The Role of Lymphoma-derived Cytokines in the Induction of Systemic Vasculitis

Mali Wang^*
*Correspondence: Mali Wang, Department of Immunopathology & Molecular Oncology, University of Cambridge, Cambridge CB2 1TN, UK, Email:

Introduction

Systemic vasculitis comprises a heterogeneous group of disorders characterized by inflammation and necrosis of blood vessels, leading to ischemic tissue injury and multi-organ involvement. It can occur as a primary autoimmune condition or as a secondary phenomenon linked to infections, drugs, or malignancies. One of the most intriguing and clinically challenging scenarios involves the development of vasculitis in patients with lymphoid malignancies, particularly lymphomas. Among the possible pathogenic mechanisms, the aberrant production of cytokines by lymphoma cells has emerged as a key driver in the development of paraneoplastic or lymphoma-associated vasculitis. These cytokinesâ??critical mediators of immune regulation and inflammationâ??can influence vascular endothelial integrity, leukocyte recruitment andimmune activation, ultimately triggering a vasculitic cascade. This cytokine-driven model provides an essential framework to understand the interplay between neoplasia and systemic autoimmunity and has significant diagnostic and therapeutic implications [1].

Description

Lymphomas, especially non-Hodgkin B-cell lymphomas and T-cell lymphomas, are associated with a wide spectrum of immune dysregulation syndromes, including autoimmune cytopenias, glomerulonephritis andvasculitis. While the direct invasion of vessels by malignant cells may occur, most cases of lymphoma-associated vasculitis are believed to be paraneoplastic, meaning that the vasculitis results not from physical infiltration but from the immune and inflammatory milieu created by the tumor. In this context, cytokines produced by the tumor microenvironment play a pivotal role. These moleculesâ??such as interleukins (IL-1, IL-6, IL-10), tumor necrosis factor-alpha (TNF-α), interferons andvascular endothelial growth factor (VEGF)â??are not only products of the lymphoma cells themselves but also of tumor-associated macrophages, dendritic cells andT-cells, all of which contribute to systemic inflammation. One of the central cytokines implicated in lymphoma-associated vasculitis is interleukin-6 (IL-6). Produced in high quantities by both malignant B-cells and reactive cells within the tumor niche, IL-6 has pleiotropic effects on the immune system. It stimulates hepatic production of acute-phase reactants such as C-reactive protein (CRP), supports B-cell maturation and antibody production andinduces T-helper 17 (Th17) cell differentiation, which is known to play a role in autoimmune vasculitis. High IL-6 levels correlate with systemic symptoms such as fever, fatigue andweight lossâ??features that are common to both lymphoma and vasculitis. Moreover, IL-6 increases vascular permeability and promotes endothelial activation, making vessels more susceptible to immune-mediated damage. These actions create a pro-inflammatory environment conducive to the development of vasculitis in susceptible individuals [2].

VEGF, another cytokine frequently secreted in the lymphoma microenvironment, especially in AITL and other angiogenic lymphomas, is critical for new blood vessel formation but also disrupts vascular integrity. It increases endothelial permeability, facilitates leukocyte extravasation andmay contribute to the edema and tissue damage seen in vasculitic lesions. Additionally, VEGF promotes the expression of adhesion molecules and chemokines, amplifying the recruitment of inflammatory cells to the vessel wall. The cumulative effect of these cytokines is the creation of a systemic pro-inflammatory and pro-autoimmune state. In some patients, this environment may directly lead to vasculitic syndromes, including cutaneous leukocytoclastic vasculitis, polyarteritis nodosa, or ANCA-associated small-vessel vasculitis. In other cases, cytokine-driven inflammation may unmask latent autoimmunity or trigger autoantibody production, such as ANCAs or anti-endothelial cell antibodies, which in turn initiate and perpetuate the vasculitic process [3].

An additional layer of complexity is added by the phenomenon of cytokine redundancy and synergy. Cytokines often do not act in isolation; rather, they function within networks where one cytokine amplifies the effect of another. For instance, IL-6 and TNF-α can synergize to induce endothelial activation and systemic symptoms, while IFN-γ can enhance the effects of IL-1 and TNF-α on macrophages. In the lymphoma setting, the combination of these factors creates a cytokine storm-like milieu, particularly in advanced or aggressive disease. Such a storm may present with features mimicking systemic vasculitis, including fever, rash, arthralgia andorgan dysfunction, even in the absence of true vasculitic pathology. Diagnosis of lymphoma-associated vasculitis driven by cytokines requires careful differentiation from primary vasculitis. Clinical suspicion should be high in patients with known lymphoma who develop new vasculitic symptoms, particularly if these symptoms arise in parallel with signs of lymphoma progression. Laboratory findings such as elevated CRP and ESR, polyclonal hypergammaglobulinemia andcytokine profiling may support the diagnosis. Histopathological examination of biopsy specimens remains the gold standard for confirming vasculitis and for ruling out direct neoplastic infiltration. Cytokine immunostaining, flow cytometry andgene expression profiling can provide additional information on the inflammatory and neoplastic milieu [4].

Treatment strategies must target both the underlying lymphoma and the vasculitic process. In some cases, effective treatment of the lymphoma leads to resolution of the vasculitis, supporting the paraneoplastic cytokine-driven hypothesis. Chemotherapy regimens such as CHOP (cyclophosphamide, doxorubicin, vincristine andprednisone) may simultaneously address both the malignant and inflammatory components. Targeted therapies like rituximab, which depletes B-cells, are particularly useful in B-cell lymphomas and can ameliorate vasculitic symptoms by reducing autoantibody production. Corticosteroids are often used for their anti-inflammatory effects, but their use must be balanced against the need for definitive lymphoma therapy and the risk of masking lymphoma-related symptoms. In refractory cases or when vasculitis persists despite lymphoma control, additional immunomodulatory agents such as tocilizumab (an IL-6 receptor antagonist) or TNF inhibitors may be considered. These biologics target specific cytokines and may help to dampen the inflammatory cascade, although their use must be cautiously weighed against the risk of infection and potential tumor progression. Emerging therapies that target multiple cytokine pathways or that modulate the tumor microenvironment may offer future avenues for more effective treatment [5].

Conclusion

In conclusion, lymphoma-derived cytokines play a central role in the induction of systemic vasculitis, highlighting the intricate and bidirectional relationship between cancer and autoimmunity. These cytokines orchestrate a complex interplay of immune activation, endothelial dysfunction andinflammatory cell recruitment that culminates in vascular injury. Recognition of this cytokine-driven mechanism is critical for accurate diagnosis and effective management of patients presenting with vasculitis in the setting of lymphoma. Ongoing research into the molecular and cellular underpinnings of this overlap will further illuminate the pathogenesis of paraneoplastic vasculitis and guide the development of novel therapeutic strategies aimed at both controlling malignancy and preventing immune-mediated vascular injury.

Acknowledgement

None.

Conflict of Interest

None.

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