Biomedicines, 2025

A team at the University of Alcalá in Spain (Fraile-Martinez and colleagues) compared circulating cytokines and chemokines in 40 patients with chronic venous disease and 38 healthy controls using a multiplex assay. CVD patients showed increased levels of IL-1β, IL-2, IL-5, IL-6, IL-7, IL-8, IL-12, IL-17A, IL-23, TNF-α, IFN-γ, GM-CSF, fractalkine and ITAC, with a decrease in IL-13. And in the correlation analysis, the strong, highly interconnected cytokine network seen in healthy controls — particularly among TNF-α, IL-1β, IL-17A and IL-23 — was replaced in patients by fewer, weaker and different correlations. The authors describe this as inflammatory network disruption.

Two independent groups, different populations, different methods, the same structural finding: a coordinated network in health, a disrupted one in venous disease, with the Th1/Th17 axis prominent.

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7. Integrating with the established model

None of this discards the mechanical model — it extends it. Venous reflux → venous hypertension → abnormal shear stress on the endothelium → ICAM-1 and VCAM-1 expression → leukocyte recruitment → IL-15 release → local activation of Th1 and Th17 cells: an immune–mechanical feedback loop. Castro-Ferreira and colleagues argued in 2018 that endothelial dysfunction, triggered by sustained venous hypertension, is the central player perpetuating this inflammatory cycle. Consistent with local inflammation, the Pittsburgh group also found that skin temperature measured by infrared thermography was higher over diseased veins than over healthy ones. Work on monocyte subtypes (Germano and colleagues, 2025) adds that the inflammatory process in CVI alters monocyte phenotype and chemokine receptor expression as well.

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8. What it might mean — and the limits of the evidence

If CVI is in part a T cell-driven chronic immune disease, then agents targeting pathogenic Th17 — IL-17A-neutralising antibodies such as secukinumab and ixekizumab — or strategies modulating the Th1 response could, in principle, have a role as adjuncts. No clinical trial of any such approach exists in CVI. The studies described here are small and cross-sectional; they establish association, not causation. What is needed next are immune phenotyping by CEAP stage and network studies before and after treatment.

Nothing here changes current treatment. It does change how the disease is understood.

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In summary

Cytokine network analysis suggests that chronic venous insufficiency has an immunological dimension driven by T cells — Th1 and pathogenic Th17 in particular. Where healthy people show a dense, homeostatic cytokine network, CVI patients show a fragmented one in which a few inflammatory hubs (IL-17A, IL-12p70, IFN-γ) persist, and IL-15 in the vein wall appears to act as a local source of immune activation. These findings lay the groundwork for reframing CVI as both a structural disease and a T cell-driven immune disease — a hypothesis that now needs larger and longitudinal studies to test.

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References

1. Vodovotz L, Zamora R, Barclay DA, et al. Inflammatory signals and network connections implicate cell-mediated immunity in chronic venous insufficiency. Ann Transl Med. 2021;9(22):1643. (PMID: 34988152)
2. Fraile-Martinez O, García-Montero C, Gomez-Lahoz AM, et al. Evidence of Inflammatory Network Disruption in Chronic Venous Disease: An Analysis of Circulating Cytokines and Chemokines. Biomedicines. 2025;13(1):150. (PMID: 39857734)
3. Castro-Ferreira R, Cardoso R, Leite-Moreira A, Mansilha A. The Role of Endothelial Dysfunction and Inflammation in Chronic Venous Disease. Ann Vasc Surg. 2018;46:380-393. (PMID: 28688874)
4. Germano DB, Chiba LN, Ballerini APADC, et al. The phenotype of monocyte subtypes and expression of chemokine receptors in the Chronic Venous Insufficiency. Clinics (Sao Paulo). 2025;80:100595. (PMID: 40020285)